1
Masaryk University, Brno
Faculty of Medicine
1st
Department of Neurology
NEUROPSYCHOLOGICAL AND NON-MOTOR ASPECTS OF DEEP BRAIN
STIMULATION OF SUBTHALAMIC NUCLEUS
Marek Baláž, MD, Ph.D.
Habilitation Thesis
Brno 2014
2
Summary
Subthalamic nucleus (STN) is an important glutamatergic structure within basal ganglia
strongly influencing the activity of its major output channels.
STN has been involved in the pathophysiology of the parkinsonian symptoms, and the
disruption of its pathological activity by deep brain stimulation (DBS) partially reverses some
of the clinical, electrophysiological, and metabolic abnormalities related to Parkinson’s disease
(PD). STN is the most frequent subcortical structure used as a target of the neuromodulation
surgery – DBS. Implantation of deep brain electrodes during DBS surgery offers unique access
to deep brain structures and offers possibility to record electric brain activity directly from brain
itself.
There has been an increase of reports regarding cognitive disorders and other non-motor
impairments related to deep brain stimulation (DBS) surgery for Parkinson’s disease recently.
The impact of STN DBS on cognitive and behavioral functions is still not elucidated completely,
but it is evident that at least in some patients it may have clinical importance. The mechanism
by which STN regulates the motor functions in the neural circuitry is not yet fully understood
and much less is known about its influence on cognitive networks.
The aim of our research work in the scope of last few years was to investigate the participation
of STN in non-motor activities, namely the executive functions. We performed such
experiments by the recording of intracranial cognitive potentials, specifically the late complex
of evoked potentials – the P3 wave, and other electophysiological methods (oscillations, event
related synchronization and desynchronisation). We also employed sophisticated survey
methods such as disease-specific quality of life questionnaires.
In summary, results of our research indicate that STN actively participates in cognitive and
non-motor activities. Its participation in these activities is conditioned by the difficulty of the
task, i.e. it participates in more demanding cognitive tasks.
STN seems to cooperate directly with inferior frontal cortex in its cognitive-related
performance. The connection of subthalamic nucleus with dorsolateral prefrontal cortex seems
to be at best indirect. Modulation of STN activity by continuous DBS can influence wide array
3
of non-motor function in addition to its well described and usual effect on motor symptoms of
PD.
The proof of participation of subthalamic nucleus in executive functioning underlines the need
of meticulous selection of candidates for deep brain stimulation surgery of this target in PD.
2
Contents
Summary .................................................................................................................................... 2
1 List of frequently used abbreviations.................................................................................. 3
2 Deep brain stimulation of subthalamic nucleus in Parkinson's disease .............................. 4
2.1 Introduction – subthalamic nucleus............................................................................. 4
2.2 Treatment of advanced Parkinson's disease................................................................. 6
2.3 Indications of DBS STN.............................................................................................. 9
2.4 Clinical outcomes of DBS STN................................................................................. 11
2.5 Complications of DBS STN ...................................................................................... 11
2.6 Cognitive and neuropsychiatric changes after DBS STN ......................................... 12
3 Commented compilation of original publications/articles................................................ 18
3.1 Participation of subthalamic nucleus in executive functions..................................... 18
3.2 The effect of cortical repetitive transcranial magnetic stimulation on cognitive eventrelated
potentials recorded in the subthalamic nucleus in patients with Parkinson’s disease..
................................................................................................................................... 31
3.3 DBS amplitude setting can improve aspects of quality of life in patients with
Parkinson's disease ............................................................................................................... 60
3.4 The modulatory role of subthalamic nucleus in cognitive functions – a viewpoint.. 74
3.5 Quality of life after DBS in patients with advanced Parkinson's disease.................. 94
3.6 One year after deep brain stimulation of patients with Parkinson's disease:
neuropsychological results ................................................................................................. 106
3.7 Involvement of subthalamic nucleus in cognitive functions – a concept................ 119
3.8 Involvement of subthalamic nucleus and globus pallidus internus in attention...... 135
3.9 Cognitive Event-Related Potentials and Oscillations in the Subthalamic Nucleus. 159
4 Conclusion ...................................................................................................................... 165
5 Acknowledgements......................................................................................................... 166
6 References....................................................................................................................... 167
3
1 List of frequently used abbreviations
DBS – deep brain stimulation
ERP – event related potentials
ERD/ERS –event related desynchronisation/synchronisation
IPD – Idiopathic Parkinson's disease
PD – Parkinson's disease
P300 – P300 wave (event-related potential elicited during the process of decision making)
P3 – P3 wave – another name for event. Related potential known as P300
QoL – quality of life
rTMS – repetitive transcranial magnetic stimulation
STN – subthalamic nucleus
4
2 Deep brain stimulation of subthalamic nucleus in Parkinson's disease
2.1 Introduction – subthalamic nucleus
Subthalamic nucleus (STN) is a small lens-shaped midbrain nucleus lying on the dorsomedial
surface of internal capsule. Despite its relatively small size, STN is thought to play a prominent
role in the pathophysiology of Parkinson's disease (PD) (Obeso et al, 1997). STN not only plays
a key role in motor behavior, but also is a potent regulator in the limbic and associative circuits
(Temel 2005).
As the only glutamatergic structure of BG, it is a major source of excitation. STN innervates
mainly globus pallidus interna (GPi) and substantia nigra, but also globus pallidus externa
(GPe), ventral pallidum, pedunculopontine nucleus, and, to a lesser extent, striatum, nucleus
accumbens, and ventral tegmental area.
Major subcortical inputs to STN arise from ventral pallidum and GPe (the indirect pathway),
thalamus, pedunculopontine nucleus, dorsal raphe, ventral tegmental area, and pars
compacta of substantia nigra (Baunez et al, 2010).
Direct cortical projections to STN were described several decades ago (Monakow 1978), but
they were considered to be sparse, and therefore regarded as less important. According to
more recent views, STN occupies not only a crucial position in the indirect pathway of BG, but
it also receives direct cortical projections, especially from frontal lobe, namely primary motor
cortex, supplementary motor area, and dorsal and ventral divisions of premotor cortex, such
as the hyperdirect pathway from inferior frontal cortex (IFC) (Nambu 1997, Baláž 2010).
In 2004, Strafella indicated that the role of cerebral cortex in regulating the activity of STN was
not known in humans. Transcranial magnetic stimulation of motor cortex changes the
neuronal activity of STN (Strafella et al, 2004).
Diffusion Weighted Imaging (DWI) tractography demonstrated a three-way white matter
network between preSMA, IFC, and STN region in right hemisphere in tasks related to
reversing initiated motor responses, as revealed by the stop-signal paradigm (Aron, 2007). The
anatomic source of control over the putative cognitive function of STN is less well described,
but it is clear that STN is involved not only in motor but also in associative and limbic corticoBG-thalamocortical
loops.
The direct connections to STN from prefrontal cortex and the relation of STN to structures
such as nucleus accumbens and ventral pallidum (both well known for their involvement in
5
motivational processes) may explain why STN contributes to functions well beyond motor
activities.
Subthalamic nucleus (STN) is an important glutamatergic structure within the basal ganglia
strongly influencing the activity of its major output channels. The most important of those is
the reciprocal connection of globus pallidus. It completes a loop with pallidum, since
subthalamic nucleus gets inhibitory input from those areas of globus pallidus.STN has been
involved in the pathophysiology of the parkinsonian state, and the disruption of its
pathological activity partially reverses some of the clinical, electrophysiological, and metabolic
abnormalities related to Parkinson’s disease. STN is the most frequent target structure used
for the neuromodulation surgery – deep brain stimulation (DBS).
Schematic position of STN in PD and in normal state is depicted in Figure 1.
Figure 1. Schematic view on position of STN in integration of information from basal ganglia
and hyperdirect pathway
A. Situation in healthy individual; B. Parkinson´s disease (PD); C: Parkinson´s disease with
DBS STN
Used from Rektor, Bočková, Rektorová, Chrastina, Baláž, Clinical neurophysiology
6
Symbols. Solid lines and boxes: Oversimplified scheme of basal ganglia-thalamocortical (BG)
circuitry. Black lines: excitatory pathways; grey lines: inhibitory pathways, Dotted lines:
cognitive loop; (a): the hyperdirect pathway, bolt: DBS stimulation.
Adapted from: Rektor et al, 2014
Explanation. The cognitive loop remains relatively spared by the dysfunction of the motor BG
circuitry in PD (A and B), the cognitive loop is down-regulated by DBS STN (C) despite the
(relative) normalization of the motor part of the circuitry.
A unique feature of STN among basal ganglia nuclei is that it receives inputs directly from
frontal cortex, bypassing pathways involving striatum (Monakow et al., 1978; Nambu et al.,
1996), and that this hyperdirect fronto-subthalamic pathway is fast conducting (Nambu et al.,
2000) compared with much slower striatal pathways (Yoshida and Precht, 1971; Hikosaka et
al., 1993). This raises the possibility that STN is suitable for quick control of action (Isoda et al.
2008).
2.2 Treatment of advanced Parkinson's disease
PD is a progressive disorder of the central nervous system (CNS) with the annual incidence of
about 20 per 100,000 persons in the fifth decade of life to about 90 per 100,000 persons in
the seventh decade of life.
PD is traditionally considered to be a motor system disorder. The four primary symptoms are
rest tremor, rigidity or stiffness of the limbs and trunk, bradykinesia and postural instability
(usually appearing late in the course of the disease). With progression of the disease nonmotor
symptoms gain more clinical importance. However, some non-motor symptoms
predate even the onset of typical motor symptomatology. As these symptoms become more
pronounced, patients may have difficulty walking, talking, or completing simple tasks. Other
symptoms include an expressionless face, reduced manual dexterity, handwriting difficulties,
drooling, sleep problems, urination at night, depression and anxiety, constipation, and
difficulty turning in bed at night.
7
The disease is chronic and progressive, but it does not affect everyone in the same way. PD
may appear to be progressing faster in some patients than in others. Some patients become
severely disabled; others experience only minor disruptions in motor functions.
The approximate age of PD onset is 60 years (Bower et al, 1999).There exists only symptomatic
treatment for PD so far. This condition is of neurodegenerative nature and no neuroprotective
treatment was convincingly showed to be effective.
Levodopa is currently the mainstay of treatment for Parkinson's disease (Olanow et al, 2001).
However, long-term levodopa treatment is complicated by involuntary movements known as
(choreatic) dyskinesia and motor fluctuations in which patients cycle between periods of good
mobility (“on” periods) and impaired mobility (“off” periods) (Lang et al, 1999). These
complications result in disability that cannot be satisfactorily controlled by medical therapy in
the majority of patients.
Initially, changes of medication regime, addition of dopamine receptor agonist or inhibitors of
COMT enzyme may improve motor fluctuations. With further progression of disease invasive
treatment methods may be considered. Generally, medication therapies can improve quality
of life in patients with PD for many years.
Three invasive methods for treatment of advanced PD available in Czech republic include
apomorphine subcutaneous pump, intraduodenal Levodopa and deep brain stimulation
(DBS).
Apomorphine HCl is a fast-acting dopaminergic agonist after it is injected subcutaneously. It
has high affinity for D4 receptors; moderate affinity for D2, D3, D5, and adrenergic α1D, α2B,
and α2C receptors; and low affinity for D1 receptors. It is internationally approved as a therapy
for the acute intermittent treatment of “off” episodes in patients with a fluctuating response
to dopaminergic therapy (Goldenberg 2008). Via this modified insulin pump, a programmed
infusion rate is dispensed in most cases using a 12–16 h regimen. If needed, the pump can
administer apomorphine for 24 h and does not have to be discontinued overnight.
Duodopa and DBS are used more extensively than apomorphine pump.
Duodopa is a combination of Levodopa (20 mg/ml) and Carbidopa (5 mg/ml) applied in form
of a gel into the duodenum. Preceding the permanent therapy, a test application period of
Duodopa via a nasoduodenal catheter system is generally used. If this is well tolerated by the
8
patient and symptoms improve, a percutaneous, endoscopic gastrostomy (PEG) is performed
and Duodopa is delivered via a portable pump and a duodenal catheter. If the retention period
is 24 h, Duodopa is given as a monotherapy. If the Duodopa treatment is subject to a 16 h
regimen, a prolonged release Levodopa tablet is often administered before bedtime. A
number of studies have shown a significant reduction of time in “off” and a significant increase
of time in “on”, as well as a reduction of dyskinesia (as reviewed by Ossig and Reichmann,
2013).
Advances in understanding of the pathophysiology of the basal ganglia have provided
opportunities for neuromodulation strategies to manage these problems. Findings from
animal models have led to the development of neuromodulatory surgical procedures for
Parkinson's disease that target the subthalamic nucleus and pars interna of the globus pallidus
(Olanow et al, 2000, The DBS for PD Study Group 2001).
The introduction of DBS was a major step forward for the treatment of Parkinson’s disease
(PD) and other movement disorders. There have been over 100,000 DBS implants worldwide
until the end of 2013. DBS improves the cardinal motor symptoms of PD and reduces motor
fluctuations and dyskinesia. In addition, this procedure with only minimal lesionial effects,
allows for modulation of the target region in an adjustable and reversible way. &the most
frequently used target is STN.
The implanted neurostimulator enables the changes of voltage in patients electrodes and as
such allows for adaptation of stimulation over time to the needs of the individual patients and
reduction of possible side effects.
The good symptomatic benefit of DBS STN on tremor, rigidity, hypokinesia and the decrease
in duration and severity of dyskinesia after the reduction of dopaminergic medication
contributes to the spread of DBS STN procedure to the hundreds of centers worldwide.
DBS STN is not a curative treatment and does not prevent further course and development
of new symptoms of PD and has no influence on the signs and symptoms of PD that do not
respond to L DOPA.
The quadripolar intracranial electrodes are implanted in the target area and connected to the
neurostimulator via subcutaneous connective cables. The principle of DBS STN function is the
continuous high frequency stimulation of the target region.
9
The exact mechanism of DBS is not clear (Benabid et al. 2009). It is supposed that this
mechanism is highly complex and includes the inhibition or activation of various neural
structures. The overall effect depends mostly on stimulated structures (axons or neuronal
bodies) and stimulation parameters. The DBS STN is probably based on depolarisation block
of glutamatergic neurons in the STN (Koppel et al 2006). The overall effect of DBS is probably
the neural inhibition. The effect of DBS STN is related to the frequency of the stimulation,
which should be more than 100 Hz to reach the most robust symptomatic effect. Other
stimulation parameters include the pulse width (usually in the range of 60 to 90 usec) and the
amplitude. With increasing amplitude the volume of stimulated tissue (?) increases as well.
The area of neuronal tissue involved by the monopolar stimulation spreads to 2 or 3 mm from
the electrode if amplitude of stimulation in the region of 2 V are used (Pollak et al, 2002).
We consider necessary to stress the need to repeat that despite its successes DBS remains a
symptomatic treatment and does not influence the course of the PD itself and very likely it
has no influence on the neurodegeneration process itself.
As far as DBS STN is a symptomatic treatment that improves the quality of life (QoL) of
patients, there appears to be an advantage if the stimulation is used earlier in the course of
the disease (Deuschl 2012).
Currently the problems that remain unsolved are non-motor symptoms of PD. Especially gait
problems, postural instability and cognitive problems belong to so far untackled problems of
late stage PD. Even deep brain stimulation of pedunculopontine nucleus (PPN), a small
cholinergic pontine area was not able to provide solution to any of these problems (Castrioto
and Moro, 2013).
2.3 Indications of DBS STN
DBS is indicated for the treatment of drug-resistant complications of advanced PD. Higher
baseline scores on section III (motor) of the unified PD rating scale (UPDRS) and higher
baseline levodopa responsiveness are independent predictors of greater change in motor
score after surgery (Benabid et al. 2009).
Numerous factors need to be taken into account in deciding whether a patient with PD is a
candidate for DBS. Patient-related factors including age and the presence of other comorbid
disorders need to be considered. Neuropsychological and neuropsychiatric concerns relate
10
both to the presurgical status of the patient and the potential for surgery to result in new
problems postoperatively. Extremely important are factors related to the underlying PD,
including the specific parkinsonian motor signs (tremor, bradykinesia, gait dysfunction),
previous medical therapies, including benefits and adverse effects, and past surgical
treatments (Lang et al, 2006).
Because of the strict inclusion criteria, the DBS is indicated in only relatively small part of
patients with advanced PD, according to some authors it can be suggested only to about 4.5%
of the patients (Morgante et al 2008). The inclusion and exclusion criteria for this procedure
are summarized in the Tables 1 and 2.
Tab. 1. Indication criteria for DBS STN
PD with late motor complications resistant to medication changes
Good therapeutic response to L DOPA (positive L DOPA test – decrease of UPDRS motor score
by 33 %)
No affective or cognitive disorder
Age less than 70 years
No atrophy or structural changes in brain MRI (magnetic resonance imaging)
Tab. 2. Exclusion criteria for DBS STN
Insufficient response of troublesome symptoms to L DOPA
Postsynatic dopaminergic lesion, Parkinson plus syndromes (multisystem atrophy, progressive
supranuclear paralysis)
Disorders of cognitive functions, dementia
Depression
Psychotic symptoms
Diseases decreasing the life expectancy
Prominent late motor complications of PD not responsible to dopaminergic therapy (gait
disorders, falls, speech disorders)
Medical complications that rule-out the total anesthesia
11
According to: Rektor I, Baláž M: Hluboká mozková stimulace u Parkinsonovy nemoci.
Parkinsonova nemoc: doporučené postupy diagnostiky a léčby, II. Pozdní stadium, Galen 2004
2.4 Clinical outcomes of DBS STN
The main scale used to analyse the intensity of symptoms in PD is the Unified Parkinsonˈs
Disease Rating Scale (UPDRS), which is based on the rating of a series of symptoms for both
sides of the body. In a meta-analysis of 37 cohorts comprising 921 patients (Kleiner-Fisman et
al, 2006) the estimated decrease in absolute UPDRS II (activities of daily living) and III (motor)
scores after surgery in the stimulation-on, medication-off state compared with the
preoperative off -medication state was 50%. Its effect on the motor score of the Unified
Parkinson’s Disease Rating Scale (known as UPDRS III) with post-operative improvement in
medicaton off state ranges from 28 to 71% according to various authors (for a review see Benabid
et al. 2009).
DBS STN decreases the motor fluctuations by 55 to 85%, duration of L-DOPA induced
dyskinesia by about 50 to 80% and justifies the decrease of 40-80% of L DOPA equivalent dose
compared to the pre-operative dose (Houeto et al. 2000 and 2003).
The quality of life after DBS STN (as assessed by the PDQ-39 – Parkinson’s Disease Quality of
Life Questionnaire) is improved by about 34% (Krack et al. 2003). This improvement is
sustained after three years in several subscales of the Sickness Impact Profile questionnaire
(Volkmann et al. 2009). The quality of life of caregivers is also improved (Lezcano et al, 2004).
2.5 Complications of DBS STN
DBS STN is generally to be considered quite a safe procedure with low incidence of side effects
(Krack a kol. 2003). Implantation of the brain electrode carries a risk of intracranial bleeding
or contusion. In a study of 526 consecutive patients (325 patients with STN-HFS, 138 with
thalamic DBS, and 63 with DBS of the internal globus pallidus [GPi]), haemorrhages occurred
in 8.4% (range 0.2–12.5%) of all DBS cases mostly at the entry point or subcortically, but rarely
12
in the target, and more often in hypertensive patients. 3.4% of this series of patients had
asymptomatic haemorrhages, symptoms were transient in 4.4%, and permanent in only 0.6%
of patients (Benabid et al, 2007).
Reported infection rates for DBS surgery vary widely, from less than 1% to more than 15%
. Local hardware infections can arise even after several months postoperatively (Chrastina et
al, 2008). Further possible surgical complications include the risk of subdural hematoma,
pneumocefalus and skin erosion. Complications in general state, including aspiration
pneumonia, pulmonary or urinary infection, thrombophlebitis, and pulmonary embolism, can
occur in patients with severe PD (Benabid et al. 2009).
Side effect of stimulation itself are usually caused by the spread of stimulation current to
neighboring neural structures. These include corticobulbar and corticospinal tract (tonic
muscle contractions), third nerve fibers (monocular eye deviation), sensory track fibers
(paresthesia) (Pollak et al. 2002).
Side effect of stimulation current itself tend to be only transient, and recede after switching
off the stimulator, adjusting the stimulation settings or stimulating of the different electrode
contacts. Stimulation-induced dyskinesias can be a sign of accurate placement of the
electrodes, and are reversible. The side effects of the stimulation disappear usually within
short period of time – second, minutes or hours at most, depending on the respective side
effects. Most patients after DBS STN gain weight (Macia et al, 2004
2.6 Cognitive and neuropsychiatric changes after DBS STN
PD itself is a neurodegenerative disorder characterized not only by motor, by also by cognitive,
neuropsychiatric, autonomic and other nonmotor symptoms. The efficacy of DBS STN for the
motor symptoms is well described. However, the effects of DBS STN on cognitive and
neuropsychiatric symptoms are less clear (Voon et al., 2006). A range of neuropsychiatric
symptoms have been recognized in PD and are presumed to be caused by the underlying
neurodegenerative process, dopaminergic medications, underlying vulnerabilities and
psychosocial factors. These symptoms range from disorders of cognition, mood, anxiety,
hallucinations, to apathy. More recently the dopamine dysregulation syndrome as the group
of behaviours reslutling from the chronic administration of dopaminergic drugs have been
13
described (Evans 2004). Available data differ in the description of DBS STN effect on cognitive
functions. According to systematic review (Temel et al. 2006) the cognitive problems were
present in 41% of evaluated patients while the depression was present in 8%, hypomania or
mania in 4% of subjects. Most of the cognitive changes after DBS STN are transient, mild and
generally clinically insignifficant according to other paper (Voon et al. 2006).
The severity of cognitive changes is widely described from very mild, with no effect on
activities of daily living (Witt et al. 2004) to serious complications with disruption of several
cognitive domains (Saint-Cyr et al. 2000).
Data from observations and restrospective studies with low number of patient show either
the presence of postoperative cognitive deterioration (Hariz et al. 2000) or, on the contrary,
improvement in speed of information processing, verbal memory improvement, problem
solving and generating of random numbers (Jahanshahi et al. 2000).
Also other authors describe improvement in certain cognitive parameters – ranging from
mental flexibility (Witt et al. 2004) to overall cognitive improvement (Daniele et al. 2003).
Many published papers describe only minor changes in cognitive functions in patients well
selected for the DBS STN (Morrison et al. 2004).
Most outcome paper suggest that negative outcomes of DBS STN include decline in verbal
fluency (Gironell et al. 2003), declines in conditional associative learning (Koppel et al. 2006),
decrease of processing speed (Hariz et al. 2000), and decline in selected measures of executive
functions (Krack et al. 2003).
Specific patient subgroups such as older patients and patients with moderate cognitive
impairment prior to surgery seem to be at greater risk of suffering cognitive and
neurobehavioral deficits (Dujardin et al. 2001). The available data do not make clear if older
age per se or other medical conditions associated with older age are responsible for the
increased risk of cognitive changes following surgery.
According to most studies the dementia is an exclusionary criterion for DBS STN, thus there
are no large-scale studies describing the influence of DBS STN on cognitive functions in
demented patients (Voon et al. 2006). Krack and his coworkers document gradual onset of
dementia in 3 of 49 patients who were followed for 5 years following implantation of deep
electrodes in STN. None of these patients met diagnostic criteria for dementia prior to the
14
surgery. The authors attributed the development of dementia to ongoing neurodegenerative
PD as no acute changes were present following surgery in these three patients.
The methodological issues have to be taken into account as well. Number of studies evaluating
the cognitive and neurobehavioral effects of DBS included only small number of patients and
only few of them have included the control patient group of PD patients who did not have the
surgery. The absence of control groups makes it difficult to determine whether a change
occurring after DBS in surgical group might have occurred also in non-operated patients, thus
reflecting non-DBS factors (PD progression, medication effects).
(Gironell et al. 2003, Morrison et al. 2004).
Postoperative cognitive and neuropsychiatric changes can be caused by multiple factors
(Table 3).
Tab. 3 Factors that could cause the neuropsychiatric complications after DBS STN.
Preoperative psychiatric state of the patient (psychiatric disorder)
Surgery related factors (duration of operation, electrode trajectory, site of definitive electrode
implantation, number of microelectrodes used, possible surgery complications)
STN stimulation factors (placement of stimulation electrode, stimulation parameters)
Postoperative issues (adjustments of dopaminergic medication)
Psychosocial issues (patient adjustment to the postoperative state, neurobehavioral influence
)
PD related factors (non-dopaminergic symptoms, neurodegeneration)
The cognitive functions can be influenced either by the surgical procedure connected with
electrode implantation or the high frequency stimulation of target and neighboring structures.
The adjustments of dopaminergic medication (e.g. decrease of L DOPA equivalent dose after
DBS STN) could also have profound influence on neuropsychiatric performance.
The medication therapy changes have the indirect consequences, e.g. possibility of apathy and
abulia occurrence caused by the very fast decrease of dopaminergic medication. Apathy and
abulia could augment patient’s performance in neuropsychiatric testing. Too slow decrease of
medication, puts the patient to increased risk of neuropsychiatric changes (hypomania, mania,
hypersexuality) (Houeto et al. 2003).
15
The effect of surgical procedure itself is connected either by non-specific perioperative factors
(stress of the surgical procedure) or the specific factors related to selected trajectory in the
basal ganglia. From the anatomical point of view it is very likely that the occurrence of
cognitive and neuropsychiatric decline is related to the electrode placement into the vicinity
of limbic and associative structures and tracts.
Recent evidence has implicated the stimulation parameters (amplitude, pulse width,
stimulation frequency) as the intriguing factor influencing the cognitive and various nonmotor
symptoms of PD. The most important seem to be the amplitude and frequency. There
seem to be some evidence that stimulation parameters that improve the motor symptoms of
PD could, at least in some cases, worsen the cognitive performance of the patient (Koppel et
al. 2006).
Several studies approached the lead location or lead trajectory as a possible variable in
relation to neuropsychological effects of DBS STN. Chronic anteriorly located active contact
stimulation within ventral STN was found out to be one such variable (Tsai 2007). According
to another study (Witt et al, 2013) patients with DBS STN who declined in semantic verbal
fluency, Stroop task and the backward digit span task performance showed a position of the
active electrode outside the volume built by the active electrodes of stable performers.
Passage of the chronic stimulation lead through the head of the caudate increased the risk of
global cognitive decline and working memory performance after DBS STN in group of 68
patients with advanced PD. Authors suggested that the electrode path should be planned
outside the caudate nuclei, whenever possible. This study also stressed the importance of
precise positioning of the active stimulating contact within the subthalamic volume to avoid
adverse effects on semantic verbal fluency and response inhibition.
Other papers cited patient related factors as possible predictors of worsened
neuropsychological outcomes after DBS STN in PD.
Umemura found out that high preoperative UPDRS III motor score in the medication-off
period and a depressive state evaluated with BDI-II correlated significantly with decline in
executive function (Umemura, 2013). There were 57 patients included in this study.
Also other patient inherent factors (such as age, attention, dose of anti-parkinsonian
medication, scores on axial motor symptoms and a lower L-DOPA response before surgery)
were reported as predictors of neuropsychological side effects (Daniels et al., 2010; Smeding
et al., 2011).
16
Factors related to drug withdrawal factors (Thobois 2010) also have to be taken into account.
Changes in dopaminergic medication after DBS STN should be gradual and slow.
The surgery and stimulation-related modulation of STN conveyed cognitive functions can be
caused also by the relatively small size of STN. It may be impossible for electric current to avoid
the parts of STN dedicated to cognitive functioning.
The behavioral changes after bilateral DBS STN have been analysed in already cited metaanalysis
that included 1398 patients (Temel et al. 2006). There was no statistically significant
relation between the clinical characteristics of operated subjects (gender, duration of PD
before the operation, age), motor outcome of DBS and cognitive or neuropsychiatric changes.
Only patients with preoperative clinically relevant behavioural alterations can be at risk for
further deterioration after surgery.
Perriol and coworkers investigated the correlation patterns of the motor, cognitive and
behavioural consequences of DBS STN with respect to positioning of active stimulation contact
(Perriol et al. 2006). They have described the cognitive changes 12 months after surgery only
in 3 patients with a history of pre-operative, dopaminergic psychosis or post-surgical
confusion. Age and a distant history of depression were associated with occurrence of postsurgical
depression. The cognitive or affective changes had no relation to the motor outcome.
There is a ongoing debate on exact frequency and severity of cognitive and/or
neurobehavioural changes after DBS STN. However, from the available data it seems quite
clear that the patients with preoperatively disordered cognitive functions, history of
depression or behavioural problems carry increased risk of neuropsychiatric complication
after the DBS surgery. This only confirms the role of neuropsychologist in DBS team.
Meticulous neuropsychologic and neuropsychiatric examination is essential also in the time
after the surgery for assessment of long-term effects of DBS STN on cognition (Fanfrdlová et
al. 2006. Telecká et al.2010 ).
STN appears to be involved in complex cognitive behavioural functions and networks such as
the network underlying the Theory of Mind (Péron et al., 2013). Moreover, neuropsychiatric
problems such as depression (Voon et al., 2006, Thobois et al. 2010), apathy (Voon et al. 2006),
17
suicide ideation/attempt (Voon et al., 2008) were also reported after DBS STN surgery, and
were reviewed recently by Rodriguez-Oroz et al., 2012. Behavioural complications were
reported after DBS STN more frequently than after DBS Gpi. The etiology of these problems is
multifactorial and except for reduction of dopaminergic medication (Thobois et al., 2010) and
preoperative risk factors (Lim et al. 2009) includes also stimulation of contacts located in nonmotor
areas (Mallet et al., 2002, Mandat et al., 2006, Raucher-Chéné et al., 2008). The
impulsivity and mania are thought to be related to diffusion of electric current to limbic parts
of STN (Rodriguez-Oroz et al., 2012, Mallet et al., 2007, Krack et al., 2010). STN DBS might alter
the coupling between prefrontal cortex and basal ganglia during decision-making processes
(Cavanagh et al., 2011).
It is possible to outline the characteristics of a patient with increased risk of cognitive and
neurobehavioural impairment post DBS STN surgery (Tab.4). It has to be stressed that with
careful adherence to selection criteria the risk of neuropsychiatric side effects after DBS STN
is low.
We have observed cognitive disorder related to surgery only in one patient from our group of
about 45 patients after DBS STN. Transient postoperative confusion occurred in 4 patients. In
three patients the hypomania or mania was observed immediately after the surgery. The 12
month observational neuropsychological data of our group were published earlier (Telecká et
al. 2010).
Table 4.
Patient with increased risk of cognitive and neurobehavioural impairment after DBS STN
surgery
Age above 70 years
Preoperative neuropsychiatric dysfunction (diagnosed dementia, depression, behavioural
disorders)
DBS surgery complications (infection, intracranial bleeding)
Prolonged intraoperative microrecording with higher number of microelectrode trajectories.
Insufficient or overactive dopaminergic stimulation (depending on adjustments of
dopaminergic therapy postoperatively)
From: Baláž M and Rektor I., 2008
18
3 Commented compilation of original journal articles
3.1 Participation of subthalamic nucleus in executive functions.
Published in: Movement Disorders 23(4):553-7, 2008, IF: 5.6
Commentary.
The following article was the first from our studies pertaining recording from subthalamic
macroelectrodes. The aim of the study was to evaluate the P3 wave characteristic in STN with
the use of deep brain electrodes. These recordings were unique as they were centered on
event related potentials that evaluated cognitive functions.
We included ten patients with advanced PD who were treated by DBS. In the time interval
between inserting deep brain electrodes and implantation of the final neurostimulator, the
electrodes were available for recording via externalization device. This interoperation period
is usually used clinically for so called external stimulation deemed for evaluation of stimulation
effect. Altogether 14 electrodes were available for evaluation.
We evaluated P3 waves in all patients using two paradigms. One of the protocols was so called
standard auditory oddball paradigm during which a patient was asked to silently count
number of rarely occuring sounds. Recordings during this protocol did not reveal any signs of
P3 potentials generation. Other paradigm was so called dual-task protocol during which a
patient was asked to silently increase the ordinal and day of the date with each rarely
occurring sound. Dual task has an increased demand on executive functions of patients with
PD. The P3 evoked by this dual-task protocol was found to be significantly changed specially if
examined in patients with Parkinsonˈs disease by Garcia Larrea et al. Indeed, we were able to
find the generators of P3 related to this dual task within vicinity of subthalamic nucleus in 8
out of 14 electrodes.
The P3 potentials related to the increased demand on executive functions were detected by
STN contacts known to have the best effect on Parkinsonian motor signs. This could suggest
that STN participates in the executive function processing. The neuronal pools involved in
cognitive activities may be located in close vicinity to, or even overlapping with, the neurons
active in motor functions.
19
Our study confirmed the participation of subthalamic nucleus in executive functions.
However, surprisingly if compared to previous studies by our group there was no sign of
generator for P3 standard oddball protocol that was otherwise present widely within
subcortical structures as was published by our group earlier (Rektor et al, 2005).
Our results published in this paper suggested that STN stands out amongst other BG structures
in that participation of this structure in executive functions was conveyed through other
pathways than usual basal ganglia-thalamic-cortical circuitry. Overall, the findings from this
study indicated that STN played an active role in processing executive functions in patients
with the Parkinson's disease.
Participation of the subthalamic nucleus in executive functions:
An intracerebral recording study.
M. Baláž, I. Rektor, and J. Pulkrábek
1 Movement Disorders Centre, Department of Neurology, St. Anne’s University Hospital,
Medical School of Masaryk University, Pekařská 53, 656 91 Brno, Czech Republic
Corresponding author:
Dr. Marek Baláž
Department of Neurology
St. Anne’s University Hospital
Medical School of Masaryk University
Pekařská 53, Brno 656 91
telephone: +420 54318 2624
fax: +420 54318 2658
e-mail: marek.balaz@fnusa.cz.
Abstract:
Objective:
The objective of our work was to find whether the subthalamic nucleus (STN) is directly
involved in cognitive activities, specifically in executive functions.
Patients and methods:
20
Ten patients with idiopathic Parkinson’s disease had P3 potentials recorded by externalized
deep brain electrodes that were implanted in the STN or in its immediate vicinity. Two
contacts of each electrode were positioned inside the STN according to clinical effect,
perioperative microrecording, and stimulation. The P3 waves were recorded following the
auditory stimulus in a standard oddball paradigm. They were compared to the P3 waves
elicited from a protocol modified by a dual task with an increased demand on executive
functions.
Results:
The P3 potentials with a steep amplitude gradient evoked by the modified protocol were
detected by the contacts in 8 out of the 14 available electrodes, located either inside the STN
or in its immediate vicinity. The modified protocol led to an increased latency of the P3
potential in 8 of 14 electrodes. No local field potentials of the standard P3 potentials were
recorded.
Conclusion:
The P3 potentials related to the increased demand on executive functions were detected by
the STN contacts known to have the best effect on Parkinsonian motor signs. This could
suggest that the STN takes part in the executive function processing.
Introduction
In recent years, there has been a steady increase in the number of reports regarding cognitive
disorders and other non-motor disorders related to deep brain stimulation (DBS) surgery for
Parkinson’s disease (PD) (1). According to the current practice, DBS of the subthalamic nucleus
(STN) should not produce any major adverse cognitive or behavioral effects in properly
selected patients.
The mechanism by which the STN regulates motor functions in the neural circuitry is not fully
understood, and little is known about its influence on cognitive networks.
In this study, P3 cognitive event-related potentials in the STN were recorded. The late positive
complex of event-related potentials (ERP) - the P300 or P3 wave - may represent various
functions, such as the closure of sensory analysis, the update of working memory, the
attention and decision processes, and the facilitation of motor pathways in motor tasks. An
earlier study showed that P3-like potentials are generated throughout the basal ganglia,
21
notably in the putamen (2). The present study measured the amplitudes and latencies of P3
waves using a dual task protocol in order to evaluate the involvement of the STN in executive
functions.
Garcia-Larrea and Cezanne-Bert elaborated a dual task P3 paradigm that proved to be suitable
for the study of executive functions in PD (3,4). Parkinsonian patients examined with a dualtask
paradigm showed significantly greater P3 attenuation than age-matched controls, even
in tasks not requiring any motor response (4). This suggests that the executive load imposed
by the dual task is pathologically increased in PD independently of motor impairment.
In this study, we raise the question of whether the STN generates the brain potentials linked
with an oddball protocol on one hand, and the potentials evoked by cognitive processes linked
with executive functions (modified protocol) on the other hand. The impairment of executive
functions is a well-known sign of PD.
Methods and material
Patients
The present study included ten patients with L DOPA-induced motor complications of
Parkinson’s disease (6 men and 4 women with a mean age of 55.8; SD 9.61 years), indicated
for DBS surgery by the Commission for Neuromodulation Surgery of the Brno Movement
Disorders Centre. The mean preoperative UPDRS III (Unified Parkinson’s Disease Rating Scale)
was 43.6, SD 6.9 off medication; and 22.3, SD 4.1 in on-medication state. The mean duration
of the disease was 13.5 years, SD 3.2 years. All patients freely gave their informed consent to
participate in the study. The hospital ethics committee endorsed the study.
Surgical procedure
The sterotaxic frame used was the Leibinger open frame with the Praezis plus software and
the Talairach diagram. The STN coordinates used were in respect to the AC-PC (anterior
commissure – posterior commissure) line: 11.0 mm laterally, 5.0 mm below and 3.0 mm
behind the midpoint of AC-PC line. The implantation procedure was performed in two steps.
First, the stimulation leads (Medtronic, Inc.) were implanted bilaterally into the targeted
structure by a stereotaxic MRI-guided technique under local anesthesia. The lead placement
was confirmed by microelectrode recordings, which served as the reference for ascertaining
the position of each contact (electrode pole) within the STN and in relation to the adjoining
22
structures. We used the standard tungsten microelectrode 291 A (Medtronic, Denmark) with
impedance of 0.5–1.5 M for microrecording.
The motor part of the STN was identified by recording the pattern of neuronal activity,
background activity, and motor responsiveness (changes in neuronal firing in response to
passive and active manipulation of contralateral limbs during the perioperative
microrecording). We determined the dorsolateral border of the STN by microelectrode
recording of cellular firing patterns. We also assessed the lead location by evaluating the
symptom response to the intraoperative microstimulation. Once the final target coordinates
were determined, a permanent quadripolar DBS electrode (model 3389 with 0.5 mm
intercontact distance) was implanted, and the intraoperative test stimulation was performed
to optimize clinical effects. The electrode position was verified by the intraoperative use of
fluoroscopy to compare the position of the trajectories of the microrecording electrodes with
the definitive trajectory of the quadripolar macroelectorode.
In all but two patients, the best response of the Parkinsonian motor signs (tremor, rigidity,
and akinesia) to the postoperative stimulation was observed in the two central contacts of the
quadripolar electrode. In the two other patients, the best effect on motor signs was present
on the two most distal contacts.
In the second part of the operation, the electrode cables were internalized and a
neurostimulation device (Itrel III or Kinetra, Medtronic Inc., Minneapolis, USA) was implanted.
The period between the two steps of the operation ranged from 3 to 7 days. This period served
for functional assessment and testing of efficacy during the external stimulation. We also used
this period of time for measuring Event-Related Potentials (ERP) (see below).
ERP measurements
The recordings of ERP (P3) were performed during the interoperative period from the
externalized DBS electrodes. The recordings were performed on the third day after the
electrode implantation in all patients included in the study. All patients were in an onmedication
state during the ERP recording.
ERP recordings were performed using the 8-channel Nihon Kohden Neuropack 4200EP/EMG
device (Nihon Kohden Electronics, Osaka, Japan) or the 32 channel EEG system TruScan
(Deymed Diagnostic, Alien Technic, Czech Republic). Time base ranged from 0 to 1200
23
milliseconds (ms); filter range: 1 hertz (Hz) – 200 Hz; sensitivity gain: 200 microvolts (uV);
sampling 256 Hz. We used a biauricular reference electrode.
The P3 waves evoked by an auditory stimulus in the standard oddball paradigm (7) were
recorded and compared to the P3 waves elicited by the modified protocol with increased
involvement of executive and cognitive resources (4).
The auditory oddball paradigm was used with no motor activity during the test (3). Tones were
delivered through earphones at a 2 Hz frequency: frequent tones were delivered at 1000 Hz
and 70 decibel (dB) for 0.1 second (s) duration; rare (target) tones were delivered at 2000 Hz
and 70 dB for 0.1 s duration. The tones were randomly generated at 5:1 ratio.
In the first test, the subjects were instructed to recognize the target tones and to silently count
them in the standard protocol. They were asked to report the total number of target tones at
the end of each recording session.
The second test used a modified auditory oddball paradigm involving increased demands on
executive functions. The target and frequent tones were delivered with identical parameters
to those of the standard protocol described above. The tasks in this condition consisted of
silently changing the date upon each target presentation. Immediately prior to the recording,
the subjects were given a two-item date that included the day of the week and the ordinal
date (e.g. Monday, the 19th). The date had to be updated after each target stimulus. The final
outcome had to be presented at the end of the recording session (4).
Only target data were further analyzed. The main ERP component of a P3 wave was identified
visually and quantified by its latency and amplitude parameters. The peak latencies were
measured from the stimulus onset. We evaluated the first distinctive potential to appear in
the 250-600 ms window. Only the P3-like potentials with a steep voltage change were
considered to suggest nearby generators (we did not find any phase reversal pattern in our
patients) (8). Significantly larger amplitude recorded from the lead contacts within the STN,
compared to the neighboring contacts outside of the STN, particularly a steep voltage
gradient, implied a local generation of the P3-like potentials (9).
The processing steps included a statistical evaluation of quantitative data (values of
amplitudes and latencies of the P3) and a qualitative analysis (assessment of presence or
absence of steep voltage change, e.g. rise of amplitude in the contacts located within the STN
24
compared to the contacts outside of this structure). The statistical analysis of recorded
potentials was performed by comparing the number of electrodes with the presence of ERP
with an amplitude gradient within the STN to electrodes with the P3 waves but without the
amplitude gradient in the STN in each protocol.
We also compared the latencies of the P3 peaks in standard versus modified paradigms.
The Wilcoxon matched pairs test was used for the analysis of latencies, while a test of
homogeneity of binomial distribution was used to assess the presence of P3 generators.
Results
Amplitudes
The recordings were taken from 20 electrodes. In 6 electrodes, either no P3-like potentials
were present (in 3 electrodes), or only artifacts were found (in the other 3 electrodes).
We found a voltage change – a steep rise in amplitude – in the P3 potential recorded during
the modified protocol (dual task) within the STN in 8 of the 14 electrodes available for the
generator potential evaluation (Fig.1). In the remaining 6 electrodes, there were no
generators of P3-like potentials present. There were no differences regarding the age,
medication, motor state, or electrode positioning in patients where the P3 was absent from
ERP recordings.
We also observed intracerebral P3 with negative polarity (such as the one depicted in Fig.2)
due to the nature of intracerebral recording, when even a slight shift in the mutual position of
a lead and a generating structure can influence the resulting curve.
A statistical evaluation proved the occurrence of generator activity to be statistically
significant p < 0.0001 (test of homogeneity of binomial distribution). We did not observe such
a voltage change in the P3 recorded during the standard protocol.
Latencies
We observed that the modified paradigm led to an increased latency of P3 in 8 out of 14 tested
electrodes (16 out of 28 contacts) in the contacts located within the STN (contacts with the
best motor effect) (Fig.2). The mean latency of P3 from the contacts presumed to be within
the STN in the standard protocol reached 261.9 ms, SD  40.3. The mean latency was 294.8
ms  51.31 in the modified protocol. The differences between the latencies in the standard
and modified paradigms were statistically significant with p < 0.0001 (Wilcoxon matched pairs
25
test). Latencies for the contacts outside of the STN reached 252.25 ms  29.28 in the standard
protocol, compared to 259.5 ms  30.17 in the modified protocol. The difference between
these latency values was not statistically significant.
Discussion
In this study, we recorded cognitive event related potentials (P3) using standard and modified
auditory oddball protocols, where the latter was modified by an increased demand on
executive functions. We evaluated potentials that displayed an amplitude gradient in adjacent
contacts. A significantly larger amplitude in one contact than in a neighboring contact,
particularly a steep voltage gradient over a short distance, implied a local generation of ERP.
The “steep voltage changes” were considered to be generators because of their significance
as the accepted signs of proximity to a generating structure (7).
One limitation of the present study is the determination of an exact location for the recording
contacts within the STN. The absence of a phase reversal could mean that a recording contact
was positioned in the immediate vicinity of neuronal population generating the P3 rather than
in the STN itself. Due to the small volume of the STN, we cannot fully exclude the possibility
that some potentials were generated adjacent to the STN and not directly in the nucleus. On
the other hand, as the P3 local fields were recorded on the contacts with the best motor effect,
it is highly probable that the actual STN activity was recorded. The characteristics of the
electrodes used, especially the relatively small lead volume and short intercontact interval,
enabled a relatively precise localization of the signal source. A slight shift in the mutual
position of a lead and a generating structure (dipole generator) can dramatically influence the
recording.
In our recordings, no generators of the standard oddball P3 could be recorded in the STN. On
the contrary, the modified protocol with a dual task elicited a local field P3 potential within
the STN. This could indicate a specific, task-related involvement of the STN in the cognitive
processing of information. In this case, only a task with an increased demand on executive
functions produced the possible P3 local fields. These findings are more intriguing when we
consider that our target was either directly in the motor part of the STN (dorsolateral) or in its
immediate vicinity, according to the perioperation microrecording results and the effect of
DBS procedure on the motor performance of the patients. The neuronal pools involved in the
cognitive activities may be located in close vicinity to, or even overlapping with, the neurons
26
active in motor functions. The cognitively active neurons might be affected by DBS in some
cases, especially if the small size of the STN is taken into account.
The latencies of P3 in the two paradigms also differed. The P3 latency is considered to be a
measure of stimulus classification speed during memory updating. Also, there is a link
between P3 latency and the timing of attention processes. (8). We propose that the presence
of the difference in the P3 latency between the standard and modified paradigms in the
contacts with the best motor response (presumably the ones within the STN) and the absence
of these changes in the contacts outside of the STN support the role of the contacts with the
best motor response in cognitive processing of executive functions.
The basal ganglia participate in various cognitive activities. It has been suggested that the basal
ganglia system is the generator of the cognitive patterns (9,10). P3 like potentials have been
recorded in the caudate, putamen, and pallidum (2,11,12,13). The basal ganglia are also
involved in the attention processes (10). Nevertheless, the involvement of the STN in these
functions is still largely unknown. The generating of cognitive potentials related to executive
functions in the STN may indicate that the STN has an active role in processing executive
functions.
It is probable that the STN participates in the executive functions as a part of a cortico-basal
ganglia-thalamocortical loop. The existence of direct anatomical pathways linking the STN to
the prefrontal areas of the brain has been reported recently. When a voluntary movement is
about to be initiated by the cortical mechanisms, a corollary signal conveyed through the
cortico-subthalamo-pallidal “hyperdirect” pathway first inhibits the large areas of the
thalamus and cerebral cortex that are related to both the selected motor program and other
competing programs. This direct connection between the STN and the cortex could perhaps
explain the role of the STN in influencing the cognitive and executive functions (14). Our
findings may therefore suggest that a certain effect of DBS surgery on cognitive performance
could be connected to the direct influence of the operation procedure and/or stimulation on
the “cognitive” parts of the STN.
The majority of studies on cognitive function changes related to DBS for PD suggest that the
DBS-STN results in a relatively small cognitive morbidity in well-selected patients.
The most robust findings across various studies appear to be a decline in word fluency, verbal
memory, conditional associative learning, visuospatial memory, processing speed, and
27
selected measures of executive functions (15,16). However, multiple reports exist about
patients, who sustained significant cognitive decline following surgery (17,18).
Some studies have also examined the role of stimulation on neuropsychological performance.
These reports demonstrated either no significant cognitive effects, or improvements in
processing speed, working memory, and other functions with stimulation (19). Therefore, the
effect of an electrical current on the cognitive parts of the STN cannot be excluded.
As we recorded in the early postoperative phase, it is possible that this effect is transitory and
does not occur later or occurs only in patients with postoperative cognitive impairment.
Recordings of ERP have been performed in patients treated for Parkinson’s disease for many
years.There have been no examinations performed in healthy controls. As has been shown by
Garcia-Larrea, Parkinson’s disease itself influences P3 recordings. The impact of long-term LDOPA
therapy on P3 recordings cannot be excluded, and the results of our study have to be
viewed from this perspective.
Overall, the findings from this study indicate that the STN plays an active role in processing
executive functions in patients with the Parkinson disease. However, further data are needed
to understand the clinical implications of our results.
Research support: Research program of Czech Ministry of Education - MSM 002 162 2404
Acknowledgement: The authors would like to express thanks to Prof. Z. Novák and Dr. J.
Chrastina for performing all of the surgical procedures related to DBS - STN. We also thank A.
Johnson, D. Grady, and J. and R. Bettelheim for English language corrections. We also thank
the anonymous reviewers for their valuable comments and suggestions.
Fig. 1. Amplitude changes suggesting the vicinity of P3 generators.
A. Steep rise of voltage suggesting the generator activity after testing with modified protocol.
P3 recorded from STN (channels 2 and 3) compared to activity recorded outside of STN
(channels 1 and 4).
B. No difference in amplitudes between contacts inside versus outside of STN after testing
with standard protocol.
28
Fig. 2: Differences of P3 latencies of standard and modified protocols.
Diference in latency of P 3 in standard (bold black line) and modified protocols (dotted line).
This graph depicts the P3 recording of patient KG from a single contact pair within the STN
(there is no difference between P3 amplitudes present in this figure). Thick black arrow marks
the stimulus onset (0 milliseconds).
P3 P3
29
References
1. Saint-Cyr JA, Trepanier LL, Kumar R, Lozano A, Lang AE. Neuropsychological
consequences of chronic bilateral stimulation of the subthalamic nucleus in
Parkinson‘s disease. Brain 2000, 123, 2091-2108.
2. Rektor I. Bares M, Brazdil M et al. Cognitive and Movement-Related Potentials
Recorded in the Human Basal Ganglia, Movement Disorders, 2005, 20, 5:562-588.
3. L. Garcia-Larrea, G. Cezanne-Bert: P3, Positive slow wave and working memory load: a
study on the functional correlates of slow wave activity. Electroencephalography and
Clinical Neurophysiology 108 (1998) 260-273.
4. L. Garcia-Larrea , Brousolle E, Cezanne-Bert G, Maugiere F, P 300 and frontal executive
functions: application of a dual-task paradigm in normal subjects and patients with
Parkinson‘s disease and progressive supranuclear palsy. Electroencephalography. Clin.
Neurophysiol 103,148. 1997.
5. Vaughan HG, Weinberg H, Lehmann D, et al. Approaches to defining the intracranial
generators of event/related potentials and magnetic fields. In: McCallum WC, Zappoli
R, Denoth F (eds) Cerebral psychophysiology: studies in event-related potentials. EEG.
Elsevier, Paris, pp 505 – 544, 1986
6. Polich J. P300 Clinical Utility and Control of Variability. J of Clin Neurophys, 1998, 15
(1):14-33.
30
7. Graybiel AM, The basal ganglia and cognitive pattern generators. Schizophr Bull
1997;23:459-69
8. Stein S, Volpe BT. Classical parietal neglect syndrome after subcortical right frontal
lobe infarction. Neurology, 1983;33:797-9
9. Rektor I. Bares M, Kanovsky P et al. Cognitive potentials in basal ganglia –
frontocortical circuits. An intracerebral recording study. Exp Brain Res (2004) 158:289-
301.
10. Kropotov JD, Ponomarev VA. Subcortical neuronal correlates of component P300 in
man. Electroenceph clin Neurophysiol 1991;78:40-9
11. Rektor I, Bares M, Brazdil M, Kanovsky P, Rektorova I, Sochurkova D, Kubova D, Kuba
R, Daniel P. Cognitive- and movement-related potentials recorded in the human basal
ganglia. Mov Disord. 2005 May;20(5):562-8.
12. Nambu A, Tokuno H, Takada M. Functional significance of the cortico–subthalamo–
pallidal ‘hyperdirect’ pathway , Neuroscience Research Volume 43, Issue 2, June 2002,
Pages 111-117
13. Voon V, Kubu C, Krack P, Houeto J-L, Troester A I. Deep brain stimulation:
neuropsychological and neuropsychiatric issues. Mov Disord 2006;21 Suppl. 14, S305-
S327.
14. Morrison CE, Borod JC, Perrine K et al. Neuropsychological functioning following
bilateral subthalamic nucleus stimulation in Parkinson’s disease. Arch Clin
Neuropsychol 2004; 19:165-181.
15. Hariz MI, Johansson F , Shamsgovara P, Johansson E, Hariz GM, Fagerlund M. Bilateral
subthalamic nucleus stimulation in a Parkinsonian patient with preoperative deficits in
speech and cognition: persistent improvement in mobility but increased dependency
– a case study. Mov Disord 2000;15:136-139.
16. Daniele A, Albanese A, Contarino MF et al. Cognitive and behavioral effects of chronic
stimulation of the subthalamic nucleus in patients with Parkinson’s disease. J Neurol
Neurosurg Psychiatry 2003, 74: 175-182.
31
3.2 The effect of cortical repetitive transcranial magnetic stimulation on cognitive eventrelated
potentials recorded in the subthalamic nucleus in patients with Parkinson’s
disease
Published in: Exp Brain Res. 2010 Jun;203(2):317-27., IF: 2.2
Commentary
In this paper we corroborated our previous research regarding the position of STN in cognitive
and executive functions. The aim of the work was to find out whether the use of repetitive
transcranial magnetic stimulation (rTMS) over two distinct cortical structures may modulate
the electrophysiological properties of intracranial P3 waves. We again used two P3 auditory
protocols – standard auditory oddball and dual-task modified protocol that were described in
detail in previous commentary and article (2.1). Also the procedure with the recordings from
deep brain electrodes was similar to previous study. Additionally, we applied rTMS over either
dorsolateral prefrontal cortex (DPLPFC) or inferior frontal cortex between first and second
recordings of P3 waves. We planned to modulate the cortical activity of two previously
mentioned cortical areas and to follow the resulting changes in P3 waves. rTMS is presumed
to represent a suitable tool to investigate plasticity within a functional network and opens the
possibility of intervening directly with the mechanisms of cortical plasticity in the human
cortex (Siebner and Rothwell 2003). Altogether 18 patients after DBS STN were included in the
study. 1 Hz rTMS over the right IFC led to shortening of ERP latencies in both protocols. The
correlation between neuropsychological test performance and P300 latency from earlier
papers indicated that individual latency variability was related to mental processing speed,
with peak timing affected by cognitive operations specific to perceptual and attentional
processing (Polich and Herbst 2000). The speed of executive processing is thus reflected by
the latency duration. It seemed that the 1 Hz rTMS over the IFC facilitated the executive
processing. These changes were not present after the stimulation of DLPFC. The involvement
of STN in cognitive activities is selective and specific. As we stated in our earlier paper, the
standard oddball protocol did not generate ERP waves in STN, in contrast to a protocol
modified by an increased load of executive functions. Overall, the findings from this and earlier
studies indicate that STN plays an active role in processing executive functions in patients with
Parkinson’s disease, probably outside of the classical cortical-basal ganglia-thalamic circuits.
32
Direct cortico-STN connections bypassing these circuitries could explain the modulation of
STN.
This paper showed that there exists a direct functional link between IFC and STN which is
active during executive functions. No similar link was observed between DLPFC and STN.
The effect of cortical repetitive transcranial magnetic stimulation on cognitive event-related
potentials recorded in the subthalamic nucleus
M. Baláž, H. Srovnalová, I. Rektorová, I. Rektor
Department of Neurology, St. Anne’s University Hospital, Medical School of Masaryk
University, Pekařská 53, 656 91 Brno, Czech Republic
Corresponding author: rTMS and cognitive event related potentials in STN
Marek Baláž, MD
Department of Neurology
St. Anne’s University Hospital, Masaryk University
Pekařská 53, Brno 656 91, Czech Republic
Telephone: +420 543 182 624, fax: +420 543 182 658
E-mail: marek.balaz@fnusa.cz
Keywords: inferior frontal cortex; subthalamic nucleus; executive functions; ERP; P3;
hyperdirect pathway
Abstract:
We studied whether the cognitive event-related potentials (ERP) in the subthalamic nucleus
(STN) are modified by the modulation of the inferior frontal cortex (IFC) and the dorsolateral
prefrontal cortex (DLPFC) with repetitive transcranial magnetic stimulation (rTMS). Eighteen
patients with Parkinson’s disease who had been implanted with a deep brain stimulation (DBS)
electrode were included in the study. The ERPs were recorded from the DBS electrode before
and after the rTMS (1 Hz, 600 pulses) over either the right IFC (10 patients) or right DLPFC (8
patients). The ERPs were generated by auditory stimuli. rTMS over the right IFC led to a
shortening of ERP latencies from 277 ± 14 ms (SD) to 252 ± 19 ms in the standard protocol and
33
from 296 ±17 ms to 270 ±20 ms in the protocol modified by a higher load of executive
functions (both p < 0.01). The application of rTMS over the DLPFC and the sham stimulation
over the IFC showed no significant changes. The shortening of ERP latency after rTMS over the
right IFC reflected the increase in the speed of the cognitive process. The rTMS modulation of
activity of the DLPFC did not influence the ERP. Connections (the IFC-STN hyperdirect
pathway) with the cortex that bypass the BG-thalamocortical circuitries could explain the
position of the STN in the processing of executive functions.
Introduction
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective long-term
treatment for motor symptoms in advanced Parkinson’s disease (PD) (Krack et al. 2003). The
STN itself is involved in the pathophysiology of PD, and the disruption (e.g. by DBS) of its
pathological overactivity partially reverses some of the clinical, electrophysiological, and
metabolic abnormalities related to PD (Hamani et al. 2004).
There are controversial opinions on the impact of STN-DBS on cognitive and behavioral
functions. It appears that the STN has anatomically a central position within the basal gangliathalamocortical
associative and limbic circuits and is functionally a potent regulator of these
pathways. From a clinical point of view, STN-DBS modulates not only motor but also cognitive
and affective functions (Temel et al. 2005). According to some authors, DBS causes only minor
changes, related perhaps more to the effect of surgery than the stimulation itself (Okun et al.
2009). A randomized multi-center study showed that STN-DBS does not reduce overall
cognition or affectivity, although there was a selective decrease in frontal cognitive functions
and a decrease in patient anxiety after the treatment (Witt et al. 2008). According to the metaanalysis,
cognitive problems were faced by up to 41% of patients (Temel et al. 2006). A review
article underlined certain methodological differences between papers related to
neuropsychological and cognitive disorders connected with this procedure (Voon et al. 2006).
Overall, it is evident that at least in some patients the change in cognitive functions after STNDBS
may have a clinical importance.
The connections of the STN have been well characterized in both rodents and primates. Both
the subcortical and cortical connections were extensively studied with diffusion tractography
34
(Aravamuthan et al. 2007), which proved that the STN connections in humans largely matched
those found in primates. The major connections of the STN are with the globus pallidus and
substantia nigra pars reticularis. The STN receives the excitatory outputs from various parts of
the cerebral cortex, including the motor cortex, supplementary motor area, and dorsal and
ventral premotor cortex (Hamani et al. 2004).
Apart from the striatum, the subthalamic nucleus (STN) is the only structure in the basal
ganglia to receive a direct cortical projection (Albin et al. 1989; Parent and Hazrati 1995). This
independent corticosubthalamic projection originates from the motor and premotor areas
(Afsharpour 1985, Canteras et al. 1990; Bolam et al. 2002) as well as the medial prefrontal
cortex, which includes the prelimbic and ventromedial prefrontal areas (Kitai and Deniau
1981; Berendse and Groenewegen 1991; Maurice et al. 1998). This direct interaction between
the frontal cortex and the STN implicates its participation not only in sensorimotor functions
but also in higher-order cognitive processing (Chudasama et al. 2003).
In this study, we attempt to further clarify the position of the STN in cognitive function
processing. In contrast to the striatum and pallidum (Rektor et al. 2004 and 2005; Bareš et al.
2003), no cognitive ERP was generated in the STN area in our recent studies (Baláž et al. 2008;
Bočková et al. 2008) using a standard oddball protocol (see Methods). On the other hand, the
generators of P3-like potentials within the area of the STN had been elicited only after a task
with an increased demand on executive functions. This could mean that the STN is involved
only in more “difficult” tasks that can be corroborated by a circuitry possibly different from
the basal ganglia-thalamus-cortical loop (Baláž et al. 2008). The question arises whether this
role of the STN is conveyed in the cortico-basal ganglia-thalamocortical circuits or by a
different pathway.
We therefore sought to learn whether either the cortico-basal ganglia-thalamus dorsolateral
prefrontal cortex (DLPFC) loop or perhaps a pathway between the inferior frontal cortex (IFC)
and the STN (see below) modifies the cognitive performance of the STN.
The DLPFC (Brodmann areas 9, 46) has been associated with executive functions and with
higher cognitive functions (Hoshi 2006). It has been proposed that the indirect projection from
the STN to the DLPFC via the connection to the substantia nigra pars reticulata may explain
the effect of STN-DBS on cognitive functions (Jahanshahi et al. 2000).
35
The right IFC (Brodmann area 44) has been shown to participate in executive processing, e.g.
in resolving dual task interference at the perceptual attention stage. The suppression of a
proponent response and the response selection have been attributed to the IFC (Jiang 2004).
Even more intriguing, a direct connection between the IFC and the STN - the “hyperdirect”
pathway and its influence on motor aspects of STN activity - has been described (Nambu et al.
2002). The fiber-tracking studies of non-human primates show that the ventral premotor
cortex projects directly to the ipsilateral STN (Croxson et al. 2005). An fMRI paper pointed out
that the STN and the IFC were coactivated in the right hemisphere for response inhibition
(Aron and Poldrack 2006).
We used repetitive transcranial magnetic stimulation (rTMS) to influence the activity of
selected cortical structures. rTMS is presumed to represent a suitable tool to investigate
plasticity within a functional network and opens the possibility of intervening directly with the
mechanisms of cortical plasticity in the human cortex (Siebner and Rothwell 2003). The effect
of a single-pulse transcranial magnetic stimulation (TMS) over the motor cortex on STN
neuronal activity has been studied (Strafella et al. 2004). TMS of the motor cortex was shown
to modulate the neuronal activity of STN in subjects with PD, supporting the important role
played by the corticosubthalamic circuit in the modulation of the basal ganglia output. This
first study opened up new avenues for in vivo studies of corticosubthalamic interactions in
humans.
We utilized the ERPs and their parameters as a tool to observe the impact of rTMS of cortical
structures on the executive functioning of the STN and to determine the context of putative
cognitive networks comprising the STN. We measured amplitudes and latencies of the P3-like
wave. The late positive complex of event-related potentials (ERPs) - the P300 or P3 wave - may
represent various functions, including the closure of sensory analysis, the update of working
memory, the attention and decisional processes, and in a motor task the facilitation of motor
pathways (Brunia et al. 1988). It is not the intent of this paper to enter in the very complex
ongoing discussion about the exact meaning of ERP in the 300 ms range.
García-Larrea and Cézanne-Bert elaborated a dual task P300 paradigm that is suitable for the
study of executive functions. Parkinsonian patients examined with a dual-task paradigm show
significantly greater ERP attenuation than age-matched controls, even in tasks not requiring
any motor response (García-Larrea et al. 1997, García-Larrea and Cézanne-Bert, 1998). This
36
suggests that the executive load imposed by the dual task is increased in Parkinson’s disease
independently of motor impairment. Our previous results have shown that, in contrast to the
other structures of the basal ganglia, the STN participates in the generation of P3 potentials
with a modified, but not a standard oddball, protocol (Baláž et al. 2008).
To the best of our knowledge, rTMS over the IFC has not been tested in PD patients or with
the oddball P3 protocols.
Methods
Patients
18 patients with L-DOPA-induced motor complications of Parkinson’s disease (12 men and 6
women with a mean age of 55.8 ± 6.52 years), indicated for DBS surgery by the Commission
for Neuromodulation Surgery of the Brno Movement Disorders Center, participated in the
study. The mean preoperative Unified Parkinson’s Disease Rating Scale (UPDRS) III was 43.6 ±
6.9 off medication, and 22.3 ± 4.1 in the on-medication state. The mean duration of the
Parkinson’s disease before the operation was 13.5 ± 2.3 years. All patients freely gave their
informed consent to participate in the study. The hospital ethics committee endorsed the
study. The patients were divided into two groups according to the area of rTMS stimulation (8
patients with DLPFC stimulation; 10 patients with IFC stimulation). No difference between the
groups regarding age, duration of disease, or the dose of dopaminergic treatment was present
(Table 1). There was no significant difference in neuropsychological status between these two
groups. All of the patients were assessed by a neuropsychologist before their inclusion on a
waiting list for the DBS surgery. No patients with psychiatric disorders, dementia, or
behavioral problems were included in the study.
Surgical procedure (STN-DBS)
The stereotactic procedure was performed using the Leibinger open frame with the Praezis
Plus software and the Talairach diagram. The STN coordinates used were in respect to the
anterior commissure-posterior commissure (AC-PC) line: typically 12.0 mm laterally, 5.0 mm
below and 3.0 mm behind the midpoint of AC-PC line (Lanotte et al. 2002). The implantation
procedure was performed in two steps. First, the stimulation leads (Medtronic Inc., Denmark)
37
were implanted bilaterally into the targeted structure by a stereotactic MRI-guided technique
under local anesthesia. The lead placement was established by microelectrode recordings,
which served as the reference for ascertaining the position of each contact (electrode pole)
within the STN and in relation to the adjoining structures. We used the standard tungsten
microelectrode 291 A (Medtronic, Inc., Denmark) with an impedance of 0.5–
intraoperative microrecording and microstimulation. The two most distal contacts were
usually placed within the STN, as established by a microelectrode recording.
The motor part of the STN was identified by recording the pattern of neuronal activity,
background activity, and motor responsiveness (changes in neuronal firing in response to
passive and active manipulation of contralateral limbs during the perioperative
microrecording). We determined the dorsolateral border of the STN by microelectrode
recording of cellular firing patterns (Benazzouz et al. 2002). We also assessed the planned lead
position by evaluating the symptom response to the intraoperative microstimulation. Once
the final target coordinates were determined, a permanent quadripolar DBS electrode
(Medtronic, model 3389 with 0.5 mm intercontact distance and 1.5 mm electrode contact
width) was implanted. The electrode position was verified by the intraoperative use of
fluoroscopy to compare the position of the trajectories of the microrecording electrodes with
the definitive trajectory of the quadripolar macroelectrode. This procedure was repeated for
the other side.
In the second step of the surgery, the electrode cables were internalized and a
neurostimulation device (Kinetra, Medtronic Inc., Minneapolis, USA) was implanted.
The period between these two steps of the operation ranged from 3 to 4 days. This period
served for functional assessment and testing of DBS efficacy during the external stimulation.
We used this period for our measuring of the event-related potentials (ERP) and for the rTMS
study as well. No stimulation of the STN was initiated during the days that were used for our
recordings.
Event related potentials (ERPs) measurements
The recording sessions were performed on the third day after the electrode implantation in
all the patients included in the study. The sessions were carried out in the same quiet room
38
during the morning hours. All patients were in an on-medication state during the ERP
recordings.
ERP recordings were performed using the TruScan amplifier system (Deymed Diagnostic, Alien
Technic, Czech Republic) with 32-channel capability. The time base ranged from 0 to 1200
milliseconds (ms); filter range: 0.2 hertz (Hz) – 70 Hz; sensitivity gain: 200 microvolts (uV);
sampling rate 256 Hz. We used a biauricular reference electrode and a silver grounding
electrode mounted to the skin in the left clavicle region.
We measured the amplitudes and latencies of ERPs elicited in two protocols.
The ERPs evoked by an auditory stimulus in the standard oddball protocol (Squires et al., 1975)
were recorded first, followed by the modified protocol with an increased involvement of
executive resources.
The auditory presentation of stimuli was identical for both protocols. Tones were delivered
through earphones with an interstimulus interval of 2 seconds: frequent tones were delivered
at 1000 Hz and 70 decibel (dB) for 0.1-second (s) duration; rare (target) tones were delivered
at 2000 Hz and 70 dB for 0.1 s duration. The tones were randomly generated at a 5:1 ratio
(standard-target). There were approximately 30 (29 to 32) target tones presented in each
protocol. We changed the number of tones between the protocols in order to maintain the
patient concentration on the task, as there were altogether 4 tests presented to patients
during the study (standard and modified protocol pre-rTMS and again post-rTMS).
In the first test, the subjects were instructed to recognize the target tones and to silently count
them in the standard protocol. They were asked to report the total number of target tones at
the end of recording session.
The second test used a modified auditory oddball paradigm involving increased demand on
the executive functions. García-Larrea and Cézanne-Bert elaborated this dual task for the P3
paradigm that proved to be suitable specifically for the study of executive functions in
Parkinson’s disease (García-Larrea et al. 1997, García-Larrea and Cézanne-Bert 1998). The task
in this condition consisted of silently changing two parameters of the date upon each target
presentation. Immediately prior to the recording, the subjects were given a two-item date
that included the day of the week and the ordinal date (e.g. Monday the 19th). The date had
to be updated after each target stimulus. The final outcome had to be presented at the end
of the recording session (García-Larrea et al. 1997).
39
The protocols were explained to the patients before the first performance, and patients were
briefly reminded before each respective recording with an identical set of instructions.
For technical reasons (the presence of externalized electrodes and their cables on the scalp
and time limitations due to the necessity of performing the ERP measurement immediately
after the rTMS) we did not perform any ERP recordings from the scalp. After the recording of
standard and modified protocol the rTMS was applied. After rTMS the recordings of both
protocols were repeated immediately.
rTMS
rTMS was applied using the Magstim Super Rapid stimulator (Magstim Company, Whitland,
UK) and a figure-of-eight air-cooled coil (7 cm mean diameter). For the sham stimulation, we
used the same stimulator and a sham coil with an identical shape, but without the air cooling
and with minimum output.
Each patient had a brain magnetic resonance image (MRI) completed prior to the rTMS study.
The brain image was acquired and transformed into the standard (Montreal Neurological
Institute) stereotactic space using affine transformations (Jenkinson and Smith, 2001). Using
a frameless optically guided stereotactic system, the coil was placed over the appropriate
location over the scalp as marked on the MRI. During the stimulation, the coil was held
tangentially to the scalp with the handle pointing back and inducing a current flow in the
postero-anterior direction.
The coil was well fixed at the stimulation site and the position of center of the coil in relation
to the target was constantly monitored on the computer screen. The coil could be adjusted if
necessary to maintain the constant alignment of coil and targeted area to within 1 mm. The
examined patient’s chin was leaning over the holder fixed to same aluminum frame as the
coil. Frameless stereotaxy (Brainsight Frameless 1.5; Magstim Company, Whitland, UK) was
used to target the optimal position of the stimulated site and to ensure the same cortical area
stimulation in all patients. The coordinates for the IFC [X = 42, Y =26, Z = 16] were used based
on a study of inhibition in a go-no-go paradigm (Aron and Poldrack, 2006). The coordinates for
the DLPFC [X = 39, Y =26, Z = 47] were selected in accordance with previous studies
(Vanderhasselt et al. 2006; Kaffenberger et al. 2008).
40
The coil was kept at the appropriate stimulation site with only negligible deviations during the
stimulation. The position of the coil, the recording electrodes, and the areas that were
stimulated by rTMS is shown in Figure 1.
The part of the cortex modulated by the rTMS was probably limited to the stimulated area, as
a frameless stereotactic system was used for coil focusing and a low-intensity stimulation (80%
of motor threshold) was used. A spread to dispersed interconnected areas has been reported
only at higher intensities (Siebner et al. 2003). The area of spherical 8-cm-radius surface
defined by the half-maximum of the induced electric field, i.e. the quarter-maximum of power,
was approximately 20cm² for our coil, as calculated according to previous data (Hallett and
Chokroverty 2005). The distance between the peak of this surface and a point located at its
border defined above is approximately 25mm. The IFC and PFC can be treated as two points
on this surface. As the distance between them is more than 30mm, the stimulation power at
the non-target point will be less than a quarter of the stimulation power. at the target point.
One rTMS session (600 pulses) of 1 Hz stimulation was delivered to each patient over the area
of the right inferior frontal cortex (Brodmann area 44) or over the right DLPFC (Brodmann area
9, 46). The right side was selected for technical reasons – the externalized outlets of deep
brain electrodes were located over the left parietal part of the skull. No patient had the
stimulation applied over both the DLPFC and the IFC. In four patients who were stimulated
over the IFC, sham stimulation was also applied. The time difference between the sham and
active stimulations was approximately 24 hours in order to avoid any possible prolonged rTMS
effect on the intracranial recordings. The reason for using the sham stimulation only in some
of the patients was purely technical. At the beginning of our study, we had no sham coil
available.
rTMS was given with an intensity corresponding to 80% of the resting motor threshold (MT).
The MT was measured as the lowest intensity capable of producing motor evoked potentials
(MEPs) in the right first dorsal interosseus muscle. The threshold was determined for relaxed
muscle.
In summary, the stimulation parameters were: 1 Hz rTMS frequency, one block of 600 pulses
comprised of 60 pulses in 10 trains; 80% resting motor threshold intensity; the total number
of stimuli did not exceed 600 pulses per day.
41
One study reports that the influence of rTMS on cognitive functions can last up to 60 minutes
and depends on the site and the frequency of the stimulation (Evers et al. 2001). Another
report finds that the effect of 1 Hz stimulation with an intensity of 90% of motor threshold on
the cortex lasts about 15 minutes (Gerschlager et al. 2001). We performed all post-rTMS
measurements within 15 minutes (a single protocol lasted about 5-6 minutes).
Data analysis
The data related to target (rare) stimuli were further analyzed. The segments with artificial
signals (artifacts - such as ones caused by the movement of the patient - were removed). The
main ERP cognitive component was identified visually, off-line) and quantified by its latency
and amplitude parameters. The peak latencies were measured from the stimulus onset. We
evaluated the first distinctive potential, regardless of polarity, to appear approximately in the
200-600 ms window as the cognitive ERP.
The processing steps included a statistical evaluation of the qualitative data (an assessment
of clearly visible changes of latencies) and a quantitative data analysis (a comparison of values
of the amplitudes and latencies of the ERPs in respective paradigms). The ANOVA and Tukey
post-hoc test was used for the analysis of latencies. The latencies of the ERP peaks in both
standard and modified paradigms in both conditions (before and after rTMS was applied) were
compared.
Results
rTMS with 1 Hz frequency over the right IFC caused a statistically significant shortening of
latencies of ERPs in both standard and modified protocols. These changes were observed
invariably in all patients. No such changes were observable either after the sham rTMS of IFC
or after the active rTMS of the DLPFC area.
We found a voltage change – a steep rise in amplitude – in the ERPs recorded during the
modified protocol (dual task) compared to the standard protocol within the STN in 34 of the
36 electrodes available for the generator potential evaluation. These amplitude changes were
described earlier (Baláž et al. 2008). There were no changes of motor symptoms observed
after the rTMS of DLPFC or IFC in any of the patients.
1. IFC active stimulation
42
The rTMS led to a shortening of latencies in both protocols in all patients (Tables 2, 3). Overall,
the mean latencies of ERP in the standard protocol were 277 ± 14 ms before the rTMS and
252 ± 19 ms after the rTMS. In the modified protocol, the mean latency changed from 296 ±17
ms to 270 ± 20 ms. The statistical significance of both latency changes reached p<0.000001.
(ANOVA - F(3, 267)=30,167) and p=0.000017 according to the post-hoc Tukey test. A typical
latency change in a single patient is shown in Figure 2.
The changes of latencies were statistically significant on both occasions and there was no
statistical difference between the ERP latency of the standard protocol and the modified
protocol.
Amplitudes of ERPs were only slightly changed after the 1 Hz rTMS. The amplitudes were
slightly decreased in both the standard and modified protocols. The decrease was however
not statistically significant (Table 4).
2. IFC sham stimulation
In four patients (FK, JH, BK, RZ), sham rTMS stimulation was also used. There were no changes
in either the latencies or the amplitudes after the sham stimulation. The waveforms of ERPs
before and after rTMS in both protocols were almost identical, with no difference in latencies
(277 ± 1 ms before rTMS and 276 ± 1 ms after rTMS in the standard protocol, and 299 ± 1 ms
and 299 ± 1 ms in the modified protocol).
3. DLPFC active stimulation
There was no statistically significant change in latencies after the stimulation of DLPFC (Figure
3). We found only a minimal change in the latencies (Table 3). In the group of 8 patients, the
mean ERP latency changed from 274 ± 5 ms to 280 ± 5 ms after the rTMS in the standard
protocol, and from 289 ± 3 ms to 299 ± 4 ms after the rTMS in the modified protocol. This
latency difference was not found to be statistically significant (p=0.2649 - post-hoc Tukey test).
The amplitude changes were not present.
There were no noted effects of the rTMS of either area or of the sham stimulation on the test
performance of the patients. The number of errors in the counting of target signals (standard
43
protocol) or the reporting of the date and the day of the week (modified protocol) were not
statistically different between the two groups.
Discussion
In this study, we recorded cognitive ERPs using standard and modified auditory oddball
paradigms, where the latter was modified by an increased demand on executive functions.
The main component of the ERP appeared in the P3 time window. The P3, as the late positive
complex of event-related potentials, is the most conspicuous and widely used of the cognitive
ERPs. An ERP in the 300 ms range may represent various functions, such as the closure of
sensory analysis, the update of working memory, the attention and decision processes, and
the facilitation of motor pathways in motor tasks (Brunia and Damen, 1988, García-Larrea and
Cézanne-Bert 1998, Verleger 1997). The shape of intracerebral potentials frequently varies,
and it is often difficult to identify the equivalents of individual components recorded on the
scalp (Rektor et al. 2003 and 2004). We prefer to state that a cognitive process that shares
critical common features with the P3 wave very probably elicited the ERP in this study.
We applied the rTMS over the IFC or DLPFC in an attempt to study the impact of modulation
of the cortical excitability on ERP potentials recorded from the area of the STN.
1 Hz rTMS over the right IFC led to shortening of ERP latencies in both protocols. The
correlation between neuropsychological test performance and P300 latency from earlier
papers indicates that individual latency variability is related to mental processing speed, with
peak timing affected by cognitive operations specific to perceptual and attentional processing
(Polich and Herbst 2000). The speed of executive processing is thus reflected by the latency
duration. It seems that the 1 Hz rTMS over the IFC might have facilitated the executive
processing.
In contrast to the DLPFC, the IFC is linked with the STN via direct anatomical pathways , namely
the hyperdirect pathway (Nambu 2004). This cortico-subthalamo-pallidal “hyperdirect”
pathway inhibits the large areas of the thalamus and cerebral cortex that are related to both
the selected motor program and other competing programs (Nambu, 2002).
The IFC itself is proposed to have an inhibitory effect on cognition and executive control (Aron
et al. 2004). It was also suggested that the IFC excites the STN and so suppresses basal-ganglia
thalamocortical output (Aron and Poldrack 2006). This is in line with our results, because if
44
we assume that the 1-Hz rTMS had an inhibitory effect on the IFC, the overall result could be
a facilitation (by the release of the downstream structures from the IFC-STN control) of the
cognitive function reflected by the shortening of P3 latencies. We also found the P3
shortening both in the standard and modified protocols, making an inhibitory effect on
executive control very likely.
The observed effect of the rTMS of IFC on P3 latency can be interpreted as disinhibition of IFCSTN
influence on the structures further downstream. The rTMS of IFC might have interfered
with the normal ability of the STN to slow some cognitive processes (Frank et al. 2007).
It is of interest that the P3 was also shortened not only in modified but also in the standard
protocol, which was deemed not to be generated within the STN. We assume that the P3
generation recorded from the STN area might have also included other structures. The
candidates for such structures include the thalamus, and there are several areas very close to
the STN that might produce a standard P3-like potential, i.e. the zona incerta or substantia
nigra. It has been shown that there are some thalamic nuclei that generate P3 potentials,
namely the posterolateral nucleus, while some other do not, i.e. the ventroposterolateral
nucleus (Rektor et al. 2001).
According to our results, rTMS over the DLPFC had no effect on ERPs recorded from the STN.
The DLPFC is part of the prefrontal cortico-basal ganglia-thalamocortical circuits and is a
cortical region with major involvement in executive functions. Some authors presume the
existence of an indirect communication between the DLPFC and the STN via the substantia
nigra pars reticularis (Ilinsky et al. 1985, Barbas et al. 1991). It may be assumed that the STN
could participate in the executive functions as a part of a cortico-basal ganglia-thalamocortical
loop in close cooperation with DLPFC (Fig.4 A). Our data do not exclude the cooperation
between the DLPFC and STN. We have taken into account that there exists a quite important
segregation of information from various cortical areas to STN (Kolomiets et al. 2001, Strafella
et al. 2004). Therefore our study do not by any means exclude the cooperation between the
DLPFC and STN in other domains.
An interesting point is the influence that the various frequencies of rTMS can have over
various cortical regions. It is well known that a 1Hz-rTMS over the motor cortex has an
inhibitory effect on the motor function, but we lack consistent data regarding its effect on the
IFC. The rTMS of cortical areas has been shown to influence the P3 wave recorded on the scalp
by earlier studies. The 10 Hz rTMS over the frontal area in non-PD patients led to a delay of
45
the P3 component and thus presumably prolonged the cognitive processing (Jing et al. 2001).
The 10 Hz rTMS over the DLPFC was shown to have no significant effect on motor status in PD
(Olmo et al. 2007), while the 15 Hz rTMS over the left DLPFC has the potential to improve
cognitive functions in PD patients (Boggio et al. 2005) or patients with cerebrovascular disease
(Rektorová et al. 2005).
One limitation of the present study is the determination of an exact location for the recording
contacts within the STN. Due to the small volume of the STN and the absence of phase
reversals, we cannot fully exclude the possibility that some potentials were generated
adjacent to the STN and not directly within the nucleus. The presence of the cognitive ERP in
the motor part of STN could be explained by the overlap of neuronal populations in this
structure. The electrophysiological data indicate that the overlap in the STN may well be
present, as the segregation of cortical information flow that exists in the striatum is only partly
maintained in the STN (Kolomiets et al. 2001).
The characteristics of the electrodes used, especially the relatively small lead volume and
short intercontact interval, enabled a relatively precise localization of the signal source.
As we recorded in the early postoperative phase, it is possible that the microlesion effect
might have been present. However, we do not expect that a microlesion effect could have
influenced the changes in ERP latencies that we observed after the rTMS of IFC.
Recordings of ERP have been performed in patients treated for Parkinson’s disease for many
years. As has been shown by García-Larrea and others (Tachibana et al. 1997), Parkinson’s
disease itself influences P3 recordings.
The on-medication state was selected to ensure the best comfort and concentration for the
patients during the recording-stimulation-recording session. However, from the available
literature it is possible to assume that the L-DOPA itself could improve the P300 latency (Oshi
et al. 1996). Also according to the work of Stanzione (Stanzione et al. 1991) the P3 latency is
decreased in PD subjects after L-DOPA administration. On the other hand, only an insignificant
shortening of P300 latency after L DOPA was described in patients who had been newly
diagnosed with PD (Prabhakar et al. 2000). It seems that central cognitive processing is only
weakly linked to the motor functions, and thus we did not expect any major changes in overall
results if the patients would be examined in the off-L-DOPA condition.
Simultaneous DBS external stimulation was not contemplated due to time reasons (possible
limited duration of post-rTMS modulation of activity of DLPFC and/or IFC) and also due to
46
possible artifact generation. Furthermore, as has been shown, DBS does not improve the P3
recorded from the scalp (Gerschalger et al. 2001).
The behavioural tests following the TMS were not performed due to the paucity of time and
due to the demands of the experimental protocol on the patients themselves. Patients had to
perform each task altogether four times in the experimental design (twice for the standard
protocol and twice for the modified protocol). The overall appearance of tiredness in the
patients was assessed by the examiners as unsuitable for further testing. Furthermore, the
evaluation of interpatient behavioural data would be quite difficult (e.g. due to different
patients who were included into the groups of either DLPFC or IFC stimulation, the uncertainty
regarding the duration of rTMS effect and possible changes in behavioral results caused by
this effect).
Based on our data we cannot rule out the possibility that the rTMS of cortical structure could
facilitate parallel cortical-subcortical processing within the basal ganglia-thalamo-cortical
loop. However, we find very intersting, that such change was not present by the direct
stimulation of the DLPFC.
The cortical recordings of the evoked potentials were not performed mainly due to various
technical reasons. Therefore the conduction latency between cortical and subcortical
potentials could not be ascertained and this shortcoming can limit the impact of our study.
Experiments concerning the measurement of this latency can be performed in the future.
Conclusion
The cognitive processing of information in the BG appears not to follow the generally accepted
model of cortico-BG-thalamocortical circuits. The involvement of the STN in cognitive
activities is selective and specific. As we stated in our earlier paper, the standard oddball
protocol did not generate ERP waves in the STN, in contrast to a protocol modified by an
increased load of executive functions. Overall, the findings from this and earlier studies
indicate that the STN plays an active role in processing executive functions in patients with
Parkinson’s disease, probably outside of the classical cortical-basal ganglia-thalamic circuits.
Direct cortico-STN connections bypassing these circuitries could explain the modulation of the
STN. A candidate for such connection is the “hyperdirect” pathway between the inferior
frontal cortex and the STN pathways. In summary, rTMS of IFC and not of DLPFC influenced
47
the P3 recorded in the STN area, indicating that an important role is played by the IFC-STN
pathway in executive functioning.
Our findings may suggest that a certain effect of DBS on cognitive performance could be
caused by the modulation of the “cognitive” neuronal pools in the STN by surgery and/or
stimulation. Determining the exact role of the STN in cognition remains an important and
interesting challenge for future research, and further data are needed to understand the
direct clinical implications of our results.
Acknowledgements:
Funding: Research program of Czech Ministry of Education - MSM 002 162 2404
The authors declare that they have no conflict of interest.
The authors would like to express thanks to Prof. Z. Novák and Dr. J. Chrastina for performing
all of the surgical procedures related to STN-DBS. We also thank A. Johnson for English
language corrections, R. Mareček for technical support and the anonymous reviewers for their
valuable comments and suggestions.
References
Afsharpour S (1985) Topographical projections of the cerebral cortex to the subthalamic
nucleus. J Comp Neurol 236:14–28
Albin RL, Young AB, Penny JB (1989) The functional anatomy of basal ganglia disorders. Trends
Neurosci 12:366–375
Aron AR, Robbins TW, Poldrack RA.Inhibition and the right inferior frontal cortex. Trends Cogn
Sci. 2004 Apr;8(4):170-7
Aravamuthan BR, Muthusamy KA, Stein JF Aziz TZ, Johansen-Berg H (2007) Topography of
cortical and subcortical connections of the human pedunculoopontine and subthalamic nuclei.
NeuroImage 37: 694-705
Aron AR, Poldrack RA (2006) Cortical and subcortical contributions to stop signal response
inhibition: role of the subthalamic nucleus. J Neuorsci 26 (9):2424-33
48
Baláz M, Rektor I, Pulkrábek J (2008) Participation of the subthalamic nucleus in executive
functions: An intracerebral recording study. Mov Disord 23(4):553-7
Bares M, Rektor I, Kanovský P, Streitová H (2003) Cortical and subcortical distribution of
middle and long latency auditory and visual evoked potentials in a cognitive (CNV) paradigm.
Clin Neurophysiol 114(12):2447-60.
Benabid AL, Koudsie A, Benazzouz A, Le Bas JF, Pollak P (2002) Imaging of subthalamic nucleus
and ventralis intermedius of the thalamus. Mov Disord 17 Suppl 3:S123-9
Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL (2002) Intraoperative
microrecordings of the subthalamic nucleus in Parkinson's disease Mov Disord 2002;17 Suppl
3:S145-9
Berendse HW, Groenewegen HJ (1991) The connections of the medial part of the subthalamic
nucleus in the rat: evidence for a parallel organisation. In: The basal ganglia III (Bernardi G,
Carpenter MB, DiChiara G, Morelli, M, Stanzione P, eds). Plenum, New York, pp 89–98
Bočková M, Chládek J, Jurák P, Halámek J (2008). The novelty P3 in the subthalamic nucleus.
An intracerebral recording study. Mov Disord 23, Suppl 1:230
Boggio PS, Fregni F, Bermpohl F, Mansur CG, Rosa M, Rumi DO, et al (2005) Effect of repetitive
TMS and fluoxetine on cognitive function in patients with Parkinson's disease and concurrent
depression. Mov Disord 20(9):1178-84
Bolam JP, Magill JP, Bevan MD (2002) The functional organization of the basal ganglia: new
insights from anatomical and physiological analyses. In: The basal ganglia VII (Nicholson LFB,
Faull RLN, eds). Plenum, New York, pp 371–378
Brunia CHM, Damen EJP (1988) Distribution of slow brain potentials related to motor
preparation and stimulus anticipation in a time estimation task. Electroenceph Clin
Neurophysiol 69:234–243
49
Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA (1990) Afferent connections of the
subthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study
in the rat. Brain Res 513:43–59
Chudasama Y, Baunez C, Robbins TW (2003) Functional Disconnection of the Medial Prefrontal
Cortex and Subthalamic Nucleus in Attentional Performance: Evidence for Corticosubthalamic
Interaction. J Neurosci 23(13):5477–5485
Croxson PL, Johansen-Berg H, Behrens TE, Robson MD, Pinsk MA, Gross CG, Richter W, Richter
MC, Kastner S, Rushworth MF (2005) Quantitative investigation of connections of the
prefrontal cortex in the human and macaque using probabilistic diffusion tractography. J
Neurosci 28(39):8854-66
Evers S, Böckermann I, Nyhuis PW (2001) The impact of transcranial magnetic stimulation on
cognitive processing: an event-related potential study. Neuroreport 12 (13):2915-18
Frank MJ, Samanta J, Moustafa AA,Sherman SJ ( 2007) Hold Your Horses: Impulsivity, Deep
Brain Stimulation, and Medication in Parkinsonism. Science 23:318, 5854, 1309-1312
García-Larrea L, Broussolle E, Cézanne-Bert G, Mauguiere F (1997) P 300 and “frontal
executive functions”: application of a dual-task paradigm in normal subjects and patients with
Parkinson’s disease and progressive supranuclear palsy. Electroencephalography. Clin.
Neurophysiol 103:148
García-Larrea L, Cézanne-Bert G (1998) P3, Positive slow wave and working memory load: a
study on the functional correlates of slow wave activity. Electroencephalography and Clinical
Neurophysiology 108:260-73
Gerschlager W, Siebner HR, Rothwell JC (2001) Decreased corticospinal excitability after
subthreshold 1Hz rTMS over lateral premotor cortex. Neurology 57:449-55
50
Gerschlager W, Bloem BR, Alesch F, Lang W, Deecke L, Cunnington R (2001) Bilateral
subthalamic nucleus stimulation does not improve prolonged P300 latencies in Parkinson's
disease. Journal of Neurology 248(4):285-9
Hallett M, Chokroverty S (2005) Magnetic Stimulation in Clinical Neurophysiology; 2nd Edition.
Butterworth-Heinemann, Philadelphia, pp. 106–120
Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano A (2004) The Subthalamic Nucleus in the
Context of Movement Disorders. Brain 127:4-20
Hoshi E (2006) Functional specialization within the dorsolateral prefrontal cortex : A review of
anatomical and physiological studies of non-human primates. Neurosci Res 54 (2):73-84
Jahanshahi M, Ardouin CMA, Brown RG, Rothwell JC, Obeso J, Albanese A, et al (2000) The
impact of deep brain stimulation on executive function in Parkinson’s disease. Brain
123:1142-54
Jenkinson M, Smith S. A global optimisation method for robust affine registration of brain
images (2001) Med Image Anal 5(2):143-56
Jiang Y (2004) Resolving dual-task interference: an fMRI study. Neuroimage 22(2):748-54
Jing H, Takigawa M, Hamada K, Okamura H, Kawaika Y, Yonezawa T, et al (2001) Effects of high
frequency repetitive transcranial magnetic stimulation on P300 event-related potential.
Clinical Neurophysiology 112 : 304-13
Journee HL, Postma AA, Staal MJ (2007) Intraoperative neurophysiological assessment of
disabling symptoms in DBS surgery. Clinical Neurophysiology 37: 467-475
Kaffenberger T, Baumgartner T, Koeneke S, Jäncke L, Herwig U (2008) Chronometric features
of processing unpleasant stimuli: a functional MRI-based transcranial magnetic stimulation
study. Neuroreport 19(7):777-81
51
Kitai ST, Deniau JM (1981) Cortical inputs to the subthalamic nucleus: intracellular analysis.
Brain Res 214:411–415
Kolomiets BP, Deniau JM, Mailly P, Ménétrey A, Glowinski J, Thierry AM (2001) Segregation
and convergence of information flow through the cortico-subthalamic pathways. J Neurosci
21(15): 5764-72
Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD,
Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five-year follow-up of bilateral stimulation
of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 349:1925–1934
Lanotte MM, Rizzone M, Bergamasco B, Faccani G, Melcarne A, Lopiano L (2002) Deep brain
stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome
correlations with the effects of stimulation. J Neurol Neurosurg Psychiatry 72(1):53-8
Maurice N, Deniau JM, Glowinski J, Thierry AM (1998) Relationships between the prefrontal
cortex and the basal ganglia in the rat: physiology of the corticosubthalamic circuits. J Neurosci
18:9539–9546
Oishi M, Mochizuki Y, Hara M, Du C-M, Takasu T (1996) Effects of Intravenous L-Dopa on P300
and Regional Cerebral Blood Flow in Parkinsonism. Int J Neurosci 85: 147 – 154
Nambu A, Tokuno H, Hamada I, Kita H, Imanishi M, Akazawa T, Ikeuchi Y, Hasegawa N (2000)
Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey. J
Neurophysiol 84(1):289-300
Nambu A, Tokuno H, Takada M (2002) Functional significance of the cortico-subthalamopallidal
hyperdirect pathway. Neurosci Res 43(2):111-17
Nambu A (2004) A new dynamic model of the cortico-basal ganglia loop. Progr Brain Res 134:
461-6
52
Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M, Jacobson CE
4th, Wang X, Gordon CW Jr, Zeilman P, Romrell J, Martin P, Ward H, Rodriguez RL, Foote KD
(2009) Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus
pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol 65(5):586-95
del Olmo MF, Bello O, Cudeiro J (2007) Transcranial magnetic stimulation over dorsolateral
prefrontal cortex in Parkinson's disease. Clin Neurophysiol 118(1):131-9
Prabhakar S, Syal P, Srivastava T (2000) P300 in newly diagnosed non-dementing Parkinson's
disease : effect of dopaminergic drugs. Neurol India 48:239
Rektor I, Kaňovský P, Bareš M, Louvel J, Lamarche M (2001)Event-related potentials, CNV,
readiness potential, and movement accompanying potential recorded from posterior
thalamus in human subjects. A SEEG study. Neurophysiol Clin 31:253-61
Rektor I, Kaňovský P, Bareš M, Brázdil M, Streitová H, Klajblová I (2003) A SEEG study of ERP
in motor and premotor cortices and in the basal ganglia. Clin Neurophysiol 114:463-71
Rektor I, Bareš M, Kaňovský P, Brázdil M, Klajblová I, Streitová H (2004) Cognitive potentials in
the basal ganglia - frontocortical circuits. An intracerebral recording study. Exp Brain Res 158:
289-301
Rektor I, Bareš M, Brázdil M, Kaňovský P, Rektorová I, Sochůrková D (2005) Cognitive- and
movement-related potentials recorded in the human basal ganglia. Mov Disord 20(5):562-8
Rektorová I, Megová S, Bareš M, Rektor I (2005) Cognitive functioning after repetitive
transcranial magnetic stimulation in patients with cerebrovascular disease without dementia:
a pilot study of seven patients. J Neurol Sci 15:157-61
Rossini PM, Barker AT, Berardelli A, Caramia MD, Carus G, Gracco RQ (1994) Non-invasive
electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and
53
procedures for routine clinical application. Report of an IFCN Committee. Electroencephalogr
Clin Neurophysiol 91:79-92
Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into
representational cortical plasticity. Exp Brain Res 148(1):1-16
Squires NK, Squires KC, Hillyard SA (1975) Two varieties of long-latency positive waves evoked
by unpredictable auditory stimuli in man. Electroencephalography and Clinical
Neurophysiology 1975;38:387-401
Stanzione P, Fattapposta F, Giunti P, D'Alessio C, Tagliati M, Affricano C, Amabile G (1991)
P300 variations in parkinsonian patients before and during dopaminergic monotherapy: a
suggested dopamine component in P300. Electroencephalogr Clin Neurophysiol 80(5):446-53
Strafella AP, Vanderwerf Y, Sadikot AF (2004) Transcranial magnetic stimulation of the human
motor cortex influences the neuronal activity of subthalamic nucleus. Europ J Neurosci
20(8):2245-2249
Strafella AP, Paus T, Barrett J, Dagher A (2001) Repetitive transcranial magnetic stimulation of
the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci
21(15): 157
Tachibana H, Aragane K, Kawabata K, Sugita M (1997) P3 latency change in aging and
Parkinson disease. Arch Neurol 54(3):296-302
Temel Y, Blokland A, Steinbusch HWM, Visser-Vandewalle V (2005) The functional role of the
subthalamic nucleus in cognitive and limbic circuits Progr Neurobiol 76:393–413
Temel Y, Kessels A, Tan S, Topdag A, Boon P, Visser-Vandewalle V (2006) Behavioural changes
after bilateral subthalamic stimulation in advanced Parkinson’s disease: a systematic review.
Parkinsonism Relat Disord 12(5):265-72
54
Vanderhasselt MA, De Raedt R, Baeken C, Leyman L, D'haenen H (2006) The influence of rTMS
over the right dorsolateral prefrontal cortex on intentional set switching. Exp Brain Res
172(4):561-5
Verleger R. (1997) On the utility of P3 latency as an index of mental chronometry.
Psychophysiology 34(2):131-56
Voon V, Kubu C, Krack P, Houeto JL, Tröster AI (2006) Deep brain stimulation:
neuropsychological and neuropsychiatric issues. Mov Disord 21, Suppl 14:S305-27
Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO, et al (2008) Neuropsychological
and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised,
multicentre study. Lancet Neurol 7(7):605-14
Zgaljardic DJ, Borod JC, Foldi NS (2006) An examination of executive dysfunction associated
with frontostriatal circuitry in Parkinson's disease. J Clin Exp Neuropsychol 28(7):1127-44
Table 1:
Demographic and clinical characteristics of the two study groups.
Group variables DLPFC stimulation group IFC stimulation group
Age (years) 56.8 ±5.4 55.1 ± 7.0
Male-female ratio 4:4 4:6
Disease duration before the
operation (years)
13.0 ±1.85 13.2 ±2.0
Dose of dopaminergic
medication (in milligrams of
L-DOPA equivalent)
1100 ± 380 1000 ± 240
Table 2:
Latencies (ms) of the ERPs before and after rTMS over IFC, in milliseconds (the average from
the STN contacts ± SD)
55
Modified protocol Standard protocol
Patient
initials
Before rTMS After rTMS Before rTMS After rTMS
OJ 297 ± 0 284 ± 1 268 ± 1 252 ± 2
MS 289 ± 1 253 ± 1 275 ± 1 233 ± 1
OV 318 ± 2 288 ± 1 248 ± 0 241 ± 1
LS 272 ± 3 246 ± 3 270 ± 2 219 ± 1
VN 297 ± 2 276 ± 2 280 ± 1 256 ± 1
JM 282 ± 0 266 ± 0 292 ± 1 255 ± 1
FK 323 ± 1 316 ± 1 293 ± 2 266 ± 2
JH 305 ± 0 292 ± 0 286 ± 2 265 ± 1
BK 315 ± 2 291 ± 2 297 ± 1 287 ± 1
RZ 298 ± 1 282 ± 0 275 ± 1 253 ± 1
Table 3:
Latencies (ms) of the ERPs before and after rTMS of DLPFC, in milliseconds (the average from
the STN contacts ± SD)
Modified protocol Standard protocol
Patient
initials
Before rTMS After rTMS Before rTMS After rTMS
BP 311 ± 1 312 ± 1 280 ± 1 283 ± 1
JZ 322 ± 2 321 ± 1 266 ± 1 267 ± 1
VM 290 ± 0 288 ± 0 277 ± 0 280 ± 1
56
DK 297 ± 1 296 ± 1 284 ± 1 284 ± 1
IT 368 ± 1 369 ± 2 302 ± 1.8 302 ± 2
JD 301 ± 1 311± 1 269 ± 1 274 ± 1
OS 381 ± 0 377 ± 1 314 ± 2 316 ± 0
AK 313 ± 0 318 ± 0 297 ± 1 299 ± 1
Table 4.
Amplitudes (μV) of modified ERPs before and after the 1 Hz rTMS of IFC (the average of all
measured amplitudes ± SD)
Before rTMS After rTMS p-value
Amplitude in
the STN
contacts
13.78 ± 6.84 12.23 ± 2.80 p < 0.18
Amplitude
outside of the
STN
12.80 ± 6.34 11.58 ± 3.96 p < 0.22
Figure legends:
Fig. 1. The relative position of recording electrodes, rTMS coil and stimulated regions. Green
line depicts the electrode trajectory, with cross denoting the tip of the recording electrode),
red dot covers the stimulated area. Blue coil is depicted schematically over the respective
stimulated region.
MR scans are from the individual patients from respective groups (A - DLPFC, B - IFC).
The anterioposterior difference between slices is 20 mm (A) or 19 mm (B) respectively.
Fig.2. Intracranial P3 recorded from the deep brain electrodes before (bold black line) and
after (bold grey line) the 1Hz-rTMS of IFC in the individual patient. Note the shortening of
57
latency after the 1Hz-rTMS is present (292ms versus 255 ms), highlighted by the arrows.
Depicted lines represent the target signal recordings from respective contacts of quadripolar
electrodes in modified protocol only. Recording electrode contacts are marked on the left (l1
to l4 – left side; p1 to p4 – right side). Contacts p1, p2 and l1, l2 are located within the STN
itself.
Fig.3. Intracranial P3 recorded from the deep brain electrodes before (bold black line) and
after (bold grey line) the 1Hz-rTMS of DLPFC in the individual patient. The shortening of latency
after the 1Hz-rTMS is insignificant (382ms versus 375 ms). Depicted lines represent the target
signal recordings from respective contacts of quadripolar electrodes in modified protocol only.
Recording electrode contacts are marked on the left (l1 to l4 – left side; p1 to p4 – right side).
Contacts p1, p2 and l1, l2 are located within the STN itself.
Figure 1
Figure 2
58
59
Figure 3
60
3.3 DBS amplitude setting can improve aspects of quality of life in patients with
Parkinson's disease
Published in: J Neural Transm. 2013 Apr;120(4):643-8. IF 2.9
Commentary.
In this paper we have reported various aspects of stimulation parameters and their influence
on quality of life. DBS amplitude setting can improve aspects of quality of life in patients with
Parkinson's disease (PD). DBS stimulation parameters are usually aimed on improvement of
motor symptoms of PD, such as tremor, rigidity, hypokinesia. Improvements in these aspects
brought along by DBS then lead to decrease of dyskinesia – involuntary momevements often
present in advanced stages of PD. Some effects of stimulation parameters on non-motor
symptoms of PD has been described earlier (Spottke et al, 2002). Correct stimulation setting
is a challenge for clinicians involved in DBS treatment. Major improvement of quality of life is
a goal of this non-curative, symptomatic invasive treatment.
24 patients with advanced PD who were treated by DBS STN were included in the study.
Setting of DBS parameters was thought to be optimal by investigators. However we have
noticed that a certain sub-group of patients requests further increase of stimulation
parameters, despite the significant improvement of their motor functions after DBS STN.
We decided to comply with patients' wishes, increase the stimulation and observe whether it
has any effect on their QoL. We used sham stimulation increase as a suitable way that would
enable us to assess whether the real stimulation increase was not related to possible placebo
effect. We believe that without using this approach we would be unable to compare the
benefit gained from the stimulation increase in selected group of patients.
We used disease-specific questionnaire, a PDQ-39 for assesment of patients quality of life
before and after stimulation parameter changes. We found out that after the further
amplitude increase in subgroup of patients (mean increase of amplitude of 0.35 V), there was
a statistically significant additional improvement of total PDQ-39 score by another 22.9 %. In
this group the emotions, stigma and communication subscales improved after the stimulation
increase, without further change of UPDRS III. These increases of stimulation thus did not lead
61
to further changes in motor functions but in improvement of certain non-motor functions. We
were able to demonstrate that the increase of stimulation parameters (amplitude) has a
potential to improve some non-motor functions and aspects of QoL and thus has an additional
effect on quality of life in certain subset of PD patients.
Meticulous observation of stimulation effects on various aspects of PD symptoms is
warranted.
Quality of life scales such as the PDQ-39 and questionnaires should become an integral part
of the clinical protocol for patients admitted to a Parkinson’s disease surgical program. This
may help to identify factors that affect the patient’s quality of life other than the motor
activity.
DBS amplitude setting can improve aspects of quality of life in patients with Parkinson's
disease.
Marek Baláž 1,2, Martina Bočková 1,2 and Ivan Rektor 1,2
1 1st Department of Neurology, St. Anne’s University Hospital, Faculty of Medicine, Masaryk
University, Brno, Czech Republic
2 CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Corresponding author:
Ivan Rektor, MD, PhD
1st Department of Neurology, St. Anne’s University Hospital, Faculty of Medicine, Masaryk University
Pekarska 53, 656 91 Brno, Czech Republic
e-mail: ivan.rektor@fnusa.cz, telephone: + 420 603 864 046
Key words: Deep brain stimulation (DBS); Subthalamic nucleus (STN); Non-motor symptoms;
Quality of life.
Abstract:
62
Objective:
The DBS STN is a non-curative treatment, its effect on the patient's quality of life (QoL)
determines the therapeutic success of this procedure. We aimed to assess whether
stimulation parameters setting may influence also some of the non-motor aspects of QoL.
Methods:
The QoL was assessed by PDQ - 39 questionnaire. The questionnaire was administered to
patients before and after the DBS surgery. A sham change of stimulation amplitude was
performed before the actual increase.
Results:
After the further amplitude increase in subgroup of patients (mean increase of amplitude of
0.35 V), there was a statistically significant additional improvement of total PDQ-39 score by
another 22.9 %.
In this group the emotions, stigma and communication subscales improved after the
stimulation increase, without further change of UPDRS III.
Conclusion
We were able to demonstrate that the increase of stimulation parameters (amplitude) has a
potential to improve some non-motor functions and aspects of QoL and thus has an additional
effect on quality of life in certain subset of PD patients. The meticulous observation of QoL
should be a routine part of assessments before and after the DBS STN surgery, and can even
aid during the parameter setting.
Introduction:
High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred
surgical treatment for motor symptoms of advanced Parkinson’s disease (PD). As the DBS STN
is a non-curative treatment, its effect on the patient's quality of life (QoL) determines its
therapeutic success. Several studies have shown that this procedure indeed improves QoL in
PD (Deuschl et al, 2006);(Weaver et al, 2009).
63
The non-motor symptoms are prevalent in PD. In many patients the QoL appears to be
impaired more by the non-motor symptoms of PD than the motor ones (Schrag et al, 2003;
Volkmann et al, 2009) .
Non-motor factors may reasonably be included in the selection of surgical target for deepbrain
stimulation (Follett et al, 2010).
Quality of life in PD patients is influenced by motor and several non-motor aspects of the
disease. The most prominent non-motor symptoms are depression, sleep problems and pain
(Schrag et al, 2003; Schrag et al, 2000). Social aspects, such as communication, social support
and disease burden impair the quality of life as well. Progression of PD and disease severity is
associated with a decline in quality of life, but the exact longitudinal course and the
contributing factors are not well established.
Sufficient voltage is required to achieve desired clinical effects of the stimulation, however the
likelihood of side effects increases (Kuncel et al, 2004). The change of stimulation parameters
is usually reflected by the improvement of motor symptoms of the PD.
We have noticed that a certain sub-group of patients requests further increase of stimulation
parameters, despite the significant improvement of their motor functions after the DBS STN.
We decided to comply with patients wishes, increase the stimulation and observe whether it
has any effect on the QoL. We decided to use sham stimulation increase as a suitable way
that would enable us to assess whether the real stimulation increase was not related to
possible placebo effect. We believe that without using this approach we would be unable to
compare the benefit gained from the stimulation increase in selected group of patients.
We specifically aimed to assess whether stimulation parameters setting may influence also
some of the non-motor aspects of QoL.
Methods:
We compared stimulation amplitude and its relation to QoL measured by PDQ-39 scale and
NMS-Q, Non-motor symptoms questionnaire (Chaudhuri et al, 2006).To our study we included
two groups of patients with PD, 36 months after the DBS STN surgery.
64
Patients
Each group consisted of 12 patients with similar clinical profile (duration of disease, timing of
DBS surgery in course of PD, L DOPA dose, age, stimulation amplitude). Group A consisted of
12 patients (8 men, 4 women). These patients requested further increase of stimulation
parameters, despite clinically significant improvement of their motor functions after the DBS
as judged by experienced clinician (by rating of UPDRS III subscale). Average duration of the
disease at the time of the operation was 11.4 ± 3.5 years. Average age was 59.6 ± 7.8 years.
Group B consisted of 12 matched patients (7 men, 5 women) who were satisfied with their
overall clinical condition 3 years after the surgery. The characteristics of both patients groups
are presented in Table 1.
There were no neuropsychological disturbances, including the impulsivity change in either
group A or B. no neuropsychological disturbances, including the impulsivity change were
presemt in either of the groups.
Procedure:
The initial coordinates for the STN (dorsolateral part) were determined in reference to AC - PC
line (defined on the primary registration series) using indirect technique, typically 11-12 mm
lateral to and 3 mm posterior to and 5 mm ventral to intercommisural point. The final target
coordinates and electrode position were then modified with respect to direct visualisation of
STN on T2 fat sat scans and relationship of the STN to red nucleus anterior margin and largest
red nucleus crossectional area. The intraoperational microrecording and timulation were
used. There was no difference in final electrode position between the groups of patients
reported in this paper.
Assessments
The QoL was assessed by PDQ - 39 questionnaire (Jenkinson et al, 1997). The questionnaire
was administered to patients before the DBS surgery, and at 36 months after the surgery. In
both groups the assessment of QoL was repeated again, 2 months after the change of
stimulation parameter settings (performed in group A only).
65
The NMS-Q was filled in by the patients in Group A before the stimulation parameters were
increased and then again after two months. The effect of stimulation increase on individual
items of NMS-Q was recorded. The NMS-Q assessment was based on patient response with
“yes” and “no” in. An item was considered to be improved, as long as there was a change in
answer from “yes“ to “no“ in statistically significant number of patients.
Stimulation settings change
The stimulation parameters change in this preliminary study was an increase of stimulation
amplitude by 0.3 V to 0.5 V. Average amplitude increase was 0.35 V (± 0.1). The frequency
(130Hz) and pulse width (90us) were not adjusted. The stimulation increase did not lead to
dyskinesia or any other side effects in these selected patients.
A sham change of stimulation amplitude was performed before the actual increase. During
the sham stimulation change the patients were informed about the parameter increase,
which, in fact, did not occur. After two months of sham stimulation change, the actual
stimulation increase described below was performed. The sham stimulation increase was
performed in both group A and B. After the real change of stimulation amplitude settings
(performed in group A only) the assessment of QoL was performed again.
The stimulation increase did not lead either to dyskinesia or any other side effects in these
selected patients. The UPDRS III did not change either.
Statistical analysis
The ANOVA and Tukey test were used to evaluate differences between respective subscales
and the groups of patients.
Table 1:
Patient groups data before and 36 months after the DBS
Average values (± SD) of UPDRS II and III scores and PDQ-39 score. LDOPA equivalent daily
dose equivalent (LEDD) is shown in mg of the average daily dose. There were no statistically
significant differences in the overall improvement between the two groups. Group A – patient
with subsequent stimulation increase, B – control group.
66
Before DBS (medication
off)
36 months after DBS
(medication off/stimulation on)
p value average
of both groups
(difference 36
months vs.
Before DBS)
GROUP A GROUP B GROUP A GROUP B GROUP A/B
UPDRS II 21 ± 4 20 ± 5 18 ± 3 17 ± 3 0.032/0.034
UPDRS III 43 ± 8 42 ± 7 26 ± 5 24 ± 5 <0.0001 both
LEDD (mg) 1002 ± 305 1012 ± 274 600 ± 280 580 ± 240 <0.0001 both
Stimulation
amplitude* (V)
_________ __________ 2.8 V ± 0.4V 2.7 V ± 0.4V -
PDQ-39
(overall score)
74 ± 12 71 ± 10 48 ± 10 40 ± 12 0.00123/0.00142
* The frequency and pulse width were 130 Hz and 90 us in all these cases.
Results:
The quality of life significantly improved after the DBS in both groups of patients as shown by
the improvement in UPDRS III score. However, group A (patients demanding the stimulation
increase) showed less pronounced improvement of QoL (especially in emotions subscale)
compared to group B (Table 2, Table 3). After the further amplitude increase in group A (mean
increase of amplitude of 0.35 V), there was statistically significant additional improvement of
total PDQ-39 score by another 22.9 % (Fig. 1). In group A the emotions, stigma and
communication subscales improved after the stimulation increase. The UPDRS III did not
improve further, however.
After the sham stimulation increase in group B, there was no further improvement of either
motor or non-motor function present (Table 3).
A sham stimulation increase did not cause any change in PDQ-39 scale or NMS-Q.
67
The motor improvement observed in our study (UPDRS III improvement of 40 % or 43 % in
our groups) is in line with outcomes reported in several studies (Rodriguez-Oroz et al, 2005;
Simuni et al, 2002).
Table 2:
QoL subscale changes in both groups. Note the statistically significant improvements in
Emotions, Stigma, Social support and Communication subscales
PDQ - 39 Before DBS 36 months after DBS p values, 36 months
versus before the DBS
GROUP A GROUP B GROUP A GROUP B GROUP A GROUP B
Mobility 64 66 27 32 <0.0001 <0.0001
Activity of daily
living
35 37 26 28 0.11 0.27
Emotions 40 42 25 26 0.017 0.015
Stigma 50 48 27 21 0.0007 0.0002
Social support 30 28 16 17 0.014 0.021
Cognition 33 32 30 31 0.24 0.23
Communication 39 42 21 22 0.001 0.001
Body
dyscomfort
25 24 17 16 0.1120 0.1230
Table 3 Significantly improved subscales in individual patients of Group A (after the actual
stimulation parameter increase compared to sham stimulation change). No change in nonmotor
scales were present in group B after the sham stimulation change.
Group A Group B
68
At 36
months
After the
actual
increase
After the
sham
increase
At 36
months
After the
sham
increase
PDQ - 39
Overall score
48±12 37±10 47±13 38±10 39±10
Mobility 30±11 26±9 31±10 32±12 33±12
Emotions 25±8 19±10 25±8 26±9 25±9
Stigma 19±6 16±8 19±7 21±10 21±10
Communication 22±7 18±6 21±6 22±10 24±10
UPDRS III (med
off/stim on)
24 ± 5 23±4 24±5 26 ± 5 25 ± 5
Discussion:
We report improvement in PDQ-39 score of approximately 32 % after three years of DBS STN.
This result is in line with previous observation. As was noted in recently published
metaanalysis (Martinez-Martin et al, 2012) ,considering four class I studies on bilateral STN
published to date (Deuschl et al, 2006; Esselink et al, 2004; Follett et al, 2010; Williams et al,
2010) with a total of 855 patients (mean: 214; 34–366) and mean follow up of 12 months, the
average improvement in HRQoL using the PDQ-39 was 15.4 %. These results are lower than
those reported in reviews dating 4 or 5 years ago, where published trials on bilateral
subthalamic DBS showed a HRQoL improvement of 60.5% in generic measures (MartinezMartin
et al, 2007) and 33.8–34.5 % in disease-specific scales (Kleiner-Fisman et al, 2006;
Martinez-Martin et al, 2007).
Our observations suggest that the DBS may have a certain beneficial effect on non-motor
features and social aspects of the disease and also on patient's evaluation of the disease
stigma, at least in some patients.
In our study the emotions, stigma and communication as evaluated by the PDQ-39 improved
after the stimulation increase.
69
The overall NMS Q score showed no further improvement after two months of stimulation
increase. However, there was a significant improvement – i.e. significant number of patients
reported improvement in questions 13 (loss of interest), 22 and 23 (daytime sleepiness,
difficulty getting to sleep).
Both PDQ-39 scale and NMS-Q showed a partial amelioration of non-motor signs and nonmotor
aspects of QoL.
The selection of stimulation parameters for these patients may be insufficient if based only on
the purely motor assessment.
Several open studies found marked improvements in physical and psychosocial aspects of
HrQoL after STN stimulation, using generic or PD-specific scales (Spottke et al, 2002).
In general, non-motor symptoms of PD, such as mood disturbances, drive problems, pain
or sleep disorders, have an impact on HrQoL, which may equal or exceed the influence of
motor impairment (Volkmann et al, 2009). Well-known motor problems after STN-DBS, such
as poor gait, balance, or speech, had surprisingly little impact on HrQoL in this study.
A recent large short-term randomized controlled multicenter study compared HrQoL in a
group of 156 patients with severe motor symptoms of Parkinson’s disease, who were
randomly assigned in pairs to receive either bilateral DBS of the STN in combination with
medical treatment or best medical therapy alone (Deuschl et al, 2006).
At 6 months, an improvement of HrQoL (PDQ-39 score) by about 25 % was found only in the
surgically treated group, indicating that the symptomatic benefits of STN-DBS outlast the
inherent surgical risks and lead to more effective reduction of the burden of disease than
optimal drug therapy. An extended observational period, however, is necessary to assess the
stability of these results along the chronic course of PD.
The prospective study of Volkmann et al. (2009) found out sustained improvements in HrQoL
at 3 to 4 years in a relatively large proportion of parkinsonian patients that suffered from
substantial disability at baseline despite best medical treatment.
On the other hand, the work of Drapier et al.(Drapier et al, 2005) using patient's selfassessment
scales showed the clinical benefit of STN DBS on non-motor signs was quite
subtle; physical items of QoL significantly improved, whereas mental items such as emotional
well-being, social support, cognition and communication showed no improvement. The
70
authors suggest a dissociation of motor and non-motor symptoms control after bilateral STN
DBS in PD patients.
In a study by Witjas and colleagues, patients implanted with bilateral STN DBS experienced
significant benefits with sensory/painful fluctuations, dysautonomia (excessive sweating), and
cognitive fluctuations (Witjas et al, 2007). In another study by Zibetti et al. (2007), sleep and
constipation were the only symptoms that improved following bilateral STN DBS surgery in 36
PD patients.
Quality of life scales such as the PDQ-39 (Jenkinson et al, 1997) and questionnaires (NMS-Q (Chaudhuri
et al, 2008)) should become an integral part of the clinical protocol for patients
admitted to a Parkinson’s disease surgical program. This may help to identify factors that
affect the patient’s quality of life other than the motor activity.
Conclusions:
We have been able to demonstrate that the increase of stimulation parameters (amplitude)
has a potential to improve some non-motor functions and aspects of QoL and thus has an
additional effect on quality of life in certain subset of PD patients. The meticulous observation
of QoL should be a routine part of assessments before and after the DBS STN surgery, and can
even aid during the parameter setting. Certain effect of DBS STN on non-motor functions and
social aspects of QoL (such as stigma, emotion, communications) can explain the further
improvement of overall QoL after the stimulation amplitude increase.
Possible explanations for benefit of stimulation increase could be one or more of the
following:
1. influence of non-motor symptoms of PD that are difficult to ascertain during regular
visits on QoL
2. psychological aspect related to stimulation change
3. improvement of apathy, which is sometimes observed after the DBS STN
Further study with random design and larger number of subjects is warranted.
71
Especially important will be to describe the subjects who may benefit from an increase of the
stimulation parameters beyond the values that improve the usual motor symptoms of PD.
Acknowledgements: The authors would like to express thanks to Prof. Z. Novák and Dr. J.
Chrastina for performing all of the surgical procedures related to STN-DBS. We also thank Z.
Novotný for support with statistical evaluations.
Conflict of interest: The authors declare that they have no conflict of interest.
References:
Chaudhuri KR & Martinez-Martin P (2008) Quantitation of non-motor symptoms in
Parkinson's disease. Eur J Neurol 15 Suppl 2:2-7.
Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, Brown RG, Koller W,
Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye D, Forbes A,
Tluk S, Dhawan V, Bowron A, Williams AJ & Olanow CW (2006) International multicenter pilot
study of the first comprehensive self-completed nonmotor symptoms questionnaire for
Parkinson's disease: the NMSQuest study. Mov Disord 21:916-23.
Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C,
Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss
M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W,
Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V,
Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J & German
Parkinson Study Group NuS (2006) A randomized trial of deep-brain stimulation for
Parkinson's disease. N Engl J Med 355:896-908.
Drapier S, Raoul S, Drapier D, Leray E, Lallement F, Rivier I, Sauleau P, Lajat Y, Edan G & Vérin
M (2005) Only physical aspects of quality of life are significantly improved by bilateral
subthalamic stimulation in Parkinson's disease. J Neurol 252:583-8.
Esselink RA, de Bie RM, de Haan RJ, Lenders MW, Nijssen PC, Staal MJ, Smeding HM,
Schuurman PR, Bosch DA & Speelman JD (2004) Unilateral pallidotomy versus bilateral
subthalamic nucleus stimulation in PD: a randomized trial. Neurology 62:201-7.
Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, Marks WJ, Rothlind J, Sagher O, Moy
72
C, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein JM,
Stoner G, Starr PA, Simpson R, Baltuch G, De Salles A, Huang GD, Reda DJ & Group CS (2010)
Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med
362:2077-91.
Jenkinson C, Fitzpatrick R, Peto V, Greenhall R & Hyman N (1997) The Parkinson's Disease
Questionnaire (PDQ-39): development and validation of a Parkinson's disease summary
index score. Age Ageing 26:353-7.
Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE & Deuschl G
(2006) Subthalamic nucleus deep brain stimulation: summary and meta-analysis of
outcomes. Mov Disord 21 Suppl 14:S290-304.
Kuncel AM & Grill WM (2004) Selection of stimulus parameters for deep brain stimulation.
Clin Neurophysiol 115:2431-41.
Martinez-Martin P & Deuschl G (2007) Effect of medical and surgical interventions on healthrelated
quality of life in Parkinson's disease. Mov Disord 22:757-65.
Martinez-Martin P & Kurtis MM (2012) Health-related quality of life as an outcome variable
in Parkinson's disease. Ther Adv Neurol Disord 5:105-17.
Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, Kulisevsky J,
Albanese A, Volkmann J, Hariz MI, Quinn NP, Speelman JD, Guridi J, Zamarbide I, Gironell A,
Molet J, Pascual-Sedano B, Pidoux B, Bonnet AM, Agid Y, Xie J, Benabid AL, Lozano AM, SaintCyr
J, Romito L, Contarino MF, Scerrati M, Fraix V & Van Blercom N (2005) Bilateral deep
brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up. Brain
128:2240-9.
Schrag A, Hovris A, Morley D, Quinn N & Jahanshahi M (2003) Young- versus older-onset
Parkinson's disease: impact of disease and psychosocial consequences. Mov Disord 18:1250-
6.
Schrag A, Jahanshahi M & Quinn N (2000) What contributes to quality of life in patients with
Parkinson's disease? J Neurol Neurosurg Psychiatry 69:308-12.
Simuni T, Jaggi JL, Mulholland H, Hurtig HI, Colcher A, Siderowf AD, Ravina B, Skolnick BE,
Goldstein R, Stern MB & Baltuch GH (2002) Bilateral stimulation of the subthalamic nucleus
in patients with Parkinson disease: a study of efficacy and safety. J Neurosurg 96:666-72.
Spottke EA, Volkmann J, Lorenz D, Krack P, Smala AM, Sturm V, Gerstner A, Berger K, Hellwig
D, Deuschl G, Freund HJ, Oertel WH & Dodel RC (2002) Evaluation of healthcare utilization
73
and health status of patients with Parkinson's disease treated with deep brain stimulation of
the subthalamic nucleus. J Neurol 249:759-66.
Volkmann J, Albanese A, Kulisevsky J, Tornqvist AL, Houeto JL, Pidoux B, Bonnet AM, Mendes
A, Benabid AL, Fraix V, Van Blercom N, Xie J, Obeso J, Rodriguez-Oroz MC, Guridi J, Schnitzler
A, Timmermann L, Gironell AA, Molet J, Pascual-Sedano B, Rehncrona S, Moro E, Lang AC,
Lozano AM, Bentivoglio AR, Scerrati M, Contarino MF, Romito L, Janssens M & Agid Y (2009)
Long-term effects of pallidal or subthalamic deep brain stimulation on quality of life in
Parkinson's disease. Mov Disord 24:1154-61.
Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Rothlind J, Sagher O, Reda D, Moy
CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J,
Stoner G, Heemskerk J, Huang GD & Group CS (2009) Bilateral deep brain stimulation vs best
medical therapy for patients with advanced Parkinson disease: a randomized controlled trial.
JAMA 301:63-73.
Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, Scott R, Ives N, Rick C, Daniels J,
Patel S, Wheatley K & Group PSC (2010) Deep brain stimulation plus best medical therapy
versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a
randomised, open-label trial. Lancet Neurol 9:581-91.
Witjas T, Kaphan E, Régis J, Jouve E, Chérif AA, Péragut JC & Azulay JP (2007) Effects of
chronic subthalamic stimulation on nonmotor fluctuations in Parkinson's disease. Mov
Disord 22:1729-34.
Zibetti M, Torre E, Cinquepalmi A, Rosso M, Ducati A, Bergamasco B, Lanotte M, Lopiano L.
Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain
stimulation of the subthalamic nucleus. Eur Neurol. 2007;58(4):218-23.
74
3.4 The modulatory role of subthalamic nucleus in cognitive functions – a viewpoint
Published (online) in: Clinical Neurophysiology 11/2014; DOI: 10.1016/j.clinph.2014.10.156.
IF: 3.0
Commentary:
In the following paper our group formulated a viewpoint on the modulatory role of
subthalamic nucleus in cognitive functioning by thorough review of several previous papers
by ourselves and by other prominent authors in the field.
This paper was recently accepted for publication in Clinical Neurophysiology, after minor
revision recieving excellent reviews.
I was a corresponding author for this article and contirbuted to whole process of article
preparation from conception of idea to literature review, authored several articles that were
reviewed in this paper and also played a prominent role in manuscript wiriting.
The modifications of electrophysiological activities of subthalamic nucleus (STN) by non-motor
tasks, i.e. movement observation, emotional stimuli and impulse control, were reported
repeatedly.
Despite being a small structure, STN is apparently involved in a variety of functions.
Based on our own electrophysiological recordings and results of other groups we believe that
it acts as an indirect modulator which may be involved in tuning the functional systems. STN
may modulate specific cognitive activities via contextual modulation of certain cortical areas.
Our findings support the hypothesis of a cortical-STN bypass (via hyperdirect pathway) of a
“classical” basal ganglia-thalamocortical circuitry, at least during the processing of certain
cognitive functions. The modulation of cognitive functions appears to be selective, probably
determined by the involvement of cortical neuronal populations interconnected with STN.
There could also exist a spatial overlap of areas within STN regulating various functions. That
may explain the fact that some non-motor symptoms of Parkinson's disease may improve
after deep brain stimulation of STN. These improvements are likely to be caused by
75
combination of direct stimulation effect on non-motor function and overall beneficial effect
of motor improvement on quality of life.
The modulatory role of subthalamic nucleus in cognitive functions – a viewpoint
Ivan Rektor1, Martina Bočková1, Jan Chrastina2, Irena Rektorová1, Marek Baláž1
Central European Institute of Technology – CEITEC, Masaryk University, Brno
and Movement Disorders Centre, Departments of Neurology1 and Neurosurgery2, St. Anne's
Hospital, Medical School of Masaryk University, Brno, Czech Republic
Address correspondence to:
Marek Baláž MD, PhD
Movement Disorders Centre, First Department of Neurology, and CEITEC, Masaryk University
St. Anne's University Hospital, Pekarska 53
656 91 Brno
Czech Republic
phone: +420 543-182-637
fax: +420 543-182-624
e-mail: marek.balaz@fnusa.cz
Conflict of interest: Authors report no conflict of interest in relation to this article.
Acknowledgments: The study was supported by the project ‘‘CEITEC - Central European
Institute of Technology'' (CZ.1.05/1.1.00/02.0068).
Highlights:
 reviewed findings support the idea that STN may play a unique role that differs from
the role of other structures chained in the BG-thalamocortical circuitries
 it seems that at least a partial overlap of cognitive (and other specific non-motor)
functions and motor functions exists within STN.
 subthalamic nucleus could serve as a nexus that integrates motor, cognitive,
emotional, and reward-based components of behaviour
76
Abstract
The modifications of electrophysiological activities of subthalamic nucleus (STN) by nonmotor
tasks, i.e. movement observation, emotional stimuli and impulse control, were
reported repeatedly.
Despite being a small structure, STN is apparently involved in a variety of functions.
Based on our own electrophysiological recordings and results of other groups we believe
that it acts as an indirect modulator which may be involved in tuning the functional
systems. STN may modulate specific cognitive activities via contextual modulation of
certain cortical areas. Our findings support the hypothesis of a cortical-STN bypass (via
hyperdirect pathway) of “classical” basal ganglia-thalamocortical circuitry, at least during
the processing of certain cognitive functions. The modulation of cognitive functions
appears to be selective, probably determined by the involvement of cortical neuronal
populations interconnected with STN. There could also exist a spatial overlap of areas
within STN regulating various functions. That may explain the fact that some non-motor
symptoms of Parkinson's disease may improve after deep brain stimulation of STN. These
improvements are likely caused by combination of direct stimulation effect on non-motor
function and overall beneficial effect of motor improvement on quality of life.
Key words: electrophysiology; non-motor functions; cognitive functions; DBS; subthalamic
nucleus
Introduction
A direct way of studying the function of subthalamic nucleus (STN) is a neurophysiological
recording of event related electrical activities, i.e. the evoked potentials and oscillations, via
intracranial deep brain electrodes (Kühn et al., 2005a; Rektor et al., 2009). The modifications
of electrophysiological activities of STN by non-motor tasks, i.e. movement observation,
emotional stimuli and impulse control, were observed and reported (Kühn et al., 2005b;
Marceglia et al., 2009; Rodriguez-Oroz et al., 2011). STN recordings related to cognitive tasks
performed by our group contributed largely to formulation of this review (Baláz et al., 2008;
Baláz et al., 2010; Bočková et al., 2011; Rektor et al., 2009, Aulická et al., 2014).
77
STN function captivated researchers' interest by motor as well as non-motor effects of deep
brain stimulation (DBS) on this structure. The involvement of STN in a broad spectrum of
various non-motor functions was reported – attention (Bočková et al., 2011, Mallet et al.
2007), executive functions (Baláz et al., 2008, Voon et al., 2006), verbal learning and memory
(Coulthard et al. , 2012), control of impulses (Rodriguez-Oroz et al., 2011), verbal abstract
reasoning, conflict resolution (Brittain et al., 2012), facial emotion recognition (Le Jeune et al.,
2008) and emotions (Kühn et al., 2005a, for review see Baunez et al., 2011). STN appears to
be involved in complex cognitive behavioural functions and networks such as the network
underlying the Theory of Mind (Péron et al., 2013). Moreover, neuropsychiatric problems such
as depression (Voon et al., 2006, Thobois et al. 2010), apathy (Voon et al. 2006), suicide
ideation/attempt (Voon et al., 2008) were also reported after DBS STN surgery, and were
reviewed recently by Rodriguez-Oroz et al., 2012. Behavioural complications were reported
after DBS STN more frequently than after DBS Gpi. The etiology of these problems is
multifactorial and except for reduction of dopaminergic medication (Thobois et al., 2010) and
preoperative risk factors (Lim et al. 2009) includes also stimulation of contacts located in nonmotor
areas (Mallet et al., 2002, Mandat et al., 2006, Raucher-Chéné et al., 2008). The
impulsivity and mania are thought to be related to diffusion of electric current to limbic parts
of STN (Rodriguez-Oroz et al., 2012, Mallet et al., 2007, Krack et al., 2010). STN DBS might alter
the coupling between prefrontal cortex and basal ganglia during decision-making processes
(Cavanagh et al., 2011).
Neuroimaging studies further support engagement of STN in performance cognitive tasks and
other non-motor functions (e.g. Aron et al., 2007, Coxon et al., 2012, Haegelen et al., 2010,
Herz et al., 2014, Kalbe et al., 2009, Le Jeune et al., 2008, Le Jeune et al., 2009, Le Jeune et al.,
2010, Manes et al., 2014, Mansfield et al., 2011, Mathys et al., 2014, Lambert et al., 2012,
Schroeder et al. 2002, Ballanger et al., 2009b).
In line with observations made in humans, the encoding of cognitive (Baunez and Lardeux,
2011), behavioural (Teagarden and Rebec, 2007), and reward-based (Lardeux et al., 2009)
tasks in STN was found in rats.
Animal models brought relevant data on non-motor effects of STN manipulation well before
it was shown in humans (reviewed by Baunez and Gubellini 2010). Study by Baunez in 1995
for the first time revealed possible side effects that might be related to the involvement of
STN in non-motor behaviour. Generally, the evidence gained from animal models (Darbaky et
78
al., 2003; Temel et al., 2005) seem to confirm that STN high frequency stimulation (HFS) at
parameters inducing beneficial effects on motor functions does not always correlate with
beneficial cognitive effects reported in human patients (Perriol et al., 2006).With only few
existing works describing STN stimulation in monkeys it appears that STN neurons respond to
reward (Darbaky et al., 2005), suggesting that STN manipulations may affect motivation.
The studies in rats have raised the issue of non-motor involvement of STN and lead to a better
consideration of these aspects in clinical studies and patients’ management: the current
interest for motivational and emotional effects of STN DBS in PD patients reflects also the
recent interest for these processes in animal models.
When it comes to cognitive and motivational processes, mainly rat data are available. These
studies highlighted the integrative function of STN, placing it at the interface between
motivation and action. There was often a parallel to these findings in clinical observations of
PD patients with STN DBS, but it would be important to perform further studies on monkeys,
especially because of the fact that they could allow specific investigation of the sub-territories
within STN (limbic, associative and motor areas) that are impossible to perform in the rat given
the small size of STN in this species.
Results of fMRI pig study also suggested that STN DBS may have modulatory effects not only
on circuits that facilitate motor function but also on those involved in higher cognitive and
emotional processing (Min et al 2012).
The overlap of processing of motor and non-motor activities within STN
Neurophysiological recordings from STN
We have shown (Balaz et al., 2008; Baláz et al., 2010; Bočková et al., 2011, Rektor et al., 2009,
Aulická et al. 2014) that there is a spatial overlap of parts regulating certain cognitive and
motor functions in STN in patients with Parkinson's disease (PD). The local fields of cognitive
related potentials were recorded through the electrode contact located in STN sites with the
best motor effect. We studied event related potentials and oscillations while performing
various cognitive tasks including the oddball paradigm, (both standard and one modified by a
dual task), a three-stimulus paradigm, Ericsson´s flanker task and a protocol with writing
letters in an executive function task. A deep electrode contact was submerged in the neuronal
79
tissue, and thus the potentials were recorded from its immediate vicinity. This means that the
neuronal pools generating activities related to motor and cognitive tasks were either very
close to each other or that some neurons were active in both tasks.
Of note, similarly to STN, we also observed a spatial overlap of several cognitive and motor
control functions in pallidum and striatum. We recorded event related potentials evoked
during various auditory, somatosensory and visual cognitive tasks, in motor as well as nonmotor
paradigms, and the Bereitschaftspotential on contacts of the same electrode (Rektor
et al., 2005). These data were obtained in patients with epilepsy. To our knowledge, recordings
of cognitive event related activities in pallidum and striatum have not yet been reported in
patients with PD.
To sum it up, it seems that at least a partial overlap of cognitive (and other specific non-motor)
and motor functions exists within STN. This notion may also support the view of an integrative
role of STN.
The integration model of STN function
STN is apparently involved in a variety of functions, both motor (Benabid et al., 2009) and nonmotor
(Fasano et al., 2012), although it is a small structure (Parent et al., 2001, Yelnik, 2008).
It is hard to imagine how the limited number of STN neurons could process all these functions
separately despite certain distribution of motor and non-motor functions along the
dorsoventral axis of STN (Rodriguez-Oroz et al., 2011). Functional imaging (FDG-PET, SPECT
and fMRI) showed that stimulation of STN induced modifications of the pattern of brain
activation not only within the nucleus itself, but it involved large-scale cerebral networks
(Sestini et al., 2009, Ballanger et al., 2009a; Kalbe et al., 2009, Péron et al., 2010, Le Jeune et
al., 2010, Ray et al., 2011). The functional linkage of the nucleus with other subcortical and
cortical structures may be conveyed by separated cortico-basal ganglia-thalamocortical
circuits.
According to “classical models” the functionally segregated sections of STN subserve motor,
emotion, and cognitive processing (Parent and Hazrati, 1995, Alexander et al., 1990, Hamani
et al., 2004). A recent probabilistic tractography study further supported the existence of
three distinct sub-regions within the human STN (Lambert et al. 2012). The authors claimed
that there are unique limbic and motor STN zones, and the associative zone might represent
80
an overlapping, somatotopically arranged transition between the two, thus providing an
anatomical substrate for communication between two distinctive closed networks.
Conversely, Alkemade and Forstmann (2014) used ultra-high resolution 7T MRI in an attempt
to distinguish subregions of STN but their preliminary results rather point towards delineated
subdivisions, or an organization without strict anatomical boundaries or septa. The authors
assume that there is at least partial overlap between putative functional zones within STN.
An integrative model was proposed in which emotional, cognitive, behavioural, and motor
functional modalities were not processed in a segregated manner but were all modified within
the small volume of the nucleus. This nucleus could serve as a nexus that integrates motor,
cognitive, emotional, and reward-based components of behaviour (Kalbe et al., 2009, Mallet
et al., 2007).
This “integrative model” differs from that of Haber et al. (Haber et al., 2006) in which
integration was based on the reciprocal striato-nigro-striatal and cortico-thalamo-cortical
circuits and from that of Temel and colleagues (Temel et al., Tan et al., 2006) in which STN was
a regulator of associative and limbic circuits, but not an integrator.
Integrative model of STN thus shows that its individual functions at least partially overlap and
are integrated within this structure and therefore various effects of STN stimulation (such as
effect on the array of above metioned non-motor functions) can be explained by this model.
STN modulates the cortico-subcortical circuitry when processing cognitive activities
We suggest that STN is engaged in tuning of the cognitive functional networks. Our findings
support the idea that STN may play a unique role that differs from the role of other structures
chained in the BG-thalamocortical circuitries. For example, in contrast to our results from
striatum/pallidum mentioned above (Rektor et al., 2005; Rektor et al., 2004) the standard
oddball cognitive potentials (P3) were not generated in STN (Balaz et al., 2008; Bočková et al.,
2011). In patients with epilepsy, the epileptic spikes were recorded in STN but not in other BG
structures (Rektor et al., 2002; Urrestarazu et al., 2009).
Classical hypotheses of segregated connection of STN in cortico-basal ganglia-thalamocortical
circuits were described above. Indeed, other hypotheses (Joel, 2001; Parent et al., 2001) have
also been proposed with respect to STN functional connectivity, including the "hyperdirect"
81
pathways between STN and cortex that bypass the well-known BG circuitries (Obeso et al.,
2007) and might underlie the processing of at least some of the cognitive functions (Nambu
et al., 2002). From experimental data in rats it appears that STN is involved in attentional
processes possibly via this hyperdirect pathway (Baunez and Lardeux, 2011). Using viral
tracers in prefrontal cortical sites in monkeys Haynes and Haber (Haynes and Haber, 2013)
revealed presence of massive hyperdirect parallel projections between prefrontal cortex and
STN. These data support the idea of strategic position of STN in the control of non-motor
behaviour. The authors also demonstrated significant overlap of functional territories within
STN. This overlap may enable the hyperdirect pathway to combine movement with both
emotions and cognition – an association which is constant in involuntary behaviours
(Martinez-Fernandez et al., 2013).
In humans, results of previous studies suggested that the hyperdirect pathway enables STN
to use performance-monitoring signals to adjust motor behaviour (Frank et al., 2007). We
reported that repetitive transcranial magnetic stimulation (rTMS) of inferior frontal cortex
(IFC), but not of dorsolateral prefrontal cortex (DLPFC), increased the speed of processing
executive functions (shortening of latencies of event-related potentials) in STN during a dual
task performance (Baláz et al., 2010). IFC is a source of the hyperdirect pathway to STN
(Nambu et al., 2002), while DLPFC is included in the cortico-thalamocortical circuitry. Our
findings supported the role of a “hyperdirect“ cortico-STN bypass of the usual BGthalamocortical
circuitry in processing of cognitive functions. Of note, we were able to
replicate our pilot results and we improved attention and enhanced cognitive speed by rTMS
applied over the same IFC coordinate in another PD cohort (Srovnalova et al., 2011) and also
in subjects with mild cognitive impairment due to Alzheimer’s disease (Eliasova et al. 2014).
As STN is the only BG structure, except for striatum, that receives a direct cortical projection
(Nambu et al., 2002), it is in a position to receive information directly from cortex earlier than
from BG - thalamocortical circuitry. Consequently, STN may have a modulatory influence on
processing activities in the rest of the circuitry. The number of STN neurons is known to be
small and STN may be targeted by the direct as well the hyperdirect pathway. Therefore, the
information processed by the two pathways is very probably integrated within STN and it may
play a central role in regulation of cortical areas via and the modulation of cortico - subcortical
circuits (Figure 1). As it was shown by FDG-PET study STN DBS modifies metabolic activity in
large cortical distributed networks (Le Jeune et al 2010).
82
The multifunctional and task-specific involvement of STN in cognitive activities
The involvement of STN in cognitive functions is documented less than its role in motor
function regulation.
STN is a structure that takes part in multiple functions with respect to cognition. It can be
assumed that STN is implicated in executive functions (Baláz et al., 2008; Baláz et al., 2010;
Rektor et al., 2009, Aulická et al. 2014), attentional and orientation responses (Bočková et al.,
2011), as well as in impulse control (Rodriguez-Oroz et al., 2011). Both STN DBS in PD patients
and lesional experiments in rats showed impairment of response inhibition in go/no go tasks
(Ballanger et al., 2009b; Baunez and Lardeux, 2011), suggesting that STN could play a critical
role in "holding a response" (Frank et al., 2007). It has been documented using both PET and
MRI techniques, that STN modulates non-motor basal ganglia-thalamocortical circuitry during
conflict tasks requiring response inhibition (Schroeder et al. 2002, Aron et al. 2007). STN DBS
selectively interferes with the normal ability to slow down when faced with decision conflict
and can therefore produce impulsitivity in behaviour/impusive behaviour. Increased response
conservativeness is associated with activation of STN (Frank et al. 2007, Mansfield et al. 2011).
Cognitive action control is thought to rely on an interconnected network consisting of right
inferior frontal cortex (r-IFC), pre-supplementary motor area (preSMA), and STN (Coxon et al.
2012, Herz et al. 2014).
STN has also critical importance in successful decision making when multiple pieces of
information must be combined (Coulthard et al. 2012). Furthermore, the data from FDG-PET
study of fear recognition confirm the role of STN in limbic functions (Le Jeune et al., 2008).
The role of STN in associative and limbic circuitry suggests that it is a key basal ganglia
structure for motivation (Le Jeune et al. 2009).
STN seems to play role also in language functions. It was found to have connectivity with
regions involved in cognitive linguistic processes (Manes et al., 2014). Relationship between
changes in the left frontal (dorsolateral prefrontal cortex and Broca area) PET activity and
changes in cognitive outcome after deep brain stimulation of STN were observed (Kalbe et al.
2009).
De-coupling of brain areas involved in self-relevant but motor-unrelated cognitive processing
(i.e. precuneus and posterior cingulate cortex) from STN motor network may represent a
83
potential mechanism behind the age-dependent decline in motor performance (Mathys et al.
2014).
A central role of STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits
was suggested (Hilker et al., 2004).
To sum it up, STN might modulate selective cognitive functions. Thanks to the central position
and the integration of various functions STN may be a substrate for contextual modulation of
targeted cortical areas.
STN appears to be involved in the modulation of only certain cognitive activities. We
observed the involvement of STN in tasks with increased cognitive load but not in simpler
cognitive tasks. Simple oddball evoked P3 like potentials were recorded only as a far field
potential in STN while the dual task evoked local field of P3-like potentials directly in the
nucleus (Baláz et al., 2008). Similarly, oscillatory activities in STN were evoked by writing
letters in an executive task paradigm (where subjects were asked to write a letter different
from the letter on a screen), but not by simple letter copying (Rektor et al., 2009). In a three
stimulus paradigm the distractor stimulus evoked an early potential with a latency around 200
ms in STN that has not been observed in the scalp recordings. This demonstrated the
engagement of STN in attentional and orienting responses (Bočková et al., 2011). The
involvement of STN in processes controlling human behaviour, e.g. selection and inhibition of
competing alternatives, was demonstrated by the Ericsson´s flanker task -related activation of
the STN. Both conditions, i.e. congruent and incongruent, induced oscillatory changes in STN
with significantly higher activation during incongruent trial. When compared with the activity
recorded in anterior cingulate in epileptic patients, in STN not only ERD beta but also ERD
alpha activity was significantly more activated by the incongruent condition (Aulicka et al.,
2014).
In line with our results, task-specific effects on attentional performance after a lesion of STN
were observed in rats (Baunez and Robbins, 1997; Temel et al., 2005).
Also the imaging studies in humans show that the effects of STN-DBS are task-specific and
depend on particular networks involved in those specific tasks (e.g. Kalbe al., 2009, Mallet et
al. 2009, Coulthard et al. 2012). According to a cortico-subthalamic coherence study STN
appears to be implicated in motor and behavioural complications in PD, specifically engaging
different anatomical and functional territories (Rodriguez-Oroz et al., 2011). Therefore, the
84
selection of tasks modulated by STN may be determined by the selective involvement of these
specific cortical neuronal populations that are interconnected with STN.
In any case, the exact role of STN and BG in cognitive functions remains an important and
interesting challenge for future research.
The role of STN in emotions and behaviour
Cognitive processes are closely related to emotions. According to multicomponential view on
emotions the emotional reactions were determined by the subjective cognitive evaluation of
events, based on the meaning of these event for the individual’s wellbeing and the pursuit of
their goals (Péron et al., 2013).This function appeared to be not selective for any single
category of emotions (e.g. fear) or subprocess involved in different emotions (e.g. autonomic
responses), but rather a more general capacity, implying a kind of “meta-role” (Péron et
al.,2013). STN acted as a coordinator of neural patterns and was involved in a whole range of
emotional processes. STN DBS may change the integration of limbic informations by disrupting
emotional processes within STN, or by hampering the normal function of a limbic circuit
(Haegelen et al. 2010). STN may play some role in the evaluation of behavioural significance
due to changes of environment (Sauleau et al., 2009). The authors found out that warning
cues evoked a complex temporal sequence of activities in STN area that differed according to
behavioural relevance of cues and dopaminergic state. These data appeared to represent
neural processes at the basal ganglia end of circuits between basal ganglia and frontal cortex
concerned with attentional processes leading to behavioural resources. STN does not
necessarily has to be a place where these processes related to behavioural relevance arise,
but it is at least an important node in a circuit elaborating such responses. This hypothesis is
in line with our opinion, that many various functions are represented in STN.
STN may also participate in inhibition of certain behavioural processes (Ballanger et al.,
2009b). It has been proposed that STN may act as a "gate-control" for selection of behavioural
action (Baunez and Lardeux, 2011).
The modulatory role of STN – the viewpoint
85
STN has been considered as a relay station in the indirect pathway functionally positioned
between external and internal globus pallidus (Alexander et al., 1990). A new concept of the
hyperdirect pathways that bypass the circuitries and connect several cortical areas and STN
directly emerged. To what extent and how STN integrates information received via the
hyperdirect and indirect pathways has been unknown so far. The small size of the nucleus
indicates that an integration of information processed by the two pathways may occur in STN.
The spatial overlap of various functions inside STN described above may be a substrate for this
integration or combination of the motor, cognitive, and emotional components of behaviour
(Mallet 2007). The simple fact that STN has a very direct link with cortex means that at least
some information is processed within STN earlier than the one that is elaborated within the
BG circuitry. STN is in the position where it can modulate the function of the output part of
the well-known “classical“ BG circuitries. It has been shown in animal models, that within the
prefrontal cortex-BG circuits, STN participates in the shaping of the inhibitory influence of the
direct striato-nigral pathway on the output part of the circuitry (Maurice et al., 1999).
Regarding the cognitive activities, we suggest two ways of STN participation. Firstly, STN is a
relay nucleus that participates in processing of cognitive and behavioural activities within the
cortico-BG- thalamocortical loop. In addition to this known function we suggest that STN may
(under direct cortical control conveyed by the hyperdirect pathway) exert a modulatory
control over the output part of the cortico - BG - thalamo - cortical loop.
References
Alexander GE, Crutcher M, DeLong M. Basal ganglia-thalamo-cortical circuits: Parallel
substrates for motor, oculomotor, “prefrontal,” and “limbic” functions. Prog Brain Res. 1990;
85:119–46.
Alkemade A, Forstmann BU. Do we need to revise the tripartite subdivision hypothesis of the
human subthalamic nucleus (STN)? NeuroImage 2014; 95: 326–329
Aron AR, Behrens TE, Smith S, Frank MJ, Poldrack RA. Triangulating a cognitive control network
using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI. J Neurosci.
2007;27(14):3743-52.
Aulická Š, Jurák P, Chládek J, Daniel P, Halámek J, Baláž M, Chrastina J, Rektor I. Subthalamic
nucleus involvement in executive functions with increased cognitive load: a subthalamic
86
nucleus and anterior cingulate cortex depth recording study. J Neural Transm. 2014;
10.1007/s00702-014-1191-5
Balaz, M., Rektor, I., and Pulkrabek, J. Participation of the subthalamic nucleus in executive
functions: An intracerebral recording study. Mov Disord 2008; 23 (4): 553-557.
Ballanger, B., Jahanshahi, M., Broussolle, E., and Thobois, S. PET functional imaging of deep
brain stimulation in movement disorders and psychiatry. J Cereb Blood Flow Metab 2009a; 29
(11): 1743-1754.
Ballanger, B., van Eimeren, T., Moro, E., Lozano, A.M., Hamani, C., Boulinguez, P., Pellecchia,
G., Houle, S., Poon, Y.Y., Lang, A.E., and Strafella, A.P. Stimulation of the subthalamic nucleus
and impulsivity: release your horses. Ann Neurol 2009b; 66 (6): 817-824.
Baláz, M., Rektor, I., and Pulkrábek, J. Participation of the subthalamic nucleus in executive
functions: An intracerebral recording study. Mov Disord 2008; 23 (4): 553-557.
Baláz, M., Srovnalová, H., Rektorová, I., and Rektor, I. The effect of cortical repetitive
transcranial magnetic stimulation on cognitive event-related potentials recorded in the
subthalamic nucleus. Exp Brain Res 2010; 203 (2): 317-327.
Baunez C, Gubellini P, Chapter 12 - Effects of GPi and STN inactivation on physiological, motor,
cognitive and motivational processes in animal models of Parkinson’s disease, In: Anders
Björklund and M. Angela Cenci, Editor(s), Progress in Brain Research, Elsevier, 2010, Volume
183, Pages 235-258, ISSN 0079-6123, ISBN 9780444536143, http://dx.doi.org/10.1016/S0079-
6123(10)83012-2.
Baunez, C., Nieoullon, A., & Amalric, M. (1995). In a rat model of parkinsonism, lesions of the
subthalamic nucleus reverse increases of reaction time but induce a dramatic premature
responding deficit. Journal of Neuroscience, 15 (10), 6531–6541.
Baunez, C. and Lardeux, S. Frontal cortex-like functions of the subthalamic nucleus. Front Syst
Neurosci 2011; 5: 83.
Baunez, C. and Robbins, T.W. Bilateral lesions of the subthalamic nucleus induce multiple
deficits in an attentional task in rats. Eur J Neurosci 1997; 9 (10): 2086-2099.
Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic
nucleus for the treatment of Parkinson's disease. Lancet Neurol. 2009, 8(1):67-81.
Biseul, I., Sauleau, P., Haegelen, C., Trebon, P., Drapier, D., Raoul, S., Drapier, S., Lallement, F.,
Rivier, I., Lajat, Y., and Verin, M. Fear recognition is impaired by subthalamic nucleus
stimulation in Parkinson's disease. Neuropsychologia 2005; 43 (7): 1054-1059.
87
Bočková, M., Chládek, J., Jurák, P., Halámek, J., Baláž, M., and Rektor, I. Involvement of the
subthalamic nucleus and globus pallidus internus in attention. J Neural Transm 2011; 118 (8):
1235-1245.
Cavanagh JF, Wiecki TV, Cohen MX, Figueroa CM, Samanta J, Sherman SJ, Frank
MJ.Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold.
Nat Neurosci. 2011 Sep 25;14 (11):1462-7.
Coulthard, EJ, Bogacz, R, Javed, S, Mooney, LK, Murphy, G, Keeley, S, and Whone, AL. Distinct
roles of dopamine and subthalamic nucleus in learning and probabilistic decision making.
Brain 2012; 135: 3721-3734.
Coxon JP, Van Impe A, Wenderoth N, Swinnen SP. Aging and inhibitory control of action:
cortico-subthalamic connection strength predicts stopping performance. J Neurosci.
2012;32(24):8401-12
Darbaky, Y., Baunez, C., Arecchi, P., Legallet, E., and Apicella, P. Reward-related neuronal
activity in the subthalamic nucleus of the monkey. Neuroreport 2005; 16 (11): 1241-1244.
Eliasova I, Anderkova L, Marecek R, Rektorova I. Non-invasive brain stimulation of the right
inferior frontal gyrus may improve attention in early Alzheimer's disease: A pilot study. J
Neurol Sci. 2014. doi: 10.1016/j.jns.2014.08.036. [Epub ahead of print]
Fasano A, Daniele A, Albanese A. Treatment of motor and non-motor features of Parkinson's
disease with deep brain stimulation. Lancet Neurol. 2012; 11(5):429-42.
Frank, M.J., Samanta, J., Moustafa, A.A., and Sherman, S.J. Hold your horses: impulsivity, deep
brain stimulation, and medication in parkinsonism. Science 2007; 318 (5854): 1309-1312.
Haber SN, Kim KS, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal
region in primates that interface with associative cortical connections, providing a substrate
for incentive-based learning. J Neurosci. 2006; 26(32):8368-76.
Haegelen C, García-Lorenzo D, Le Jeune F, Péron J, Gibaud B, Riffaud L, Brassier G, Barillot C,
Vérin M, Morandi X. SPECT and PET analysis of subthalamic stimulation in Parkinson's disease:
analysis using a manual segmentation. J Neurol. 2010;257(3):375-82
Haynes WIA, Haber SN. The Organization of Prefrontal-Subthalamic Inputs in Primates
Provides an Anatomical Substrate for Both Functional Specificity and Integration: Implications
for Basal Ganglia Models and Deep Brain Stimulation. J Neurosci 2013; 33(11):4804–4814.
Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM. The subthalamic nucleus in the context
of movement disorders. Brain. 2004; 127:4–20.
88
Herz DM, Christensen MS, Bruggemann N, Hulme OJ, Ridderinkhof KR, Madsen KH, Siebner
HR. Motivational tuning of fronto-subthalamic connectivity facilitates control of action
impulses. J Neurosci. 2014 Feb 26;34(9):3210-7
Hilker R, Voges J, Weisenbach S, Kalbe E, Burghaus L, Ghaemi M, Lehrke R, Koulousakis
A,Herholz K, Sturm V, Heiss WD. Subthalamic nucleus stimulation restores glucose metabolism
in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in
advanced Parkinson's disease. J Cereb Blood Flow Metab. 2004; 24(1):7-16.
Joel, D. Open interconnected model of basal ganglia-thalamocortical circuitry and its
relevance to the clinical syndrome of Huntington's disease. Mov Disord 2001; 16 (3): 407-423.
Kalbe, E., Voges, J., Weber, T., Haarer, M., Baudrexel, S., Klein, J.C., Kessler, J., Sturm, V., Heiss,
W.D., and Hilker, R. Frontal FDG-PET activity correlates with cognitive outcome after STN-DBS
in Parkinson disease. Neurology 2009; 72 (1): 42-49.
Krack P, Hariz MI, Baunez C, Guridi J, Obeso JA. Deep brain stimulation: from neurology to
psychiatry? Trends Neurosci. 2010; 33(10):474-84.
Kühn, A.A., Hariz, M.I., Silberstein, P., Tisch, S., Kupsch, A., Schneider, G.H., Limousin-Dowsey,
P., Yarrow, K., and Brown, P. Activation of the subthalamic region during emotional processing
in Parkinson disease. Neurology 2005a; 65 (5): 707-713.
Kühn, A.A., Trottenberg, T., Kivi, A., Kupsch, A., Schneider, G.H., and Brown, P. The relationship
between local field potential and neuronal discharge in the subthalamic nucleus of patients
with Parkinson's disease. Exp Neurol 2005b; 194 (1): 212-220.
Lardeux, S., Pernaud, R., Paleressompoulle, D., and Baunez, C. Beyond the reward pathway:
coding reward magnitude and error in the rat subthalamic nucleus. J Neurophysiol 2009; 102
(4): 2526-2537.
Le Jeune, F., Péron, J., Biseul, I., Fournier, S., Sauleau, P., Drapier, S., Haegelen, C., Drapier, D.,
Millet, B., Garin, E., Herry, J.Y., Malbert, C.H., and Vérin, M. Subthalamic nucleus stimulation
affects orbitofrontal cortex in facial emotion recognition: a PET study. Brain 2008; 131 (Pt 6):
1599-1608.
Le Jeune F, Drapier D, Bourguignon A, Péron J, Mesbah H, Drapier S, Sauleau P, Haegelen C,
Travers D, Garin E, Malbert CH, Millet B, Vérin M. Subthalamic nucleus stimulation in Parkinson
disease induces apathy: a PET study. Neurology. 2009;73(21):1746-51
89
Le Jeune F, Péron J, Grandjean D, Drapier S, Haegelen C, Garin E, Millet B, Vérin M.Subthalamic
nucleus stimulation affects limbic and associative circuits: a PET study. Eur J Nucl Med Mol
Imaging. 2010; 37(8):1512-20.
Lambert C, Zrinzo L, Nagy Z, Lutti A, Hariz M, Foltynie T, Draganski B, Ashburner J, Frackowiak
R. Confirmation of functional zones within the human subthalamic nucleus: patterns of
connectivity and sub-parcellation using diffusion weighted imaging. Neuroimage.
2012;60(1):83-94
Lim SY, O'Sullivan SS, Kotschet K, Gallagher DA, Lacey C, Lawrence AD, Lees AJ, O'Sullivan DJ,
Peppard RF, Rodrigues JP, Schrag A, Silberstein P, Tisch S, Evans AH. Dopamine dysregulation
syndrome, impulse control disorders and punding after deep brain stimulation surgery for
Parkinson's disease. J Clin Neurosci 2009; 16(9):1148-52.
Mallet L, Mesnage V, Houeto JL, Pelissolo A, Yelnik J, Behar C, Gargiulo M, Welter ML, Bonnet
AM, Pillon B, Cornu P, Dormont D, Pidoux B, Allilaire JF, Agid Y. Compulsions, Parkinson's
disease, and stimulation. Lancet. 2002; 360(9342):1302-4.
Mallet, L., Schüpbach, M., N'Diaye, K., Remy, P., Bardinet, E., Czernecki, V., Welter, M.L.,
Pelissolo, A., Ruberg, M., Agid, Y., and Yelnik, J. Stimulation of subterritories of the subthalamic
nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc
Natl Acad Sci USA 2007; 104 (25): 10661-10666.
Mandat TS, Hurwitz T, Honey CR. Hypomania as an adverse effect of subthalamic nucleus
stimulation: report of two cases. Acta Neurochir (Wien) 2006;148(8):895-7.
Manes JL, Parkinson AL, Larson CR, Greenlee JD, Eickhoff SB, Corcos DM, Robin DA.
Connectivity of the subthalamic nucleus and globus pallidus pars interna to regions within the
speech network: a meta-analytic connectivity study. Hum Brain Mapp. 2014;35(7):3499-516
Mansfield EL, Karayanidis F, Jamadar S, Heathcote A, Forstmann BU. Adjustments of response
threshold during task switching: a model-based functional magnetic resonance imaging study.
J Neurosci. 2011;31(41):14688-92
Marceglia, S., Fiorio, M., Foffani, G., Mrakic-Sposta, S., Tiriticco, M., Locatelli, M., Caputo, E.,
Tinazzi, M., and Priori, A. Modulation of beta oscillations in the subthalamic area during action
observation in Parkinson's disease. Neuroscience 2009; 161 (4): 1027-1036.
Martinez-Fernandez R, Krack P, Castioto A. Prefrontal — STN Projections, the Highway for
Emotion and Cognition Control. Mov Disord 2014; 29 (3): 305.
90
Mathys C, Hoffstaedter F, Caspers J, Caspers S, Südmeyer M, Grefkes C, Eickhoff SB, Langner
R. An age-related shift of resting-state functional connectivity of the subthalamic nucleus: a
potential mechanism for compensating motor performance decline in older adults. Front
Aging Neurosci. 2014;6:178.
Maurice, N., Deniau, J.M., Glowinski, J., and Thierry, A.M. Relationships between the
prefrontal cortex and the basal ganglia in the rat: physiology of the cortico-nigral circuits. J
Neurosci 1999; 19 (11): 4674-4681.
Min HK, Hwang SC, Marsh MP, Kim I, Knight E, Striemer B, Felmlee JP, Welker KM, Blaha CD,
Chang SY, Bennet KE, Lee KH. Deep brain stimulation induces BOLD activation in motor and
non-motor networks: An fMRI comparison study of STN and EN/GPi DBS in large animals,
NeuroImage 2012; 63: 3:1408-1420.
'hyperdirect' pathway. Neurosci Res 2002; 43 (2): 111-117.
Obeso, J.A., Rodriguez, M.C., and DeLong, M.R. Basal ganglia pathophysiology. A critical
review. Adv Neurol 74: 3-18, 1997.
Nambu, A., Tokuno, H., and Takada, M. Functional significance of the cortico-subthalamopallidal
Parent A, Hazrati LN. Functional anatomy of the basal ganglia. II. The place of
subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain Res Rev.
1995; 20:128–5.
Parent, A., Lévesque, M., and Parent, M. A re-evaluation of the current model of the basal
ganglia. Parkinsonism Relat Disord 2001; 7 (3): 193-198.
Péron J, Le Jeune F, Haegelen C, Dondaine T, Drapier D, Sauleau P, Reymann JM, Drapier S,
Rouaud T, Millet B, Vérin M. Subthalamic nucleus stimulation affects theory of mind network:
a PET study in Parkinson's disease. PLoS One. 2010;5(3), e9919.
Péron J, Frühholz S, Vérin M, Grandjean D. Subthalamic nucleus: a key structure for emotional
component synchronization in humans. Neurosci Biobehav Rev. 2013; 37(3):358-73.
Perriol MP, Krystkowiak P, Defebvre L, Blond S, Destee A, Dujardin K. Stimulation of the
subthalamic nucleus in Parkinson’s disease: Cognitive and affective changes are not linked to
the motor outcome. Parkinsonism & Related Disorders 2006; 12(4): 205–210.
Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F. Manic episode with psychotic
symptoms in a patient with Parkinson's disease treated by subthalamic nucleus stimulation:
improvement on switching the target. J Neurol Sci. 2008; 273(1-2):116-7.
91
Ray N, Antonelli F, Strafella AP. Imaging Impulsivity in Parkinson's Disease and the
Contribution of the Subthalamic Nucleus. Parkinsons Dis. 2011; ID 594860, doi:
10.4061/2011/594860.
Rektor, I., Baláz, M., and Bocková, M. Cognitive activities in the subthalamic nucleus. Invasive
studies. Parkinsonism Relat Disord 2009 ; 15 Suppl 3: S83-86.
Rektor, I., Bares, M., Brázdil, M., Kanovský, P., Rektorová, I., Sochurková, D., Kubová, D., Kuba,
R., and Daniel, P. Cognitive- and movement-related potentials recorded in the human basal
ganglia. Mov Disord 2005; 20 (5): 562-568.
Rektor, I., Bares, M., Kanovský, P., Brázdil, M., Klajblová, I., Streitová, H., Rektorová, I.,
Sochůrková, D., Kubová, D., Kuba, R., and Daniel, P. Cognitive potentials in the basal gangliafrontocortical
circuits. An intracerebral recording study. Exp Brain Res 2004; 158 (3): 289-301.
Rektor, I., Kuba, R., and Brázdil, M. Interictal and ictal EEG activity in the basal ganglia: an SEEG
study in patients with temporal lobe epilepsy. Epilepsia 2002; 43 (3): 253-262.
Rodriguez-Oroz, M.C., López-Azcárate, J., Garcia-Garcia, D., Alegre, M., Toledo, J., Valencia,
M., Guridi, J., Artieda, J., and Obeso, J.A. Involvement of the subthalamic nucleus in impulse
control disorders associated with Parkinson's disease. Brain 2011; 134 (Pt 1): 36-49.
Rodriguez-Oroz MC, Moro E, Krack P. Long-term outcomes of surgical therapies for Parkinson's
disease. Mov Disord. 2012; 27(14):1718-28.
Sauleau, P., Eusebio, A., Thevathasan, W., Yarrow, K., Pogosyan, A., Zrinzo, L., Ashkan, K., Aziz,
T.,
Schroeder U, Kuehler A, Haslinger B, Erhard P, Fogel W, Tronnier VM, Lange KW, Boecker H,
Ceballos-Baumann AO.Subthalamic nucleus stimulation affects striato-anterior cingulate
cortex circuit in a response conflict task: a PET study. Brain 2002;125(Pt 9):1995-2004.
Srovnalova H, Marecek R, Rektorova I. The role of the inferior frontal gyri in cognitive
processing of patients with Parkinson's disease: A pilot rTMS study. Mov Disord
2011;26(8):1545-8.
Vandenberghe, W., Nuttin, B., and Brown, P. Involvement of the subthalamic nucleus in
engagement with behaviourally relevant stimuli. Eur J Neurosci 2009; 29 (5): 931-942.
Sestini S, Scotto di Luzio A, Ammannati F, De Cristofaro MT, Passeri A, Martini S, Pupi
A.Changes in regional cerebral blood flow caused by deep-brain stimulation of the
subthalamic nucleus in Parkinson's disease. J Nucl Med. 2002; 43(6):725-32.
92
Tan SK, Temel Y, Blokland A, Steinbusch HW, Visser-Vandewalle V.The subthalamic nucleus:
From response selection to execution. J Chem Neuroanat 2006; 31(3):155-61.
Teagarden, M.A. and Rebec, G.V. Subthalamic and striatal neurons concurrently process
motor, limbic, and associative information in rats performing an operant task. J Neurophysiol
2007; 97 (3): 2042-2058.
Temel, Y., Blokland, A., Steinbusch, H.W., and Visser-Vandewalle, V. The functional role of the
subthalamic nucleus in cognitive and limbic circuits. Prog Neurobiol 2005; 76 (6): 393-413,
200.
Thobois S, Ardouin C, Lhommée E, Klinger H, Lagrange C, Xie J, Fraix V, Coelho Braga MC,
Hassani R, Kistner A, Juphard A, Seigneuret E, Chabardes S, Mertens P, Polo G, Reilhac A,
Costes N, LeBars D, Savasta M, Tremblay L, Quesada JL, Bosson JL, Benabid AL, Broussolle E,
Pollak P, Krack P. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's
disease: predictors and underlying mesolimbic denervation. Brain 2010; 133(Pt 4):1111-27.
Urrestarazu, E., Iriarte, J., Alegre, M., Guridi, J., Rodríguez-Oroz, M.C., Obeso, J., Viteri, C., and
Artieda, J. Subthalamic role on the generation of spikes in temporal epilepsy. Epilepsy Res
2009; 83 (2-3): 257-260.
Voon V, Kubu C, Krack P, Houeto JL, Tröster AI. Deep brain stimulation: neuropsychological
and neuropsychiatric issues. Mov Disord. 2006;21 Suppl 14:S305-27.
Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schüpbach M, D'Ambrosia J, Thobois S,
Tamma F, Herzog J, Speelman JD, Samanta J, Kubu C, Rossignol H, Poon YY, Saint-Cyr JA,
Ardouin C, Moro E. A multicentre study on suicide outcomes following subthalamic
stimulation for Parkinson's disease. Brain. 2008 ;131(Pt 10):2720-8.
Yelnik J. Modeling the organization of the basal ganglia. Rev Neurol (Paris) 2008; 164: 969–76.
Legend - Figure 1. Schematic view on position of STN in integration of information from basal
ganglia and hyperdirect pathway
A. Situation in healthy individual; B. Parkinson´s disease (PD); C: Parkinson´s disease with DBS
STN
Symbols. Solid lines and boxes: Oversimplified scheme of the basal ganglia-thalamocortical
(BG) circuitry. Black lines: excitatory pathways; grey lines: inhibitory pathways, Dotted lines:
cognitive loop;
93
(a): the hyperdirect pathway, bolt: the DBS stimulation.
Explanation. The cognitive loop remains relatively spared by the dysfunction of the motor BG
circuitry in PD (A and B), the cognitive loop is down-regulated by the DBS STN (C) despite the
(relative) normalization of the motor part of the circuitry
94
3.5 Quality of life after DBS in patients with advanced Parkinson's disease
Published in: Ces Slov Neurol N 2011 74, č. 5, s. 564-568. IF 0.37
Commentary:
In the following paper we analysed long-term quality of life after DBS in patients with
advanced Parkinson's disease (PD). DBS does not halt neurodegenerative process and is also
a non-curative treatment and one of its main goals should be the improvement of patients'
quality of life (QoL). This paper was a first report in Czech neurological literature on influence
of DBS STN on QoL. DBS brings along usually quite speedy improvement of major parkinsonian
motors symptomatology. However, aim of this treatment, taking into consideration its
relatively high financial and personal costs,should be a long-term positive effect on lives of PD
patients. We included 26 patients who were observed for 3 years in this study.
We employed disease-specific quality of life questionnaire (PDQ-39). Disease specific
questionnaires are designed specifically to capture the influence of respective signs of disease
on QoL. PDQ-39 contains 39 items centered on limitations on various acitivities brought along
by PD within preceding 30 days. Questions relate to eight key areas of health and daily
activities, including both motor and non-motor symptoms. It is scored on a scale of zero to
100, with lower scores indicating better health and high scores more severe symptoms.
We found improvement of 46 % in overall score of PDQ-39 3 years after surgery. The UPDRS
III (Unified Parkinson’s Disease Rating Scale – subset III - reflecting purely the motor functions)
was better by 31 % after 3 years.
Regarding PDQ-39 subscores most changes were present in motor subscores, but important
positive statistically significant changes were also in the areas of communication, social
support and stigma of disease which belong to non-motor symptomatology.
Overall, our data confirmed a long-term positive influence of DBS on QoL in PD patients. Nonmotor
aspects of QoL were improved alongside with motor symptomatology.
Kvalita života po hluboké mozkové stimulaci u pacientů s pokročilou Parkinsonovou nemocí
Autoři: M. Baláž, M. Bočková, M. Bareš, I. Rektorová, V. Dírerová, I. Rektor
Autoři - působiště: Centrum pro abnormní pohyby a parkinsonizmus I. neurologická klinika LF
MU a FN u sv. Anny v Brně
95
Článek: Cesk Slov Neurol N 2011; 74/107(5): 564-568
Souhrn
Cíl:
Cílem práce je popsat vliv hluboké mozkové stimulace subthalamického jádra na jednotlivé
aspekty kvality života u pacientů s Parkinsonovou nemocí.
Soubor a metodika:
Práce sleduje kvalitu života ve skupině 26 pacientů s Parkinsonovou nemocí před operací, po
12 a 36 měsících od provedení hluboké mozkové stimulace. Kvalita života byla hodnocena
pomocí dotazníku PDQ-39.
Výsledky:
Kvalita životů pacientů se zlepšila o 46 % po třech letech od operace (p < 0,001). UPDRS III
skóre se zlepšilo o 38 % po jednom roce a o 31 % po třech letech (p < 0,001).
Závěry
V našem souboru jsme zjistili statisticky signifikantní zlepšení skóre PDQ-39 po 12 i 36 měsících
od operace u všech pacientů. Nejvýrazněji se zlepšení odrazilo v motorických příznacích, které
jsou DBS STN nejvíce ovlivněny. Lze pozorovat i efekt na sociální důsledky Parkinsonovy
nemoci (stigma, sociální podpora, komunikace). Hluboká mozková stimulace má dlouhodobý
efekt na kvalitu života.
Klíčová slova
hluboká mozková stimulace – kvalita života – Parkinsonova nemoc
Úvod
Parkinsonova nemoc je neurodegenerativní onemocnění s motorickými, senzitivními,
autonomními i neuropsychiatrickými příznaky. Základem terapie je dopaminergní medikace,
která má efekt především na motorické příznaky.
96
Vlivem dopaminergní terapie a progrese onemocnění se u velké části pacientů objevují pozdní
hybné komplikace, například motorické fluktuace a dyskinezy [1]. U části pacientů je vhodnou
terapií motorických příznaků v pozdním stadiu PN hluboká mozková stimulace (Deep Brain
Stimulation, DBS). Nejčastějším cílem implantace hlubokých elektrod u PN je subthalamické
jádro (STN) [2].
DBS STN zlepšuje skóre v Jednotné škále pro hodnocení PN (Unified Parkinson’s Disease Rating
Scale, UPDRS) ve stavu bez medikace – OFF – po roce od operace přibližně o 60 %. Výrazný
efekt DBS na jednotlivé podškály (UPDRS II a UPDRS III) trvá i více než pět let od implantace
systému (zlepšení o cca 43–57 %) [2].
DBS STN však není prevencí dalšího rozvoje onemocnění a obvykle neovlivňuje symptomy PN,
které nereagují na podávání L-DOPA (zárazy v chůzi, nemotorické příznaky). Vzhledem k tomu,
že PN je chronicky progredující neurodegenerativní onemocnění, je důležitým předpokladem
DBS STN, aby přínos této procedury dlouhodobě převažoval nad nežádoucími účinky, a efekt
operace se má projevit především zlepšením kvality života pacientů.
Kvalita života pacienta s PN je ovlivňována motorickými i nemotorickými příznaky a dalšími
faktory, jako je například délka trvání nemoci a věk pacientů [3]. Není snadné určit, zda mají
na kvalitu života významnější efekt symptomy motorické nebo nemotorické. Zajímavým
pozorováním je, že mohutnost efektu L-DOPA na motorické symptomy před operací je
prediktorem efektu DBS STN nejen na hybnost (reflektovanou především škálou UPDRS), ale i
kvalitu života [4]. Na druhou stranu je některými autory považován dopad nemotorických
(například neuropsychiatrických) příznaků za rozhodující faktor ovlivňující kvalitu života [3,5–
8].
V současnosti se ke sledování kvality života u PN užívají dva hlavní typy dotazníků – generické
a specifické [9,10]. Generické dotazníky (například EuroQOL Five Dimensions – EQ5D, Sickness
Impact Profile – SIP, Questions on Life Satisfaction – QLS) pokrývají velké množství aspektů
kvality života a dají se použít u rozličných nemocí. To poté umožňuje srovnání kvality života
mezi jednotlivými onemocněními.
97
Dotazníky specifické jsou sestaveny podle příznaků jednotlivých nemocí a dovolují hodnocení
dopadu konkrétních příznaků onemocnění na stav pacienta (například Parkinson’s Disease
Quality of Life Questionnaire – PDQL, Parkinson’s Disease Quality of Life Scale – PDQUALIF).
Nejčastěji používaným specifickým dotazníkem u PN je Dotazník kvality života u Parkinsonovy
nemoci – Parkinson’s Disease Questionnaire (PDQ-39). Kvalita života pacientů po DBS STN byla
sledována několika autory [9,11–13] a ti udávají celkové zlepšení od 14 do 62 %. Podle
Volkmanna et al [9] mají nemotorické symptomy PN (změny nálady, bolesti, poruchy spánku)
stejný nebo dokonce časem i větší efekt na kvalitu života než příznaky motorické. Zatím nelze
jednoznačně určit, které jednotlivé faktory se nejvíce podílejí na zlepšení kvality života.
V naší práci jsme se zaměřili na hodnocení dlouhodobého vlivu hluboké mozkové stimulace
pomocí dotazníku PDQ-39 a sledování změn jednotlivých částí dotazníku před operací a po 12
a 36 měsících od DBS STN.
Soubor a metodika
Soubor
Do studie bylo zařazeno 26 pacientů po DBS STN. Všichni byli pacienty indikovanými k DBS STN
v Centru pro abnormní pohyby a parkinsonizmus ve FN u sv. Anny v Brně v letech 2003 až
2006, kteří v čase hodnocení studie dosáhli dobu 36 měsíců od operace. Do studie nebyli
zahrnuti pouze dva pacienti, kteří zemřeli v kratší době než tři roky po DBS STN (oba z příčin
nesouvisejících s DBS STN – náhodné utonutí šest měsíců po operaci, plicní embolie po 34
měsících od operace).
Soubor zahrnuje celkem 11 žen a 15 mužů s pokročilou PN. Průměrný věk v době operace byl
59,3 ± 7,4 let. Trvání PN v čase operace dosáhlo 10,3 ± 3,2 let. Průměrné trvání léčby přípravky
L-DOPA 8,4 ± 2,9 let, stadium PN dle Hoehnové a Yahra dosáhlo v době operace ve stavu OFF
průměrně 3,02 ± 0,5.
Hluboká mozková stimulace
98
Pacienti byli indikováni k provedení DBS STN podle standardních kritérií již opakovaně
popsaných v domácí [8,14,15] i zahraniční literatuře [16]. Hlavními indikacemi k provedení DBS
STN byly pozdní motorické komplikace Parkinsonovy nemoci (především ON-OFF fluktuace a
dyskineze) neovlivnitelné úpravami medikace.
Při DBS neurochirurg do STN stereotakticky zavedl stimulační elektrodu. Během zavádění
elektrod byl proveden perioperační elektrofyziologický monitoring a perioperační
mikrostimulace. S odstupem 3–7 dnů od zavedení elektrod byl do podkoží v subklavikulární
oblasti implantován stimulátor. Podrobný popis průběhu operace je také dostupný v literatuře
[2,17].
Efekt hluboké mozkové stimulace v našem souboru pacientů považujeme za velmi dobrý, je
reflektován změnou skóre jednotlivých položek UPDRS (tab. 1).
Tab. 1. Charakteristika souboru pacientů.
Před DBS
(medikace off)
12 měsíců po DBS
(medikace
off/stimulace on)
Hodnota p
(rozdíl 12
měsíců po
vs. před
DBS)
36 měsíců po
DBS(medikace
off/stimulace on)
Hodnota p
(rozdíl 36
měsíců po vs.
před DBS)
UPDRS II 21,8 ± 4,3 18,2 ± 3,9 0,0032 19,3 ± 4,1 0,0407
UPDRS III 41,6 ± 9,2 25,79 ± 5,0 <0.0001 28, 8 ± 5,2 <0.0001
LED (mg) 1042 ± 305 580 ± 240 <0.0001 630 ± 280 <0.0001
Amplituda
stimulace (V)
Bez stimulace 2,8 V ± 0,4V - 3,4 V ± 0,5V <0.0001 mezi
12 a36 měs.
PDQ-39
(celkové skóre)
75,16 ± 13,2 40,2 ± 16,3 0,000123 49,3 ± 16,5 0,01
Hodnocení kvality života
99
U pacientů bylo v rámci standardního předoperačního vyšetření provedeno šetření kvality
života pomocí dotazníku PDQ-39. PDQ-39 je dotazník vyplňovaný přímo pacientem, obsahuje
39 dotazů na jednotlivé potíže a omezení způsobená Parkinsonovou nemocí pociťovaná v
průběhu posledního měsíce [18].
Tento dotazník pacienti vyplnili i 12 a 36 měsíců po DBS STN.
Před operací pacienti vyplnili dotazník kvality života ve stavu ON (během účinku dopaminergní
medikace), zatímco po DBS STN ve stavu ON a se zapojenou stimulací (ON/ON).
Ve výsledcích referujeme i změnu v položkách UPDRS II (aktivity denního života), UPDRS III a
IV. Škála UPDRS byla hodnocena před operací u pacientů během tzv. definovaného OFF stavu
(12 hod bez dopaminergní medikace). V období po operaci bylo hodnocení UPDRS provedeno
se zapojenou stimulací, bez medikace (ON stimulace/OFF medikace). Dále jsou v tabulkách
uvedeny i průměrné parametry stimulace a dávka dopaminergní medikace, kterou pacienti
užívali v konkrétním čase.
Statistické hodnocení
Ke statistické analýze byly použity ANOVA a Tukeyův test (ke srovnání rozdílů mezi
jednotlivými podškálami).
Výsledky
Změny v parametrech UPDRS, amplitudě stimulace a dávce levodopa ekvivalentu (LED) jsou
shrnuty v tab. 1. Zlepšení hybnosti, které bylo jasně patrné po roce, bylo zachováno i po dalších
dvou letech. Délka trvání dyskinez poklesla v průměru o 68,5 %.
Tak jak bylo možné předpokládat, LED byla významně snížena po DBS STN a toto snížení
medikace bylo stále významné i po 36 měsících. U dvou pacientů bylo možno po dobu více než
12 měsíců zcela přerušit podávání dopaminergní léčby a po 36 měsících byly u čtyř pacientů
podávány pouze agonisté dopaminových receptorů.
100
Při analýze naší skupiny pacientů jsme nepozorovali vliv věku nebo délky trvání nemoci na
míru zlepšení kvality života.
Po 36 měsících byla průměrná amplituda stimulace 3,4 ± 0,5 V. Frekvence nastavení byla u
všech pacientů 130 Hz. Šířka pulzu dosáhla 90 µs, s výjimkou dvou pacientů, kde byla
nastavena na 60 µs.
Kvalita života se ve škále PDQ-39 významně zlepšila po 12 a 36 měsících ve srovnání se stavem
před operací (graf 1). Mírné zvýšení celkového skóre mezi 12 a 36 měsíci nebylo statisticky
významné (p = 0,19). Hvězdička (*) označuje statisticky signifikantní změnu.
Graf 1. Grafické zobrazení celkového skóre kvality života (PDQ-39 – osa Y) před operací DBS,
po 12 a 36 měsících (na ose X). Vertikální sloupce zobrazují 0,95 interval konfidence.
Zajímavé výsledky přineslo hodnocení jednotlivých podškál PDQ-39. DBS mělo významný vliv
na většinu podškál, a to na motorické příznaky (mobilita) i sociální důsledky PN (stigma,
sociální podpora, komunikace). V oblastech, jako aktivity denního života, emoce, kognice,
tělesný dyskomfort se však kvalita života pacientů signifikantně po 36 měsících nezlepšila
(emoce sice zlepšeny po 12 měsících, ale zlepšení po 36 měsících od implantace již nebylo
patrné). Tab. 2 shrnuje výsledky podškál a příslušné hodnoty p.
Tab. 2. Podškály PDQ-39.
Podškála PDQ –
39
Před DBS 12 měsíců po
DBS
P 36 měsíců po
DBS
p
Mobilita 64,1 32,8 <0,0001 44,4 0,0034
Aktivity
denního života
35,9 26,7 0,1116 30,8 0,2746
Emoce 40,2 25,8 0,0171 31,9 0,1512
101
Stigma 50,8 27,8 0,0007 25,8 0,0002
Sociální
podpora
30 16,4 0,0141 17,5 0,0340
Kognice 33 21,8 0,0564 40,8 0,1526
Komunikace 39,7 21 0,0027 26,6 0,0359
Tělesný
dyskomfort
25,3 17,3 0,1120 18,9 0,1968
Diskuze
Zlepšení kvality života po DBS STN se v různých pracích pohybuje v poměrně širokém rozpětí
14 až 62 % [19,20]. Někteří autoři pozorovali pouze zlepšení motorických, jiní i nemotorických
příznaků PN (neuropsychiatrické příznaky).
V našem souboru jsme zjistili statisticky signifikantní zlepšení skóre PDQ-39 po roce i po 36
měsících od operace u všech pacientů. Jak se dá předpokládat, nejvýrazněji se zlepšení
odrazilo v motorických příznacích, které jsou prostřednictvím DBS STN nejvíce ovlivněny. Z
tohoto pohledu se naše výsledky přibližují závěrům jiných otevřených studií [12,20–22]. Za
zajímavé považujeme však i statisticky signifikantní zlepšení v podškálách stigma, komunikace
a sociální podpora, které odrážejí sociální důsledky Parkinsonovy nemoci.
Mírné zhoršení kvality života po 36 mě- sících ve srovnání se stavem po roce od DBS je
pravděpodobně výsledkem progrese PN a akcentace příznaků, které jsou jen málo ovlivnitelné
pomocí DBS, resp. dopaminergní terapie. Nejvýraznější zhoršení, pokud jde o nárůst bodového
hodnocení mezi 12 a 36 měsíci, bylo v podškále kognice a emocí. Tento výsledek je v souladu
s publikovanými studiemi [24,25]. U části pacientů po DBS STN bylo pozorováno zhoršení
kognitivních (především verbální fluence, verbální paměti, asociativní učení, vizuospaciální
paměť) a také některých neuropsychiatrických funkcí [6]. Za příčiny tohoto jevu se považují
preoperační faktory (předchozí psychiatrické nemoci), vlivy operace (trvání procedury,
trajektorie elektrod, chirurgické komplikace), působení stimulace (umístění elektrod,
102
stimulační parametry), psychosociální změny po DBS STN a změny související s PN
(neurodegenerativní proces, nedopaminergní symptomy). Porucha kognitivních funkcí v
anamnéze je jednou z hlavních kontraindikací hluboké mozkové stimulace. Je vhodné
potenciální kandidáty informovat o možném mírném poklesu některých kognitivních
schopností po DBS STN [26].
Limitací naší studie může být to, že se jedná o retrospektivní zpracování dat z databáze
pacientů. Pacienti indikovaní k DBS jsou však poměrně malá skupina (podle literárních údajů
je k DBS indikovaných zatím pouze do 4,5 % s PN [23]) a v jejich případě dochází již k jisté
preselekci (věk, stupeň pokročilosti PN, menší výskyt jiných onemocnění, dobrý
neuropsychologický a kognitivní stav, nepřítomnost dalších kontraindikací k operačnímu
výkonu), a proto srovnání se skupinou jiných pacientů shodující se pouze ve věku a trvání
onemocnění nemusí mít dostatečnou výpovědní hodnotu.
Předmětem dalšího studia mohou být externí faktory, které zlepšení kvality podmiňují. Při
analýze naší skupiny pacientů jsme nepozorovali vliv věku nebo délky trvání nemoci na míru
zlepšení kvality života. Zajímavou otázkou je studium korelace zlepšení mezi kvalitou života a
motorickými příznaky (vyjádřenými ve škále UPDRS III). Podle práce autorů Lezcano et al [13]
se korelace zlepšení motoriky a kvality života, jež je přítomna po 12 měsících, snižuje po dvou
letech. Uvedení autoři předpokládají, že po iniciálním zlepšení motoriky, které se projeví na
úpravě kvality života po 12 měsících, mají na kvalitu života po dvou letech větší vliv jiné než
motorické příznaky PN (např. komunikace). V našem souboru bylo možno (i vzhledem k
nutnosti mírného zvýšení amplitudy stimulace a medikace (LED) mezi 12 a 36 měsíci)
pozorovat mírnou progresi onemocnění, která se odrazila i v mírném nárůstu skóre PDQ-39
po 36 měsících ve srovnání se stavem po jednom roce. Tato progrese byla v oblasti
motorických příznaků kompenzována úpravami stimulačních parametrů a medikace jen
částečně (mírné zhoršení motorického skóre ve stavu OFF v UPDRS, nárůst skóre aktivit
denního života a motoriky ve škále PDQ-39).
Hodnocení a sledování kvality života u pacientů indikovaných k DBS STN považujeme za velmi
významné, přestože hodnocení kvality života je subjektivní a u PN není zcela jasné, které
dotazníky jsou pro tento účel nejvhodnější. Při terapeutické metodě, jež není kurativní a má
103
nezanedbatelné náklady personální a finanční, je nutné indikovat pacienty, kteří mají z této
léčby co největší benefit. I proto je kvalita života parametr, který by měl být neurology i
neurochirurgy pozorně sledován i při zavádění nových terapeutických metod u PN. Přikláníme
se k názoru, že je vhodné upravit kritéria k indikacím DBS STN tak, aby zahrnovala i aspekty
související s kvalitou života [20] tak, aby byla metoda nabídnuta pacientům, u kterých můžeme
očekávat zlepšení právě v aspektech/doménách nejlépe ovlivnitelných působením stimulace
(motorika, aktivity denního života).
MUDr. Marek Baláž, Ph.D.
Centrum pro abnormní pohyby a parkinsonizmus
I. neurologická klinika LF MU a FN u sv. Anny v Brně
Pekařská 53
656 91 Brno
e-mail: marek.balaz@fnusa.cz
Přijato k recenzi: 30. 11. 2010
Přijato do tisku: 6. 4. 2011
Poděkování
Děkujeme prof. MUDr. Z. Novákovi, Ph.D., a MUDr. J. Chrastinovi, Ph.D., za provedení
stereotaktických neurochirurgických výkonů a Ing. Z. Novotnému za zpracování statistiky.
Podpořeno výzkumným záměrem MŠMMT 002 162 2404.
Literatura
1. Kanovský P, Kubová D, Bares M, Hortová H, Streitová H, Znojil V et al. Levodopa-induced
dyskinesias and the continuous subcutaneous infusions of apomorphine: results of two-years,
prospective follow-up. Mov Disord 2002; 17(1): 188–191.
2. Chrastina J, Zbořilová E, Smrčka V, Nádvorník P. Renesance stereotaktické léčby
parkinsonského třesu. Cesk Slov Neurol N 1996; 59/92(5): 265–268.
104
3. Schrag A, Hovris A, Morley D, Quinn N, Jahanshahi M. Young versus older-onset Parkinson’s
disease: impact of disease and psychosocial consequences. Mov Disord 2003; 18(11): 1250–
1256.
4. Smeding HM, Speelman JD, Huizenga HM, Schuurman PR, Schmand B. Predictors of
cognitive and psychosocial outcome after STN DBS in Parkinson’s Disease. J Neurol Neurosurg
Psychiatry 2011; 82(7): 754–760.
5. Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with
Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000; 69(3): 308–312.
6. Voon V, Kubu C, Krack P, Houeto JL, Tröster AI. Deep brain stimulation: neuropsychological
and neuropsychiatric issues. Mov Disord 2006; 21 (Suppl 14): S305–S327.
7. Parsons TD, Rogers SA, Braaten AJ, Woods SP, Tröster AI. Cognitive sequelae of subthalamic
nucleus deep brain stimulation in Parkinson’s disease: a meta-analysis. Lancet Neurol 2006;
5(7): 578–588.
8. Baláž M, Rektor I. Neuropsychologické a kognitivní vlivy hluboké mozkové stimulace
subtalamického jádra u pacientů s Parkinsonovou nemocí. Neurol Prax 2008; 9(5): 278–282.
9. Volkmann J, Albanese A, Kulisevsky J, Tornqvist AL, Houeto JL, Pidoux B et al. Long-term
effects of pallidal or subthalamic deep brain stimulation on quality of life in Parkinson’s
disease. Mov Disord 2009; 24(8): 1154–1161.
10. Ferrara J, Diamond A, Hunter C, Davidson A, Almaguer M, Jankovic J. Impact of STN-DBS
on life and health satisfaction in patients with Parkinson’s disease. J Neurol Neurosurg
Psychiatry 2010; 81(3): 315–319.
11. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K et al. A randomized
trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355(9): 896–908.
12. Just H, Ostergaard K. Health-related quality of life in patients with advanced Parkinson’s
disease treated with deep brain stimulation of the subthalamic nuclei. Mov Disord 2002; 17(3):
539–545.
13. Lezcano E, Gómez-Esteban JC, Zarranz JJ, Lambarri I, Madoz P, Bilbao G et al. Improvement
in quality of life in patients with advanced Parkinson’s disease following bilateral deep-brain
stimulation in subthalamic nucleus. Eur J Neurol 2004; 11(7): 451–454.
14. Urgošík D,Vladyka V. Neurochirurgická léčba Parkinsonovy nemoci. In: Růžička E, Roth J,
Kaňovský P et al (eds). Parkinsonova nemoc a parkinsonské syndromy. Extrapyramidová
onemocnění II. Praha: Galén 2000: 200–209.
105
15. Urgošík D, Jech R, Růžička E. Hluboká mozková stimulace u nemocných s
extrapyramidovými poruchami pohybu stereotaktická procedura a intraoperační nálezy. Cesk
Slov Neurol N 2011; 74/107(2): 175–186.
16. Defer GL, Widner H, Marié RM, Rémy P, Levivier M. Core assessment program for surgical
interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999; 14(4): 572–584.
17. Peto V, Jenkinson C, Fitzpatrick R, Greenhall R. The development and validation of a short
measure of functioning and well being for individuals with Parkinson’s disease. Qual Life Res
1995; 4(3): 241–248.
18. Erola T, Karinen P, Heikkinen E, Tuominen J, Haapaniemi T, Koivukangas J et al. Bilateral
subthalamic nucleus stimulation improves health-related quality of life in Parkinsonian
patients. Parkinsonism Relat Disord 2005; 11(2): 89–94.
19. Lyons KE, Pahwa R. Long-term benefits in quality of life provided by bilateral subthalamic
stimulation in patients with Parkinson disease. J Neurosurg 2005; 103(2): 252–255.
20. Martínez-Martín P, Valldeoriola F, Tolosa E, Pilleri M, Molinuevo JL, Rumià J et al. Bilateral
subthalamic nucleus stimulation and quality of life in advanced Parkinson’s disease. Mov
Disord 2002; 17(2): 372–377.
21. Lagrange E, Krack P, Moro E, Ardouin C, Van Blercom N, Chabardes S et al. Bilateral
subthalamic nucleus stimulation improves health-related quality of life in PD. Neurology 2002;
59(12): 1976–1978.
22. Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP et al. The PRIAMO
study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in
Parkinson’s disease. Mov Disord 2009; 24(11): 1641–1649.
23. Morgante L, Morgante F, Moro E, Epifanio A, Girlanda P, Ragonese P et al. How many
Parkinsonian patients are suitable candidates for deep brain stimulation of subthalamic
nucleus? Results of a questionnaire. Parkinsonism Relat Disord 2007; 13(8): 528–531.
24. Emre M. Treatment of dementia associated with Parkinson’s disease. Parkinsonism Relat
Disord 2007; 13 (Suppl 3): S457–S461.
25. Burn DJ, Tröster AI. Neuropsychiatric complications of medical and surgical therapies for
Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17(3): 172–180.
26. Telecká S, Baláž M, Rektorová I, Fanfrdlová Z, Rektor I. Jeden rok po hluboké mozkové
stimulaci pacientů s Parkinsonovou nemocí – neuropsychologické výsledky. Cesk Slov Neurol
N 2010; 73/106(1): 57–61.
106
3.6 One year after deep brain stimulation of patients with Parkinson's disease:
neuropsychological results
Published in: Cesk Slov Neurol N 2010; 73/106(1): 57-61. IF 0.37
Commentary:
The following paper summarizes initial neuropsychological outcomes by our group on results
of neuropsychological test in patients with advanced Parkinson's disease who underwent DBS
STN. Neuropsychological testing and assessment of function is an important prerequisite for
DBS STN indication. It was proven that DBS (see e.g. Krack et al 2003) can worsen the cognitive
and psychiatric status of the patient in case of pre-existent affective disorder (depression) or
cognitive dysfunction (mild cognitive impairment or dementia).
Postoperative evaluation of neuropsychological function is an important step in care of
patient with DBS.
In this paper a wide array of well established neuropsychological tests was used both for initial
analysis and for final evaluation after one year in group of 19 patients with advanced PD
indicated for DBS STN surgery. These included Wechsler Adult Intelligence Scale Revised,
Mattis Dementia Rating Scale, Wechsler Memory Scale, Rey-Osterrieth Complex Figure, Stroop
Test, Tower of London, Lexical Fluency, Category Fluency, Beck Depression Inventory and
Montgomery-Asberg Depression Rating Scale.
Patients were strictly evaluated during so called ON state (with good control of motor
parkinsonian symptoms) to eliminate negative effect of PD symptoms such as slowness of
movements on neuropsychological testing. In all patients sufficient improvement of motor
function occurred after DBS STN. There were no siginificant surgical complications present.
We found minor, but statistically significant worsening of attention, executive function and
verbal fluency one year after DBS. Our result are in congruence with data published by
international groups of authors (e.g. Voon et al, 2006).
As a co-author I participated in preparing the general idea for article, collected data related to
DBS procedure, an took major part in preparation of this article.
107
Jeden rok po hluboké mozkové stimulaci pacientů s Parkinsonovou nemocí:
neuropsychologické výsledky
S. Telecká, M. Baláž, I. Rektorová, Z. Fanfrdlová, I. Rektor
Centrum pro abnormní pohyby a parkinsonismus, I.neurologická klinika LF MU a FN u sv. Anny,
Brno
Sabina Telecká, I. neurologická klinika FN u sv. Anny v Brně, Pekařská 53, 656 91 Brno,
sabina.telecka@fnusa.cz
Podpořeno Výzkumným záměrem MŠM 002162240
Souhrn:
Cíl studie: Zhodnotit stav kognitivních schopností rok po hluboké mozkové stimulaci
subtalamického jádra u pacientů s Parkinsonovou nemocí.
Soubor a metodika: 19 pacientů bez příznaků demence podstoupilo neuropsychologické
vyšetření před a rok po DBS operaci v motorickém stavu “ON”. Pro datovou analýzu byl použit
Wilcoxonův párový test.
Výsledky: U všech pacientů bylo zaznamenáno dlouhodobé zlepšení motorického výkonu a
motorických komplikací při stimulaci “ON”. Analýza ukázala pokles výkonu v případě
Stroopova testu, části “Slova-Barvy”, verbální fluence sémantické i lexikální, Doplňování
obrázků a testu slovního učení „Seznam slov – oddálené vybavení“.
Závěr: Zjistili jsme mírný, avšak statisticky signifikantní pokles výkonu u testů měřících
pozornost, exekutivní schopnosti a verbální paměť (volné vybavení); zatímco nálada (deprese)
nebyla DBS nijak ovlivněna.
Klíčová slova: hluboká mozková stimulace, subtalamické jádro, kognitivní schopnosti,
exekutivní, deprese
Zkratky:
DBS – hluboká mozková stimulace
PN – Parkinsonova nemoc
STN – subtalamické jádro
108
Key words: deep brain stimulation, sutthalamic nucleus, cognitive functions, executive,
depression.
Úvod
Hluboká mozková stimulace (deep brain stimulation, DBS) je indikována nejčastěji k terapii
pozdních hybných komplikací Parkinsonovy nemoci (PN), které neodpovídají na úpravy
farmakoterapie. Nejčastějším anatomickým cílem DBS u pokročilé PN je subtalamické jádro
(STN). Jde o bezpečný a účinný postup, který u pacientů výrazně zlepšuje hybné symptomy
PN, pozdní hybné komplikace a zvyšuje kvalitu života [1,2,3].
Výtečný symptomatický efekt na třes, rigiditu a hypokinézu, spolu s možností snížení
dopaminergní terapie v pooperačním období, přispěl k rozšíření této metody. DBS STN snižuje
motorické fluktuace, čas trvání levodopou (L-DOPA) indukovaných dyskinezí a umožní snížit
antiparkinsonskou terapii L-DOPA ekvivalentu ve srovnání s předoperačním stavem [4].
Díky výraznému efektu na motorické skóre (v UPDRS III – Unified Parkinson Disease Rating
Scale III – jednotná škála k hodnocení tíže hybných symptomů PN – výrazné pooperační
zlepšení), snížení motorických fluktuací (trvání dyskinezí a off stavů) a zlepšení kvality života
pacientů (PDQ-39 – Parkinson Disease Quality of Life - snížení skóre) v dlouhodobém
sledování, je DBS mimořádně efektivním terapeutickým postupem u pacientů s pozdními
hybnými komplikacemi PN [1].
Antiparkinsonskou medikaci je možno posléze redukovat, což vede k signifikantnímu snížení
nežádoucích účinků (viz webové stránky NINDS – DBS,
www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm).
DBS má jako každý funkční neurochirurgický výkon rizika spojená s chirurgickou intervencí
(krvácení, infekce), působením stimulace (ovlivnění okolních anatomických struktur) a další
rizika přináší umístění cizího materiálu (infekce, rejekce, lokální iritace kůže) [5].
Z hlediska neuropsychologického literatura nejčastěji hovoří o snížení schopností v oblasti
verbální paměti a verbální fluence [např. 6,7].
Výraznějším nežádoucím účinkům je však možno se vyhnout přísným dodržením indikačních a
vylučujících kritérií, Tab. 1 [blíže viz 1]. Z psychologického hlediska jde především o to
nezařazovat pacienty trpící významnějším kognitivním deficitem nebo psychiatrickými
symptomy (halucinace, psychóza, těžší forma deprese).
109
Neuropsychologické charakteristiky pacientů s PN
Neuropsychologický deficit u PN je charakterizován progresivním „dysexekutivním“
syndromem s paměťovým deficitem a poruchou abstraktního myšlení [např.8], viz též Tab. 2.
Kognitivní poruchy mírného stupně jsou časté již v rané fázi onemocnění a mohou progredovat
do demence až u 78,2 % pacientů v pozdním stádiu nemoci [9]. Demence významně snižuje
kvalitu života pacientů a zkracuje dobu jejich přežití, způsobuje dvojnásobný nárůst mortality
[8]. Riziko rozvoje demence u pacientů s PN je 1,7-5,9 x vyšší než u běžné populace stejného
věku, vzdělání a pohlaví [10].
Většina pacientů také prožívá deprese, mnohdy kombinované s úzkostí. Psychotické projevy
jsou častější především u pacientů s kognitivním deficitem; celkově se však objevují u menší
části nemocných zejména jako nežádoucí efekt dopaminergní terapie.
110
Jeden rok po STN DBS u pacientů s PN - neuropsychologické výsledky z našeho pracoviště
Cíl výzkumu:
Zhodnotit kognitivní schopnosti a změny nálady po DBS STN u pacientů s PN.
Soubor a Metodika:
19 pacientů bez příznaků demence (průměrný věk 58,8 ± 8,2 roku; vzdělání 12,6 ± 2,1 roku,
skóre Mattisovy škály demence 141 ± 3,8) podstoupilo neuropsychologické vyšetření před a
po DBS operaci v motorickém stavu “ON” (mediánový interval mezi DBS a
neuropsychologickým vyšetřením byl 11 měsíců). Pro datovou analýzu byl použit Wilcoxonův
párový test.
Testová baterie:
Wechslerova inteligenční škála pro dospělé (Wechsler Adult Intelligence Scale Revised, WAISR,
WAIS-III; [11]): Nejčastěji používaná metoda ke komplexnímu mapování intelektových
schopností pacientů. V našem výzkumu jsme použili zkrácenou verzi [12], obsahující subtesty
Doplňování obrázků, Počty, Symboly, Podobnosti.
Mattisova škála demence (Mattis Dementia Rating Scale, DRS; [13]): Často používaná
screeningová zkouška. Obsahuje subtesty měřící pozornost (opakování čísel), iniciaci a
perseveraci (schopnost začít a dokončit určitou činnost), konstrukci (kopírování vzorů dle
předlohy), konceptualizaci (podobnosti) a verbální a nonverbální krátkodobou paměť
(opakování vět, rozpoznávání obrazců).
Wechslerova paměťová škála (Wechsler Memory Scale, WMS-III; [14]) – část Seznam slov:
Jeden z tzv. testů verbálního učení - zaměřuje se na verbální učení, organizaci a paměť.
Součástí testu je také složka znovupoznání.
Test komplexní figury (Rey-Osterrieth Complex Figure, R-O; [15]): Hojně využívaný test, který
mapuje vizuo-spaciální konstrukční schopnosti, vizuálně-motorickou kontrolu a pozornost a
mnestickou kapacitu – bezprostřední i oddálenou. Lze využít i část „znovupoznání“ (recall).
Stroopův test (Stroop Test; [16]): Měří schopnost přepínání pozornosti (shifting); je měřítkem
flexibility. Je citlivý na detekci mozkových poškození, zejména ve frontální oblasti.
Londýnská věž (Tower of London, TOL; [17]): Test mapuje exekutivní schopnosti, především
schopnost strategického plánování a vizuálně-prostorového řešení problému a schopnost
dodržení nalezeného schématu.
111
Lexikální cílená verbální fluence (Lexical Fluency): Úkolem je za jednu minutu vytvořit co
nejvíce slov začínajících na dané písmeno (neplatná jsou vlastní jména, číslice a stejná slova
s rozdílnou příponou). V anglosaské literatuře jsou používána písmena F,A,S; u nás N,K,P)
Sémantická cílená verbální fluence (Category Fluency): v případě fluence sémantické je úkolem
za jednu minutu vyjmenovat co nejvíce slov spadajících do určené kategorie – např. „zvířata“,
„potraviny“ či „oblečení“.
Beckova škála deprese (Beck Depression Inventory, BDI; [18]): Sebeposuzovací stupnice, která
se používá v klinické praxi i ve výzkumu. Položky jsou zaměřeny na afektivní, kognitivní,
motivační a fyziologické symptomy deprese. Dotazník měří aktuální stav, ne depresivitu jako
rys osobnosti.
Škála MADRS (Montgomery-Asberg Depression Rating Scale; [19]): Objektivní škála určená
k posuzování míry deprese; je citlivá k zachycení změn v čase, je validizována pro diagnostiku
deprese u PN.
Výsledky:
U všech pacientů bylo zaznamenáno dlouhodobé zlepšení motorického výkonu a motorických
komplikací při stimulaci “ON”.
Medián stimulačních parametrů byl 2,6 V± 0,4 V, 130 Hz a 90 usec. U všech 19 pacientů bylo
zapojení stimulace monopolární (s aktivní katodou v oblasti STN).
Významné zlepšení motorického skóre (UPDRS III) bylo zjištěno u všech stimulovaných
pacientů. UPDRS III při medikaci OFF/ stimulaci ON pokleslo o 68,5 % a při medikaci ON/
stimulaci ON o 70 % ve srovnání se stavem před operací. Medián stimulačních parametrů byl
2,6 V, 130 Hz a 90 usec.
Tabulka 3 ukazuje porovnání souborů výsledků neuropsychologických testů před a po operaci.
Hodnota p je pravděpodobností shody obou souborů; při nízké hodnotě p
o shodě souborů zamítáme.
Analýza ukázala statisticky signifikantní změny u následujících testů (vždy se jednalo o pokles
výkonu ve srovnání se situací před operací): Stroopův test, část “Slova-Barvy” (p = 0,004),
Verbální fluence: sémantická (p = 0,018) a lexikální (p = 0,022), Doplňování obrázků (subtest
WAIS-R; p = 0,016); Seznam slov – oddálené vybavení (subtest WMS-III; p = 0,019). Pokles ve
112
výkonu u sledovaných schopností byl spíše mírný, v celkovém klinickém dojmu se výrazněji
neprojevuje.
V období 1 roku po DBS se u pacientů neprojevují žádné psychiatrické symptomy jako jsou
bludy, halucinace, porucha kontroly impulzů (patologické hráčství, neadekvátní sexuální
chování, patologické nakupování, žravost), či kompulzívní nadužívání dopaminergní medikace
(dopamine dysregulation syndrom). Rovněž se neobjevil statisticky signifikantní rozdíl v míře
deprese.
Diskuse:
U sledovaných pacientů jsme zjistili mírný, ale signifikantní pokles v oblasti pozornosti,
exekutivních schopností a verbální paměti. Nepozorovali jsme žádné změny nálady.
Pokud jde o kognitivní změny po DBS STN, výsledky jednotlivých studií se liší a nejsou
konzistentní.
Nejčastěji v literatuře nacházíme informace o mírných parciálních změnách kognitivních
schopností, zejména u verbální fluence, verbální paměti a pozornosti [např.6,20,21]. York et
al. [7] hovoří o mírném frontostriatálním kognitivním deficitu (verbální fluence, pozornost,
rychlost zpracování informací a verbální paměť). Naše výsledky jsou v souladu s výsledky
těchto studií.
Podstatné je, že uváděné selektivní kognitivní změny nemívají dle literatury výraznější vliv na
kvalitu života pacientů [2,22]. Nejedná se o signifikantní změny v globálním kognitivním
výkonu [2, 23]. Pokud se objeví demence, je to obvykle přičítáno přirozenému vývoji PN, nikoli
vlivu DBS [např.20, 3]. V naší práci jsme se však na hodnocení kvality života nezaměřovali,
nemůžeme se tudíž k dopadu mírného zhoršení výkonu v některých kognitivních testech na
kvalitu života našich konkrétních pacientů vyjádřit.
Witt et al. [2] zjistili pokles výkonu ve Stroopově testu a verbální fluenci, zatímco verbální
paměť, pracovní paměť a pozornost podle nich zůstaly beze změn. V některých studiích nebyl
pozorován žádný pokles kognitivních schopností [např.24]. Existuje dokonce i práce, která
referuje o zlepšení některých kognitivních schopností po DBS STN: např. v případě některých
aspektů exekutivních schopností - pracovní paměti, řešení problémů, rychlost zpracování
informace, mentální flexibility [25].
113
Patofyziologie selektivních kognitivních změn pozorovatelných u pacientů po STN DBS není
doposud plně objasněna. Změny by mohly souviset s implantací elektrod a zejména s jejich
přesným umístěním, s vlastní stimulací a použitými stimulačními parametry, nebo i se změnou
dopaminergní medikace (jejím snížením) po STN DBS [2,26,27] .
Recentní randomizovaná studie porovnávající kognitivní efekty STN DBS a DBS vnitřního
pallida u pacientů s PN [28] prokázala po 7 měsících sledování srovnatelný pozitivní efekt na
hybné symptomy PN, avšak zhoršení v testu verbální fluence v porovnání s výkonem před DBS
pouze v případě stimulace STN, a to zejm. v „off“ stavu (po vypnutí stimulace). Autoři uzavírají,
že zhoršení kognitivního výkonu v testu verbální fluence u pacientů s STN DBS souvisí
pravděpodobně spíš s chirurgickým výkonem (implantací elektrod) než s vlastní stimulací.
Hypotézy o kauzálních mechanismech těchto změn vycházejí zejména ze studií na zvířecích
modelech PN nebo z výsledků studií s použitím funkčních zobrazovacích metod (PET) u
pacientů s PN. Např. Campbell et al. [27] zjistili pomocí vyšetření H2
15O PET, že pacienti s
kognitivním deficitem navozeným DBS měli stimulací navozené zvýšení regionálního průtoku
krve v oblasti dorsolaterálního prefrontálního kortexu a předního cingula a naopak pacienti se
zlepšením kognitivních funkcí v důsledku stimulace měli snížený průtok krve ve stejných
oblastech mozku. Co je ale podkladem těchto změn na buněčné úrovni, není jasné. Autoři
např. uvádějí hypotézu, že vnucená frekvence vybíjení STN na jedné straně zlepšuje motorické
funkce pacientů s PN, na druhé straně může interferovat s fázickou aktivitou dopaminergních
neuronů mající vztah ke kognitivním funkcím.
Pokud se týká psychiatrických potíží, Voon et al. [29] popisují přechodné a terapeuticky
ovlivnitelné neuropsychiatrické symptomy (přechodná zmatenost, pooperační hypománie,
transientní apatie, zrakové halucinace); a dále epizody pooperační deprese – které mají
tendenci se v průběhu dalších let postupně zmírňovat. V našem souboru jsme nezjistili žádnou
výraznější změnu depresivní symptomatologie, v korelaci s jinými autory [např.7].
Závěr:
Zjistili jsme mírný, avšak statisticky signifikantní pokles výkonu u testů měřících pozornost,
exekutivní schopnosti a verbální paměť (volné vybavení); zatímco nálada (deprese) nebyla DBS
114
nijak ovlivněna. Naše výsledky jsou srovnatelné s výsledky dalších studií publikovaných v
literatuře.
Potenciální kandidáti DBS by měli být informováni o možnosti mírného poklesu některých
kognitivních schopností, při současné šanci výrazné úpravy motorických obtíží.
Budoucí studie by měly být zaměřeny na detailnější studium patofyziologických mechanismů
kognitivních a behaviorálních změn u pacientů po DBS a na hledání rizikových faktorů
predikujících individuální změny navozené DBS.
Literatura
1. Baláž M, Rektor I. Neuropsycholgické a kognitivní vlivy hluboké mozkové stimulace
subtalamického jádra u pacientů s Parkinsonovou nemocí. Neurol. pro praxi, 2008;
9(5): 305-307.
2. Witt K, Daniela C, Reiff J, Krack P et al. Neuropsychological and psychiatric changes
after deep brain stimulation for Parkinson´s disease: a randomised, multicentral study.
Lancet Neurol, 2008; 7: 605-614.
3. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin
PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P. Five-year follow-up of bilateral
stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med
2003;349:1925-34
4. Houeto JL, Damier P, Bejjani PB, Staedler C, Bonnet AM, Arnulf I et al. Subthalamic
stimulation in Parkonson´s disease: a multidisciplinary approach. Arch Neurol. 2000;
57 (4): 461-465.
5. Chrastina J, Novák Z, Baláž M, Krupa P, Říha I, Jančálek R, Rektor I. Subthalamic nucleus
stimulation – surgical problems. Neurologie pro praxi, 2006; 2 (Suppl B, Handbook of
the 38th International Danube Symposium for Neurological Sciences and Continuing
Education, Brno 6-8 April 2006): B45.
6. Higginson CI, Wheelock VL, Levine D, King DS, Pallas CTE, Sivgardt KA. The clinical
significance of neuropsychological changes following bilateral subthalamic nucleus
deep brain stimulation for Parkinson´s disease. J Clin and Exp Neurops, 2008: 416-419.
7. York MK, Dulay M, Macias A, Levin HS, Grossmann R, Simpson R et al. Cognitive
declines following bilateral subttahalmic nukleus deep brain stimulation for the
treatment of Parkinson´s disease.
115
8. Rektorová I. Neurodegenerativní demence. Minimonografie. Cesk Slov Neurol N 2009;
72/105:97-109.
9. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and
characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch
Neurol 2003;60:387-92.
10. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y et al. Clinical diagnostic
kriteria for dementia associated with Parkinson´s disease. Mov Disord. 2007; 22 (12):
1689-1707.
11. Wechslerova inteligenční škála pro dospělé – III.vydání. Psychodiagnostika. Brno, 1999.
12. Randolph Ch, Mohr E, Chase TN. Assessment of intellectual function in dementing
disorders: validity of WAIS-R short forms for patients with Alzheimer's, Huntington's,
and Parkinson's disease. J Clin Experiment Neuropsychol,1993; 15: 743-753.
13. Mattis S. Dementia rating scale: professional manual. Psychological Assessment
Resources. Odessa, 1988.
14. Wechslerova paměťová škála – III.vydání. Psychodiagnostika. Brno, 1999.
15. Meyers JE, Meyers KR. Rey Komplex figure test and recognition trial. Psychological
Assessment Resources. Odessa, 1996.
16. Stroop Color and Word Test – adult version. Psychological Assessment Resources,
2002.
17. Shallice T, Evans M. The involvement of the frontal lobes in cognitive estimation.
Cortex, 1978; 14: 294-303.
18. Beck AT, Ateer RA. Beck depression inventory manual. Psychological Corporation. San
Antonio, 1993.
19. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change.
Brit J Psych, 1979; 134: 382-389.
20. Aybek S, Bronchu-Perrin A, Berney A, Chiuvé SC, Villemure JG, Burkhard PR et al. Longterm
cognitive profile and incidence of dementia after STN-DBS in Parkinson´s disease.
Mov Disord, 2007; 22(7): 974-981.
21. Klempířová O, Jech R, Urgošík D, Klempíř J, Špačková N, Roth J, Růžicka E. Deep brain
stimulation of the subthalamic nucleus and cognitive functions in Parkinson's
disease. Prague Med Rep. 2007;108(4):315-23.
116
22. Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE, Deuschl
G. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of
outcomes. Mov Disord 2006;21 (Suppl 14):S290-304.
23. Parsons TD, Rogers SA, Braaten AJ, Woods SP, Tröster AI. Cognitive sequelae of
subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis.
Lancet Neurol 2006;5:578-88.
24. Page D, Jahanshahi M. Deep brain stimulation of the subthalamic nucleus improves set
shifting but does not affect dual task performance in Parkinson´s disease. Neural
Systems and Rehabilitation Engineering, IEEE on Volume 15, Issue 2. June 2007: 198-
206.
25. Jahanshahi M, Ardouin CM, Brown RG et al. The impact of deep brain stimulation on
executive function in Parkinson´s disease. Brain, 2000; 123 (Pt 6): 1142-1154.
26. Strafella AP, Dagher A, Sadikot AF. Cerebral blood flow changes induced by
subthalamic stimulation in Parkinson's disease. Neurology 2003;60:1039-42.
27. Campbell MC, Karimi M, Weaver PM, Wu J, Perantie DC, Golchin NA, Tabbal SD,
Perlmutter JS, Hershey T. Neural correlates of STN DBS-induced cognitive variability in
Parkinson disease. Neuropsychologia 2008;46:3162-9.
28. Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M,
Jacobson CE 4th, Wang X, Gordon CW Jr, Zeilman P, Romrell J, Martin P, Ward H,
Rodriguez RL, Foote KD. Cognition and mood in Parkinson's disease in subthalamic
nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann
Neurol 2009;65:586-95.
29. Voon V, Kubu C. Krack P, Houeto JL, Tröster AI. Deep brain stimulation:
neuropsychological and neuropsychiatric issues. Mov Disord, 2006 Jun; 21; Suppl.14:
S305-S327.
117
 Věk nad 70 let
 Předoperační neuropsychiatrické dysfunkce (nediagnostikovaná demence,
deprese, behaviorální poruchy
 Komplikace operačního výkonu DBS (infekce, hemoragie, léze)
 Nadměrně prodlužovaná perioperační elektrofyziologie s větším množstvím
trajektorií mikroelektrod
 Nadměrná nebo nedostatečná dopaminergní stimulace (v závislosti na
pooperačních změnách dopaminergní terapie)
Tabulka 1: Pacienti s vyšším rizikem kognitivního postižení po DBS STN – možné rizikové
faktory [1]
 Exekutivní schopnosti + pozornost
Dysexekutivní syndrom: potíže při vytváření a flexibilitě pracovních plánů a
strategií, přepínání pozornosti („set shifting“), distribuci pozornosti, cílené
verbální fluenci
 Paměťové schopnosti
Snížená pracovní paměť, snížená výbavnost informací (s přetrvávajícím
benefitem nápovědy), potíže při asociativním učení
 Vizuo-spaciální schopnosti (alterovaná exekutivní složka)
 Může být postižena řeč
Tabulka 2: Neuropsychologický deficit u PN
Neuropsychologický
test
N Před DBS
průměr
Sm.
odch.
Po DBS
průměr
Sm.
odch.
Wilcoxonův
test, p (2-tail)
WAIS-R 12 108,5 11,5 101,3 7,9 0,136
WAIS-R – Počty 13 10,8 2,2 9,6 1,9 0,917
WAIS-R – Podobnosti 13 11,2 2,1 11,0 2,1 0,861
WAIS-R –
Doplňování obrázků
13
13,0 2,7 11,4 2,4
0,016
118
WAIS-R – Číselné
symboly
12
8,4 1,6 7,7 1,4
0,784
Mattis DRS 13 140,6 4,5 135,2 9,7 0,701
R-O bezprostřední 17 59,1 11,8 56,3 13,2 0,356
R-O oddálená 17 56,2 10,4 54,2 12,9 0,670
R-O znovupoznání 9 50,3 8,1 50,7 12,6 0,594
Stroop – Slova 18 54,5 11,8 51,0 7,4 0,965
Stroop – Barvy 18 39,7 6,6 42,2 12,0 0,214
Stroop – Slova-Barvy 18 41,1 9,2 37,8 10,7 0,004
Londýnská věž 11 45,0 14,0 39,3 11,9 0,722
Lexikální fluence 19 35,7 10,9 28,1 13,4 0,022
Sémantická fluence 19 20,8 6,3 15,8 6,0 0,018
Seznam slov –
bezprostřední
19
10,0 3,6 8,7 3,8
0,507
Seznam slov –
oddálený
19
11,2 3,0 12,4 3,6
0,019
Seznam slov –
znovupoznání
14
10,9 2,9 10,7 2,4
0,331
MADRS 18 6,0 3,2 6,3 4,4 0,571
BDI 17 8,1 4,3 9,7 7,3 0,522
Tabulka 3 – Srovnání souborů výsledků testů před a po operaci
119
3.7 Involvement of subthalamic nucleus in cognitive functions – a concept
Publikováno v: Journal of the Neurological Sciences, 2011, 310, 1-2, 96-99. IF: 2.3
Commentary:
The involvement of subthalamic nucleus (STN) in a broad spectrum of various non-motor
functions – attention, executive functions, verbal learning and memory, verbal abstract
reasoning, conflict resolution, and emotions – has been reported. In following review we
describe a variety of changes that appeared in recent respective literature. We also define a
concept of STN functioning within the structures involved in cognitive functions. The STN has
an anatomically central position within basal ganglia (BG)-thalamocortical motor, associative
and limbic circuits. Recent studies have demonstrated that specific oscillations in the STN are
involved in cognitive and behavioral information processing. STN might interfere with nonmotor
functions as an indirect modulator rather than a regulator. Mechanisms modulating the
motor and non-motor functions might differ. STN has been implicated in control of non-motor
behaviors via the tuning of specific circuits depending on the task. STN might modulate
selected non-motor functions via contextual modulation of certain cortical areas. Based on
intracerebral recordings, we proposed that the non-motor activities in BG are organized in
some way other than the well-known organization of the cortico-BG-thalamocortical circuits.
These findings support the hypothesis of a cortico-STN bypass of the BG-thalamocortical
circuitry under some circumstances.
Overall, it is evident that at least in some patients the change in cognitive functions after STNDBS
may have clinical importance. The exact mechanisms of possible cognitive after-effects of
STN-DBS are not known.
120
Involvement of the subthalamic nucleus in cognitive functions – a concept
Marek Baláž, Martina Bočková, Irena Rektorová, Ivan Rektor
Central European Institute of Technology – CEITEC, Department of Neurology, St. Anne’s
University Hospital, Medical School of Masaryk University, Pekařská 53, 656 91 Brno, Czech
Republic
Abstract
The involvement of the subthalamic nucleus (STN) in a broad spectrum of various non-motor
functions – attention, executive functions, verbal learning and memory, verbal abstract
reasoning, conflict resolution, and emotions – has been reported. The STN has an anatomically
central position within the basal ganglia(BG)-thalamocortical motor, associative and limbic
circuits. The STN might interfere with non-motor functions as an indirect modulator rather
than a regulator. Mechanisms modulating the motor and non-motor functions might differ.
The STN has been implicated in control of non-motor behaviors via the tuning of specific
circuits depending on the task. The STN might modulate selected non-motor functions via
contextual modulation of certain cortical areas. Based on intracerebral recordings, we
proposed that the non-motor activities in the BG are organized in some way other than the
well-known organization of the cortico-BG-thalamocortical circuits. These findings support
the hypothesis of a cortico-STN bypass of the BG-thalamocortical circuitry under some
circumstances. The exact role of the STN and the BG in non-motor functions remains an
important and interesting challenge for future research.
Key words: Subthalamic nucleus; Basal ganglia; Cognitive functions; Deep brain stimulation;
Hyperdirect pathway
Introduction
The role of the basal ganglia (BG) in cognition is largely unknown, but it has been suggested
that the BG play an integrative role in cognitive processing 1.
121
Within the BG, the subthalamic nucleus (STN) has received significant attention as a
therapeutic target, because its inactivation by high-frequency stimulation has been
successfully used to treat Parkinson’s disease (PD) 2. Inactivation of the STN by deep brain
stimulation (DBS) is used mainly to improve motor deficits.
The STN, however, appears to be involved in the processing of certain cognitive and executive
functions. Experimental and clinical observations have suggested that this structure is
involved in modulating motivation and seems to be sensitive to drugs of abuse 3,4; this is
probably why STN-DBS may improve dopamine dysregulation syndrome, impulse control
disorders, and punding in PD 5. It seems that the STN has an anatomically central position
within the basal ganglia-thalamocortical associative and limbic circuits and is functionally a
potent regulator of these pathways. In our review, we try to establish evidence from published
papers that describe the participation of the STN in cognitive functions.
1. STN and cognition, anatomical connections
The STN is a small lens-shaped midbrain nucleus lying on the dorsomedial surface of the
internal capsule. The STN is thought to play a prominent role in the pathophysiology of PD 6.
The STN not only plays a key role in motor behavior, but is also a potent regulator in the limbic
and associative circuits 7.
As the only glutamatergic structure of the BG, it is a major source of excitation. The STN
innervates mainly the globus pallidus interna (GPi) and the substantia nigra, but also the
globus pallidus externa GPe), ventral pallidum, pedunculopontine nucleus, and, to a lesser
extent, the striatum, nucleus accumbens, and ventral tegmental area.
The major subcortical inputs to the STN arise from the ventral pallidum and the GPe (the
indirect pathway), the thalamus, pedunculopontine nucleus, dorsal raphe, ventral tegmental
area, and pars compacta of the substantia nigra 8.
Before the 1970s, the literature was conclusive on human corticosubthalamic connections 9.
Direct cortical projections to the STN were described 10, but they were considered to be
sparse, and therefore regarded as less important. According to recent views, the STN has not
only a crucial position in the indirect pathway of the BG, but it also receives direct cortical
projections, especially from the frontal lobe, namely the primary motor cortex, supplementary
122
motor area, and the dorsal and ventral divisions of the premotor cortex, such as the
hyperdirect pathway from the inferior frontal cortex (IFC) 11-14.
In 2004, Strafella indicated that the role of the cerebral cortex in regulating the activity of the
STN was not known in humans. Transcranial magnetic stimulation of the motor cortex changes
the neuronal activity of the STN 15.
Diffusion Weighted Imaging (DWI) tractography demonstrated a three-way white matter
network between the preSMA, the IFC, and the STN region in the right hemisphere in tasks
related to reversing initiated motor responses, as revealed by the stop-signal paradigm 16.
The anatomic source of control over the putative cognitive function of the STN is less well
described, but it is clear that the STN is involved not only in motor but also in associative and
limbic cortico-BG-thalamocortical loops.
The direct connections to the STN from the prefrontal cortex and the relation of the STN to
structures such as the nucleus accumbens and the ventral pallidum (both well known for their
involvement in motivational processes) may explain why the STN contributes to functions well
beyond motor activities.
2. STN and cognition, clinical relevance
From a clinical point of view, STN-DBS modulates not only motor but also cognitive and
affective functions 7. In some patients, STN-DBS has been followed by cognitive impairment
and other neuropsychiatric disturbances such as depression, (hypo)mania, personality
changes, hypersexuality, apathy, and aggression. About half of STN-DBS patients did not
experience behavioral changes 7,17-20. According to some authors, DBS causes only minor
changes, related perhaps more to the effect of surgery than the stimulation itself 21. A
randomized multicenter study showed that STN-DBS did not reduce overall cognition or
affectivity, although there was a selective decrease in frontal cognitive functions and a
decrease in patient anxiety after the treatment 22. According to a meta-analysis, cognitive
problems were faced by up to 41% of patients after STN-DBS 23.
While the impact of the STN on non-motor functions appears to be accepted by most authors,
its clinical significance is still controversial 24. This review article underlined certain
methodological differences in papers related to neuropsychological and cognitive disorders
123
connected with this procedure 24. The vast literature on cognitive short-term as well as longterm
outcomes after bilateral DBS surgery of the STN varies widely. Mild to moderate
decreases in verbal learning, abstract reasoning, and selective frontal functions (and verbal
fluency in particular) have been reported as the most common cognitive after-effect of the
procedure, while development of dementia has been generally related to the PD progression
itself 17, 21, 22, 24-32.
In a retrospective study by our group 32, we found a mild but clinically significant decline in
the results of neuropsychological tests measuring attention, executive functions, and verbal
memory (free recall) in PD patients one year after DBS STN surgery.
Overall, it is evident that at least in some patients the change in cognitive functions after STNDBS
may have clinical importance. The exact mechanisms of possible cognitive after-effects of
STN-DBS are not known. Temel et al. claimed that the STN not only plays a key role in motor
behavior, but also serves as a potent regulator in the limbic and associative circuits 7. The
precise location of the active electrode contact and the spatial extent of the effects of
stimulation as well as the frequency, voltage, and amplitude of STN stimulation, or patient
variables such as degree of dopaminergic denervation, could be involved 33,34.
3. STN animal studies and cognition
An integrative function of the STN in both motor and cognitive operations 35-37 has been
suggested. Experiments in animals have shown involvement of the STN in attentional and
motivational functions 3,4,36, 38-41. The cognitive side-effects of high-frequency STN
stimulation were shown in animal studies as well as in clinical practice. A transient decrease
in attention and accuracy of task performance was described in rats 42.
4. STN and cognitive local field potentials
Recent functional neurosurgery has provided the opportunity to record directly from the
human BG, most commonly in patients with PD undergoing DBS electrode implantation. Single
unit recordings and local field potentials can be recorded intraoperatively via microelectrodes;
local field potentials can also be measured from the DBS macroelectrodes, which are
124
externalized a few days after operation 43. In PD patients, abnormal prominent and
synchronized neuronal oscillations at frequencies 8-35 Hz were repeatedly described. This
abnormal activity is suppressed by treatments that improve parkinsonism, and it seems to be
intimately related to voluntary movement and linked to both bradykinesia and rigidity 44-
51. Changes in beta oscillatory activity were detected in the STN not only during movement
performance, but also during movement observation; therefore, the STN is probably engaged
in the human mirror system 52,53. Beta frequency modulation patterns are regulated by the
dopamine levels in the system 54 and also by the DBS stimulation 55. Disturbances in
gamma (60-80 Hz) and higher frequency range (300 Hz) oscillations and their coupling
between beta activity are an important pathophysiological mechanism in PD 56,57. Recent
studies have demonstrated that specific oscillations in the STN are involved in cognitive and
behavioral information processing: action representation is mediated through 13-35 Hz
oscillations, decision making processes through 5-12 Hz oscillations, limbic and emotional
information through 8-12 Hz oscillations 58. Evoked local field potentials related to executive
functions and attention were found in the STN during performance of both visual and auditory
cognitive paradigms 13,59,60. These papers by our group indicate a specific, task-related
involvement of the STN in cognitive activities. Cognitive processing in the STN may be
processed via the hyperdirect pathway. These recordings were performed either directly from
the motor part of the STN or from its immediate vicinity. Therefore we have suggested that
neuronal pools involved in cognitive activities may be located close to, or even overlap with,
the neurons active in motor functions 61. Our results have revealed an important
involvement of the STN in cognitive functions and emotion control and could explain the
occurrence of post-DBS behavioral disturbances.
Discussion
The involvement of the STN in a broad spectrum of various non-motor functions – attention,
executive functions, verbal learning and memory, verbal abstract reasoning, conflict
resolution, and emotions – has been reported. 2-4,7,8 Neuropsychiatric disturbances after
DBS indicate that the STN is involved in cognitive impairment as well as in depression or mania,
125
personality changes, apathy, aggression, impulse control disorder, and hypersexuality 5, 17,
18, 20-24,27-31.
The STN is involved in a variety of functions, motor and non-motor, despite the fact that it is
a very small structure. It is hard to imagine that the limited number of STN neurons could
process all these functions separately. Functional imaging shows that stimulating the STN,
even though it is quite small, induces modifications of the pattern of brain activation involving
large scale cerebral networks 62. A model was proposed in which three functional
modalities, emotional, cognitive, and motor, are not processed in a segregated manner but
can be subtly combined within the small volume of the STN. This nucleus would thus serve as
a nexus that integrates the motor, cognitive, and emotional components of behavior 63. We
have shown that there is a spatial overlap of sites regulating various functions in the STN as
the local fields of the cognitive related potentials were recorded through the electrode contact
located in the site with the best motor effect 13,59,60. Similarly, in the pallidum and
striatum, based on direct depth electrode recordings in patients with epilepsy, we also
observed a spatial overlap of several cognitive and motor control functions 1. It appears that
various non-motor and motor functions that are processed or influenced by the STN have a
common denominator that is as yet undefined.
The involvement of the STN in motor function regulations is unequivocal. DBS has an
immediate and robust clinical effect on PD. It might be explained by the functional position of
the STN within the BG-thalamocortical circuitry. The involvement of the STN in non-motor
functions is far less robust and usually temporary. The STN might interfere with non-motor
functions as an indirect modulator rather than a regulator. Mechanisms modulating the motor
and non-motor functions might differ. Similarly, we suggested in earlier works that the
mechanism for processing the motor and cognitive functions in the striatum and pallidum are
different. Based on intracerebral recordings, we proposed that the cognitive activities in the
BG are organized in some way other than the well-known organization of the cortico-BGthalamocortical
circuits. 1,64. Actually, the separated BG-thalamocortical circuitries are only
one of several hypothetical options defining the functional linkage between the BG and the
cortex. Other hypotheses 65,66 have also been proposed. In the STN, the “hyperdirect”
connections with the cortex that bypass the circuitries might underlie the processing of at
least some of the non-motor functions. Several findings support this idea. At variance with the
126
striatum/pallidum, the standard oddball cognitive (P3) potentials are not generated in the STN
59,60. Similarly, epileptic spikes were recorded in the STN but not in the other BG 67,68.
Repetitive transcranial magnetic stimulation (rTMS) of the IFC, which is a source of the
hyperdirect pathway to the STN, but not of the dorsolateral prefrontal (DLPF) cortex, which is
implicated in the cortico-thalamocortical circuitry, modifies certain cognitive potentials
recorded in the STN 59. These findings support the hypothesis of a cortico-STN bypass of the
BG-thalamocortical circuitry under some circumstances.
The involvement of the STN in the increased cognitive loads but not by more simple cognitive
tasks 59,60,61. The results of imaging studies also show that the effects of STN-DBS are task
specific and depend on the particular networks engaged by specific tasks. DBS probably tunes
specific circuits depending on the task 62. In contrast to the other BG except the striatum,
the STN is targeted by important “hyperdirect” pathways directly from the prefrontal,
inferofrontal, and pericentral cortices. This may indicate that the STN plays an important and
specific role in processing certain functions, mostly those concentrated in the frontal lobe.
Possibly, the selection of tasks modulated within the STN is determined by the selective
involvement of cortical neuronal populations that are interconnected with the STN. Our
group’s earlier data 13 demonstrated that event-related potentials evoked by an executive
function task and recorded in the STN are modulated by rTMS of the inferofrontal but not of
the DLPF cortex.
We suggested that the BG, specifically the striatum (from which we obtained the bulk of our
recordings), participate in the cognitive processing of external information 1,64. The BG may
play an integrative role in cognitive information processing, in motor as well as in non-motor
tasks. We suggested the following mechanism: the BG form a non-specific system that
progressively converges data concerning various functions from various parts of the cortex.
The converged data are processed in the BG and positively or negatively modulate the relevant
cortical areas. The BG is the site at which information from various function systems (sensory,
attention, memory, etc.) may be processed in a mutual context. This contextual modulation
may be important for the functioning of the individual cortical areas.
The STN has been implicated in inhibitory control of non-motor behaviors via the tuning of
specific circuits depending on the task 62. The STN might modulate selected non-motor
functions in a similar way, via contextual modulation of certain cortical areas. In any case, the
127
exact role of the STN and the BG in non-motor functions remains an important and interesting
challenge for future research. modulation of certain non-motor activities is selective, i.e. the
local electrical activity recorded in the STN is generated or modulated by the tasks with
increased cognitive loads but not by more simple cognitive tasks 59,60,61. The results of
imaging studies also show that the effects of STN-DBS are task specific and depend on the
particular networks engaged by specific tasks. DBS probably tunes specific circuits depending
on the task 62. In contrast to the other BG except the striatum, the STN is targeted by
important “hyperdirect” pathways directly from the prefrontal, inferofrontal, and pericentral
cortices. This may indicate that the STN plays an important and specific role in processing
certain functions, mostly those concentrated in the frontal lobe. Possibly, the selection of
tasks modulated within the STN is determined by the selective involvement of cortical
neuronal populations that are interconnected with the STN. Our group’s earlier data 13
demonstrated that event-related potentials evoked by an executive function task and
recorded in the STN are modulated by rTMS of the inferofrontal but not of the DLPF cortex.
We suggested that the BG, specifically the striatum (from which we obtained the bulk of our
recordings), participate in the cognitive processing of external information 1,64. The BG may
play an integrative role in cognitive information processing, in motor as well as in non-motor
tasks. We suggested the following mechanism: the BG form a non-specific system that
progressively converges data concerning various functions from various parts of the cortex.
The converged data are processed in the BG and positively or negatively modulate the relevant
cortical areas. The BG is the site at which information from various function systems (sensory,
attention, memory, etc.) may be processed in a mutual context. This contextual modulation
may be important for the functioning of the individual cortical areas.
The STN has been implicated in inhibitory control of non-motor behaviors via the tuning of
specific circuits depending on the task 62. The STN might modulate selected non-motor
functions in a similar way, via contextual modulation of certain cortical areas. In any case, the
exact role of the STN and the BG in non-motor functions remains an important and interesting
challenge for future research.
Acknowledgement: The authors would like to express thanks to A. Johnson for language
corrections.
128
References
1. Rektor I, Bares M, Brázdil M, Kanovský P, Rektorová I, Sochurková D, Kubová D, Kuba
R, Daniel P. Cognitive- and movement-related potentials recorded in the human basal
ganglia. Mov Disord. 2005;20(5):562-8.
2. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE,
Benabid AL. Effect on parkinsonian signs and symptoms of bilateral subthalamic
nucleus stimulation. Lancet 1995;345:91-5.
3. Baunez C, Amalric M, Robbins TW. Enhanced food-related motivation after bilateral
lesions of the subthalamic nucleus. J Neurosci. 2002;22:562-8.
4. Baunez C, Dias C, Cador M, Amalric M. The subthalamic nucleus exerts opposite control
on cocaine and 'natural' rewards. Nat Neurosci. 2005;8:484-9.
5. Lim SY, O'Sullivan SS, Kotschet K, Gallagher DA, Lacey C, Lawrence AD, et al. Dopamine
dysregulation syndrome, impulse control disorders and punding after deep brain
stimulation surgery for Parkinson's disease. J Clin Neurosci. 2009;16:1148-52.
6. Obeso JA, Rodriguez MC, DeLong MR. Basal ganglia pathophysiology. A critical review.
Adv Neurol. 1997;74:3-18.
7. Temel Y, Blokland A, Steinbusch HW, Visser-Vandewalle V. The functional role of the
subthalamic nucleus in cognitive and limbic circuits. Prog Neurobiol. 2005
Aug;76(6):393-413.
8. Baunez C, Gubellini P. Effects of GPi and STN inactivation on physiological, motor,
cognitive and motivational processes in animal models of Parkinson's disease. Prog
Brain Res. 2010;183:235-58.
9. Marani E, Heida T, Lakke EA, Usunoff KG. The subthalamic nucleus. Part I:
development, cytology, topography and connections. Adv Anat Embryol Cell Biol.
2008;198:1-113, vii.
10. Monakow KH, Akert K, Künzle H. Projections of the precentral motor cortex and other
cortical areas of the frontal lobe to the subthalamic nucleus in the monkey. Exp Brain
Res. 1978 Nov 15;33(3-4):395-403.
11. Nambu A, Takada M, Inase M, Tokuno H. Dual somatotopical representations in the
primate subthalamic nucleus: evidence for ordered but reversed body-map
129
transformations from the primary motor cortex and the supplementary motor area. J
Neurosci. 1996;16(8):2671-83.
12. Nambu A, Tokuno H, Inase M, Takada M. Corticosubthalamic input zones from
forelimb representations of the dorsal and ventral divisions of the premotor cortex in
the macaque monkey: comparison with the input zones from the primary motor cortex
and the supplementary motor area. Neurosci Lett. 1997;239(1):13-6.
13. Baláz M, Srovnalová H, Rektorová I, Rektor I. The effect of cortical repetitive
transcranial magnetic stimulation on cognitive event-related potentials recorded in
the subthalamic nucleus. Exp Brain Res. 2010;203(2):317-27.
14. Srovnalova H, Marecek R, Rektorova I. The role of the inferior frontal gyri in the
cognitive processes of patients with Parkinson’s disease: An rTMS study. Mov Disord
2011, in press
15. Strafella AP, Vanderwerf Y, Sadikot AF. Transcranial magnetic stimulation of the human
motor cortex influences the neuronal activity of subthalamic nucleus. Eur J Neurosci.
2004 Oct;20(8):2245-9.
16. Aron AR, Behrens TE, Smith S, Frank MJ, Poldrack RA. Triangulating a cognitive control
network using diffusion-weighted magnetic resonance imaging (MRI) and functional
MRI. J Neurosci. 2007;27(14):3743-52.
17. Saint-Cyr JA, Trépanier LL, Kumar R, Lozano AM, Lang AE. Neuropsychological
consequences of chronic bilateral stimulation of the subthalamic nucleus in
Parkinson's disease. Brain 2000;123:2091-108.
18. Herzog J, Reiff J, Krack P, Witt K, Schrader B, Müller D, Deuschl G. Manic episode with
psychotic symptoms induced by subthalamic nucleus stimulation in a patient with
Parkinson's disease. Mov Disord. 2003;18:1382-4.
19. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs subthalamic
nucleus deep brain stimulation in Parkinson disease. Arch Neurol. 2005;62:554-60.
20. Ballanger B, van Eimeren T, Moro E, Lozano AM, Hamani C, Boulinguez P, et al.
Stimulation of the subthalamic nucleus and impulsivity: release your horses. Ann
Neurol. 2009 Dec;66:817-24.
21. Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, et al. Cognition
and mood in Parkinson’s disease in subthalamic nucleus versus globus pallidus interna
deep brain stimulation: the COMPARE trial. Ann Neurol. 2009;65(5):586-95.
130
22. Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO, et al. Neuropsychological
and psychiatric changes after deep brain stimulation for Parkinson’s disease: a
randomised, multicentre study. Lancet Neurol. 2008;7(7):605-14.
23. Temel Y, Kessels A, Tan S, Topdag A, Boon P, Visser-Vandewalle V. Behavioural changes
after bilateral subthalamic stimulation in advanced Parkinson’s disease: a systematic
review. Parkinsonism Relat Disord. 2006;12(5):265-72.
24. Voon V, Kubu C, Krack P, Houeto JL, Tröster AI. Deep brain stimulation:
neuropsychological and neuropsychiatric issues. Mov Disord 2006;21(Suppl 14):S305-
27.
25. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year followup
of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease.
N Engl J Med. 2003 Nov 13;349(20):1925-34.
26. Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the
subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol.
2009;8(1):67-81. Review.
27. Smeding HM, Speelman JD, Koning-Haanstra M, Schuurman PR, Nijssen P, van Laar T,
Schmand B. Neuropsychological effects of bilateral STN stimulation in Parkinson
disease: a controlled study. Neurology. 2006; 66(12):1830-6.
28. Aybek S, Gronchi-Perrin A, Berney A, Chiuvé SC, Villemure JG, Burkhard PR,
Vingerhoets FJ. Long-term cognitive profile and incidence of dementia after STN-DBS
in Parkinson's disease. Mov Disord. 2007 May 15;22(7):974-81.
29. York MK, Dulay M, Macias A, Levin HS, Grossman R, Simpson R, Jankovic J. Cognitive
declines following bilateral subthalamic nucleus deep brain stimulation for the
treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):789-
95.
30. Halpern CH, Rick JH, Danish SF, Grossman M, Baltuch GH. Cognition following bilateral
deep brain stimulation surgery of the subthalamic nucleus for Parkinson's disease. Int
J Geriatr Psychiatry. 2009 May;24(5):443-51. Review.
31. Fasano A, Romito LM, Daniele A, Piano C, Zinno M, Bentivoglio AR, Albanese A. Motor
and cognitive outcome in patients with Parkinson's disease 8 years after subthalamic
implants. Brain. 2010 Sep;133(9):2664-76.
131
32. Telecká S, Baláž M, Rektorová I, Fanfrdlová Z, Rektor I. Jeden rok po hluboké mozkové
stimulaci pacientů s Parkinsonovou nemocí - neuropsychologické výsledky. Cesk Slov
Neurol N 2010;73/106(1):57-61.
33. Strafella AP, Sadikot AF, Dagher A. Subthalamic deep brain stimulation does not induce
striatal dopamine release in Parkinson's disease. Neuroreport. 2003;14(9):1287-9.
34. Campbell MC, Karimi M, Weaver PM, Wu J, Perantie DC, Golchin NA, Tabbal SD,
Perlmutter JS, Hershey T. Neural correlates of STN DBS-induced cognitive variability in
Parkinson disease. Neuropsychologia. 2008;46(13):3162-9.
35. Parent A, Hazrati LN. Functional anatomy of the basal ganglia. II. The place of
subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain
Res Rev. 1995;20(1):128-54.
36. Baunez C, Robbins TW. Effects of transient inactivation of the subthalamic nucleus by
local muscimol and APV infusions on performance on the five-choice serial reaction
time task in rats. Psychopharmacology 1999;141:57-65.
37. Graybiel AM. The basal ganglia and cognitive pattern generators. Schizophrenia
Bulletin 1997;23:459-469.
38. Baunez C, Robbins TW. Bilateral lesions of the subthalamic nucleus induce multiple
deficits in an attentional task in rats. Eur J Neurosci. 1997;9:2086-99.
39. Baunez C, Robbins TW. Effects of dopamine depletion of the dorsal striatum and
further interaction with subthalamic nucleus lesions in an attentional task in the rat.
Neuroscience 1999;92:1343-56.
40. Christakou A, Robbins TW, Everitt BJ. Functional disconnection of a prefrontal corticaldorsal
striatal system disrupts choice reaction time performance: implications for
attentional function. Behav Neurosci 2001;115:812-25.
41. Rogers RD, Baunez C, Everitt BJ, Robbins TW. Lesions of the medial and lateral striatum
in the rat produce differential deficits in attentional performance. Behav Neurosci.
2001;115:799-811.
42. Baunez C, Christakou A, Chudasama Y, Forni C, Robbins TW. Bilateral high-frequency
stimulation of the subthalamic nucleus on attentional performance: transient
deleterious effects and enhanced motivation in both intact and parkinsonian rats. Eur
J Neurosci. 2007;25:1187-94.
132
43. Brown P, Williams D. Basal ganglia local field potential activity: character and
functional significance in the human. Clin Neuro. 2005;116:2510-9.
44. Engel AK, Moll CK, Fried I, Ojemann GA. Invasive recordings from the human brain:
clinical insights and beyond. Nat Rev Neurosci. 2005;6:35-47.
45. Kühn AA, Trottenberg T, Kivi A, Kupsch A, Schneider GH, Brown P. The relationship
between local field potential and neuronal discharge in the subthalamic nucleus of
patients with Parkinson's disease. Exp Neurol. 2005;194:212-20.
46. Rivlin-Etzion M, Marmor O, Heimer G, Raz A, Nini A, Bergman H. Basal ganglia
oscillations and pathophysiology of movement disorders. Curr OpinNeurobiol.
2006;16:629-37.
47. Gatev P, Darbin O, Wichmann T. Oscillations in the basal ganglia under normal
conditions and in movement disorders. Mov Disord. 2006;21:1566-77.
48. Hammond C, Bergman H, Brown P. Pathological synchronization in Parkinson's disease:
networks, models and treatments. Trends Neurosci. 2007 Jul;30(7):357-64.
49. Brown P. Abnormal oscillatory synchronisation in the motor system leads to impaired
movement. Curr Opin Neurobiol. 2007;17:656-64.
50. Weinberger M, Hutchison WD, Dostrovsky JO. Pathological subthalamic nucleus
oscillations in PD: can they be the cause of bradykinesia and akinesia? Exp Neurol.
2009;219:58-61.
51. Kühn AA, Tsui A, Aziz T, Ray N, Brücke C, Kupsch A, Schneider GH, Brown P. Pathological
synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates
to both bradykinesia and rigidity. Exp Neurol. 2009;215:380-7.
52. Marceglia S, Fiorio M, Foffani G, Mrakic-Sposta S, Tiriticco M, Locatelli M, et al.
Modulation of beta oscillations in the subthalamic area during action observation in
Parkinson's disease. Neuroscience 2009;161:1027-36.
53. Alegre M, Rodríguez-Oroz MC, Valencia M, Pérez-Alcázar M, Guridi J, Iriarte J, et al.
Changes in subthalamic activity during movement observation in Parkinson's disease:
is the mirror system mirrored in the basal ganglia? Clin Neuro 2010;121:414-25.
54. Foffani G, Bianchi AM, Baselli G, Priori A. Movement-related frequency modulation of
beta oscillatory activity in the human subthalamic nucleus. J Physiol. 2005;568:699-
711.
133
55. Giannicola G, Marceglia S, Rossi L, Mrakic-Sposta S, Rampini P, Tamma F, et al. The
effects of levodopa and ongoing deep brain stimulation on subthalamic beta
oscillations in Parkinson's disease. Exp Neurol. 2010;226:120-127.
56. Foffani G, Priori A, Egidi M, Rampini P, Tamma F, Caputo E, et al. 300-Hz subthalamic
oscillations in Parkinson's disease. Brain 2003;126:2153-63.
57. López-Azcárate J, Tainta M, Rodríguez-Oroz MC, Valencia M, González R, Guridi J, et al.
Coupling between beta and high-frequency activity in the human subthalamic nucleus
may be a pathophysiological mechanism in Parkinson's disease. J Neurosci.
2010;30:6667-77.
58. Marceglia S, Fumagalli M, Priori A. What neurophysiological recordings tell us about
cognitive and behavioral functions of the human subthalamic nucleus. Expert Rev
Neurother. 2011;11:139-49.
59. Baláž M, Rektor I, Pulkrábek J. Participation of the subthalamic nucleus in executive
functions: An intracerebral recording study. Mov Disord 2008;23:553-7.
60. Bočková M, Chládek J, Jurák P, Halámek J, Baláž M, Rektor I. Involvement of the
subthalamic nucleus and globus pallidus internus in attention. Journal of Neural
Transmission. 2011 In Press
61. Rektor I, Baláz M, Bocková M. Cognitive event-related potentials and oscillations in the
subthalamic nucleus. Neurodegener Dis. 2010;7(1-3):160-2.
62. Ballanger B, Jahanshahi M, Broussolle E, Thobois S. PET functional imaging of deep
brain stimulation in movement disorders and psychiatry. J Cereb Blood Flow Metab.
2009;29:1743-54.
63. Mallet L, Schüpbach M, N'Diaye K, Remy P, Bardinet E, Czernecki V, et al. Stimulation
of subterritories of the subthalamic nucleus reveals its role in the integration of the
emotional and motor aspects of behavior. Proc Natl Acad Sci U S A. 2007 Jun
19;104(25):10661-6.
64. Rektor I, Bareš M, Kaňovský P, Brázdil M, Klajblová I, Streitová H, Rektorová I,
Sochůrková D, Kubová D, Kuba R, Daniel P. Cognitive potentials in the basal ganglia frontocortical
circuits. An intracerebral recording study. Exp Brain Res 2004;158:289-
301.
65. Parent A, Lévesque M, Parent M. A re-evaluation of the current model of the basal
ganglia. Parkinsonism Relat Disord. 2001;7:193-8.
134
66. Joel D. Open interconnected model of basal ganglia-thalamocortical circuitry and its
relevance to the clinical syndrome of Huntington’s disease. Mov Disord 2001;16:407-
23.
67. Urrestarazu E, Iriarte J, Alegre M, Guridi J, Rodríguez-Oroz MC, Obeso J, et al.
Subthalamic nucleus role on the generation of spikes in temporal epilepsy. Epilepsy
Res 2009; 83:257-260.
68. Rektor I, Kuba R, Brázdil M. Interictal and ictal EEG activity in the basal ganglia. An SEEG
study in patients with temporal lobe epilepsy. Epilepsia 2002;43:253-62.
Research support: This paper was supported by the research program of Czech Ministry of
Education - MSM 002 162 2404.
135
3.8 Involvement of subthalamic nucleus and globus pallidus internus in attention
Published in: J Neural Transm. 2011 Aug;118(8):1235-45. IF: 2.9
Commentary:
The following paper was aimed at describing the recordings of electrical activitiy from deep brain
structures – namely subthalamic nucelus (STN) and globus pallidum internum (Gpi).
We included seven patients with advanced Parkinson’s disease (PD) and one patient with
generalised dystonia. Patients were examined in the interoperative period between deep brain
electrode implantation and implantation of a neurostimulator. Relatively low number of patients is
caused by specificity of used methods and paradigms.
ERPs and ERD/S in the alpha and beta frequency range were analysed. As a test paradigm
a visual three-stimulus protocol was used (frequent stimulus, target stimulus, and distractor).
The frequent (non-target, standard) stimuli, which were 70 % of all the stimuli, were small
blue circles. These were not to be followed by a reaction. The target stimuli, which were 15 %
of all the stimuli, were larger blue circles. The subjects were asked to press an electrically
connected button at the time of the target detection. The distractors (rare non-target stimuli),
which were present 15 % of the time, were black and white checkerboards; no response was
required.
Time frequency analysis was used to determine the event-related de/synchronizations
(ERD/S) in the alpha and beta frequency ranges. A decrease in band power indicates induced
event-related desynchronization (ERD), an increase in band power indicates event-related
synchronization (ERS). The ERD of the alpha and beta rhythms is interpreted as a correlate of
an activated cortical area with increased excitability. The ERS in the alpha and lower beta
bands can be interpreted as a correlate of a deactivated cortical area, i.e. cortical idling or
active inhibition (Pfurtscheller 2001).
The non-target and distractor-related waveforms manifested similar shapes. A specific positive ERP
peak around 200 ms and a low alpha frequency ERS were detected from the STN as a response to
the distractor stimuli in six of the patients with PD Parkinson’s disease and also in the primary
dystonia patient’s GPi. This positivity probably reflects an attentional orienting response to the
distractor stimuli.
136
We therefore presented data showing the activity of STN during attentional orientation which
expands our previous results demonstrating participation of STN in cognitive processing. Direct
intracerebral recordings remain invaluable source for getting time specific information on
functioning of deep brains structures.
As a co-author I participated in manuscript preparation and revision, I participated in patient
preparation for recording from deep brain electrodes.
Involvement of the subthalamic nucleus and globus pallidus internus in attention.
M. Bočková*, J. Chládek**, P. Jurák**, J. Halámek**, M. Baláž*, I. Rektor*
* First Department of Neurology, Masaryk University, St. Anne’s Hospital, Brno, Czech
Republic
** Institute of Scientific Instruments of the Academy of Sciences of the Czech Republic, v.v.i.,
Brno, Czech Republic
Address correspondence to:
Dr. Martina Bočková
First Department of Neurology, Medical Faculty of Masaryk University
St. Anne’s Teaching Hospital
Pekarska 53
656 91 Brno
Czech Republic
phone: + 420 543 182 623
fax: +420 543 182 624
e-mail: martina.bockova@fnusa.cz
key words: basal ganglia, ERP, ERD/S, attention, DBS
Abstract:
Background: We studied the appearance of cognitive event-related potentials (ERPs) and
event-related de/synchronizations (ERD/S) in the subthalamic nucleus (STN) and globus
137
pallidus internus (GPi). We particularly focused on the rare non-target (distractor) stimuli
processing.
Methods: ERPs and ERD/S in the alpha and beta frequency range were analysed in seven
Parkinson’s disease patients and one primary dystonia patient with implanted deep brain
stimulation (DBS) electrodes. A visual three-stimulus protocol was used (frequent stimulus,
target stimulus, and distractor).
Results: The non-target and distractor-related waveforms manifested similar shapes. A
specific positive ERP peak around 200 ms and a low alpha frequency ERS were detected from
the STN as a response to the distractor stimuli in six of the patients with Parkinson’s disease
and also in the primary dystonia patient’s GPi. This positivity probably reflects an attentional
orienting response to the distractor stimuli.
Conclusion: The STN and GPi are probably involved in attentional cerebral networks.
Introduction:
Deep brain stimulation (DBS) has become a routine functional neurosurgery operation. It is an
effective long-term treatment for motor symptoms in advanced Parkinson's disease (PD)
(Krack et al. 2003). The most frequently used DBS target is the subthalamic nucleus (STN). The
STN plays a major role in motor control and receives projections from the pallidum and from
the motor cortical areas (Nambu et al. 2002, Hamani et al. 2004, Aron et al. 2007). In addition,
the STN receives projections accounting for involvement in emotional and cognitive activities
from the anterior cingulate, and inferior frontal cortex, as well as the medial and dorsolateral
prefrontal cortices (Aron et al. 2007, Benarroch 2008). An integrative function in both motor
and cognitive operations (Parent and Hazrati 1995, Baunez 1999b, Graybiel 1997) has been
suggested. The STN has a central position within the basal ganglia-thalamocortical motor,
associative, and limbic circuits and might serve as a potent regulator of these pathways. STNDBS
may modulate cognitive and affective functions (Temel et al. 2005). That is probably why,
for some patients, the beneficial effects of STN- DBS on motor functions may be accompanied
by cognitive impairment and other neuropsychiatric disturbances (Saint- Cyr et al. 2000,
Herzog et al. 2003, Anderson et al. 2005, Bellanger et al. 2009). While the impact of STN on
non-motor functions appears to be accepted by most authors, its clinical significance is still
controversial (Voon et al. 2006). Up to 41% of PD patients treated by STN- DBS face cognitive
problems (Temel et al. 2006). However, randomized multicentre studies showed that STN-
138
DBS does not impair overall cognition or affectivity, although there was a selective decrease
in frontal cognitive functions after the treatment (Witt et al. 2008). DBS causes only minor
changes in most cases, possibly related to the effect of surgery (Okun et al. 2009). However,
at least in some patients the change in cognitive functions after STN-DBS may have a clinical
importance.
Intracranial recording studies provide direct access to the deep brain nuclei. Although the
electrical event- related activities (evoked as well as induced activities) in the cortical
structures during cognitive processing have been quite widely studied, identifying the role of
the human subcortical structures has been delayed because of their inaccessibility for scalp
measurements. Stereo-electro-encephalography (SEEG) recordings in epilepsy surgery
patients have enabled the study of electrophysiological phenomena in the basal ganglia.
Generators of cognitive event- related potentials were detected in the putamen, pallidum,
caudate, and cortex (Rektor et al. 2003, Rektor et al. 2005). Recent functional neurosurgery
has provided the opportunity to record directly from the STN and GPi, most commonly in
patients with PD and primary dystonia undergoing implantation of DBS electrodes (Brown and
Williams 2005). In studies based on direct recordings from the STN, it has been suggested that
the STN takes part in executive functions processing (Baláž et al. 2008, 2010). The role of the
frontal cortex in executive functions is well known. We wondered whether the STN might also
play a role in other cognitive functions that implicate the frontal cortices. Experiments in
animals have shown an involvement of the basal ganglia nuclei in attentional and motivational
functions (Baunez and Robbins 1997, 1999 a,b, Christakou et al. 2001, Rogers et al. 2001,
Baunez et al. 2002, 2005). Bilateral high- frequency stimulation of the subthalamic nucleus in
both intact and parkinsonian rats transiently decreased accuracy in performing a visual
attentional task, suggesting impaired attention (Baunez et al. 2007). The aim of this work was
to study the involvement of the STN in attentional and orienting processes that are linked to
the rare distractor stimuli (Squires et al. 1975, Desmedt 1981, Halgren 1995a).
Methods and materials:
Subjects
Seven Parkinson's disease patients suffering from late L-DOPA-induced motor complications
and one primary generalized dystonia patient (suffering predominantly from trunk
lateroflexion) with externalized DBS electrodes implanted in the STN or GPi participated in the
139
study (Table 1, Table 2). We had to exclude three other dystonic patients from the data
analysis because their severe abnormal movements produced too many artefacts. All patients
were indicated for the DBS surgery by the Commission for Neuromodulation Surgery of the
Brno Movement Disorders Centre. All the subjects were informed about the character of this
study and gave their informed consent. The study received the approval of the local ethics
committee. The measurements were performed during the patient’s “on” state in PD,
approximately 1 hour after morning dopaminergic medication dose. The medication was
stable in all subjects.
Before the operation, all subjects underwent a detailed neuropsychological examination; the
examination showed no signs of dementia (Table 3).
Table 1
Table 2
140
Table 3
Surgical procedure
The stereotaxic frame used during the surgical procedure (electrode implantation) was the
Leibinger open frame with the Praezis Plus software and the Talairach diagram. The STN
coordinates used were in respect to the AC-PC (anterior commissure–posterior commissure)
line: 12.0 mm laterally, 5.0 mm below, and 3.0 mm behind the midpoint of the AC-PC line. The
GPi coordinates were: 20.0 mm laterally, 4.0 mm below, and 3.0 mm in front of the midpoint
of the AC-PC line. The stimulation electrodes (Medtronic, Inc.) were implanted bilaterally into
the targeted structure by stereotaxic MRI-guided technique under local anaesthesia (general
anaesthesia in the GPi case because of generalized dystonia). The definitive electrode
placement was confirmed by four microelectrode recordings. The motor part of the STN was
identified by recording the specific patterns of neuronal activity and background activity, and
by following motor responsiveness to intraoperative stimulation. Once the final target
coordinates were determined, a permanent quadripolar DBS electrode (model 3389, with 1.5
mm contact length and 0.5 mm intercontact distance) was implanted. The electrode position
was verified by the intraoperative use of fluoroscopy comparing the position of the
microrecording electrodes trajectories with the definitive quadripolar macroelectrode
trajectory and also by a post- operative CT scan. In the immediate post-implantation period,
the electrodes remained externalized. A special externalized cable enabled the intracranial
EEG recording. The internalization and the stimulator implantation were performed within a
week after the positioning of the DBS electrodes.
141
Experimental protocol and recordings
The EEG signal was recorded in the post-operative period during which the electrodes were
externalized. For cognitive testing, a visual three-stimulus protocol was used (Conroy and
Polich 2007, Polich 2007) (see Table 2). The frequent (non-target, standard) stimuli, which
were 70% of all the stimuli, were small blue circles. These were not to be followed by a
reaction. The target stimuli, which were 15% of all the stimuli, were larger blue circles. The
subjects were asked to press an electrically connected button at the time of the target
detection. The distractors (rare non-target stimuli), which were presented 15% of the time,
were black and white checkerboards; no response was required.
Table 4
The interstimulus interval was 4 seconds. The duration of the stimulus exposure was 200 ms.
The visual stimuli were presented in a random order on a monitor 1.5 m in front of patients.
Subjects received clear instructions and practiced the task briefly before the recordings.
Subjects reclined comfortably in the monitoring bed, in a quiet room with a constant
temperature. They were instructed to remain calm, to keep their eyes fixed on the monitor,
and to avoid unnecessary movements. Subjects received clear instructions and practiced the
task briefly before the recordings.
The EEG system TruScan 32 channel (Deymed Diagnostic, Alien Technic) was used for the
recording. The recordings were monopolar, with a linked earlobe reference. The sampling rate
was 1024 Hz. Standard anti-aliasing filters were used.
142
Data analysis
The EEG signal was processed and analysed off-line using ScopeWin and ScopeMat software.
The data were first segmented according to the visual stimuli trigger onset (vertical line marks
in the EEG trace indicating the time of visual stimuli presentation to the subjects). The
segments of 4 s length were visually inspected, and segments containing artificial signals or
mistaken responses were removed. After trend elimination in each segment, data were
filtered with 0.2-40 Hz bandwidths and averaged to obtain evoked responses: event- related
potentials (ERPs). The baseline interval was determined 600-100 ms before stimuli
presentation. The mean values from the baseline intervals were subtracted within each trial.
The unipolar reference (Figure 1) analysis was followed by a bipolar montage (Figure 2)
evaluation to exclude the volume conduction from surface neocortical discharges or
transsynaptic propagation along cortical- subcortical pathways and confirm the local
generation of the potentials (Wennberg and Lozano 2003). Contacts in the STN are placed very
close together. Any EEG signal on the common reference is eliminated by a bipolar montage.
Even a small bipolar montage activity corresponding with the common reference activity can
display the origin of detected activity in the STN.
Time Frequency Analysis (TFA, Figure 3) (Akay 2000) was used to determine the event-related
de/synchronizations (ERD/S) in the alpha and beta frequency ranges. A decrease in band
power indicates induced event-related desynchronization (ERD), an increase in band power
indicates event-related synchronization (ERS) (Pfurtscheller and Aranibar 1977). The ERD of
the alpha and beta rhythms is interpreted as a correlate of an activated cortical area with
increased excitability. The ERS in the alpha and lower beta bands can be interpreted as a
correlate of a deactivated cortical area, i.e. cortical idling or active inhibition (Pfurtscheller
2001). TFA produces a matrix in which each row represents the over trials averaged signal
power envelopes in a 2 Hz frequency band width (x-axis represents time; y-axis represents
frequency). The frequency step between two lines was 1 Hz. In the baseline-normalized TFA
matrix, ERS is represented by positive values (yellow, red) and ERD by negative values (green,
blue).
Statistical analysis
Two types of statistical significances were tested:
143
 The statistical significance of the differences between the mean amplitude observed
during the baseline region and the mean value computed as a mean from the
neighbourhood of each point (150ms length) after stimuli was expressed as a probability
value (p) using a non-parametric Wilcoxon Rank Sum (Signed Rank) test for paired samples.
The amplitude changes were considered as significant when p < 0.05; see Figure 1
significance to baseline.
 The differences between stimuli were analyzed by the post hoc Scheffe test for multiple
comparisons. The level of significance was set at p<0.01; see Figure 1 inter-stimuli
significance.
Results
We evaluated the signal recorded from four contacts placed in the STN and GPi bilaterally in
each subject. The ERP shape was individual; latencies and amplitudes varied according to the
stimulus type and among the subjects, and did not fully correspond to the P300 potentials
commonly observed from scalp recordings. In six subjects (in subjects 4 and 7 only on the right
side) we found a late positivity in the latency range 400-600 ms related to the target stimuli
in the STN as well in the Gpi. The majority of the subjects were right-handed and the motor
task was performed using the right hand. For this reason, we think that the potentials are not
potentials associated with movement (they were present bilaterally or only in the right STN),
but that they are related to the cognitive activity processed by target stimuli response
performance. The non-target and distractor-related waveforms manifested similar shapes.
The amplitude of the distractor ERPs was slightly higher. The most prominent difference
between the ERPs was in the appearance of an early positive peak around 200 ms evoked by
the distractor that was not displayed after the target and non-target stimuli. This positivity
probably reflects the attentional orienting response to the distractor stimuli. This potential
was detected in all subjects except subject 3. In subject 7, the EEG signal in the domain of
frequent stimuli appeared to be contaminated by artefacts (probably tremor- related) on the
left side, however, even in this subject the distractor evoked 200 ms potential could be
recorded.
144
Figure 1
The bipolar montage analysis was also performed, and the local generation of the potentials
was confirmed. Local field sources of the distractor- evoked early positive peak were found in
six STN PD patients and in the primary dystonia Gpi (Figure 2).
145
Figure 2
The induced oscillatory activities (ERD/S) in the alpha and low beta frequency range were
analyzed using the TFA. We observed a constant early increase (ERS) in the low alpha band
power in all subjects (except subject 3), which corresponds to the specific distractor-related
146
early peak in ERPs, more pronounced on the right side. In addition, there was a late higher
alpha power decrease (ERD) related to the target stimuli (also except in subject 3), which
temporally followed the P3b-like wave in the ERPs.
Figure 3
The different results in subject 3 in comparison to the whole group could have been caused
by a worse cognitive performance of the paradigm. The percentage of this patient’s correct
responses was the lowest (86% subject 3, 98-100% other subjects). The preoperative
neuropsychological examination did not show any significant deficits in comparison to the
other subjects, only MADRS (Montgomery-Asberg Depression Rating Scale) score was the
highest in this subject. We may hypothesise only that depression or a microlesional effect in
the STN after the electrode implantation could have caused an attentional deficit during the
performance of the experimental paradigm.
Discussion
We studied the electrical phenomena accompanying the cognitive processing recorded in the
STN in seven Parkinson’s disease patients and in the GPi in one primary dystonia patient.
147
A three-stimulus visual experimental paradigm was used. This paradigm is similar to the
classical oddball task consisting of frequent (non- target) stimuli and rare (target) stimuli that
evoke cognitive event- related potential called P300 (or P3). In a three stimulus paradigm a
third, non-frequent stimulus appears without any required response (Polich 2007). This
distractor stimulus evokes a response called P3a on the scalp (Courchesne et al. 1975,
Grunwald et al. 1998, Knight 1984, Knight 1997). This response is task-irrelevant, but
insufficiently ignored, and precedes the task-relevant target stimulus evoked potential (called
P3b) (Squires et al. 1975, Schröger and Wolff 1998, Kaipio et al. 2000). The distractor-evoked
ERP had a frontocentral maximum on the scalp (latency around 375 ms), whereas the targetrelated
ERP had a parietal maximum (latency range 450-475 ms) in a study using the same
protocol that was used in this study (Conroy and Polich 2007, Polich 2007). The distractorrelated
evoked potential is interpreted as an orienting response, an involuntary rapid shift of
attention to new (never previously experienced), unexpected (out of context), or
unpredictable stimuli. The ERP occurrence indicates that the distractor stimulus has
involuntarily captured the attention and is most likely within the focus of attention (Friedman
et al. 2001). It was suggested that the distractor-related response represents the cortical
component of the early attentional system, while target processing reflects a higher cognitive
closure, perhaps including memory processes (Halgren et al. 1995a).
Intracerebral recording in epilepsy surgery patients displayed multiple cortical and subcortical
generators of various cognitive ERPs (Rektor et al. 2007). The shape of intracerebral potentials
frequently varies, and it is often difficult to identify the equivalents of individual components
recorded on the scalp. The generators (steep amplitude gradients or phase reversals indicating
a local origin of the potential) of distractor- related ERP were found in several frontal areas,
and they were also recorded in more posterior cortical areas, namely the parietal, temporal,
and limbic cortices. The latencies in the frontal lobe were shorter than that of P3a recorded
on the scalp. The latency of the distractor- evoked ERP in the prefrontal cortex was also
shorter than the latency of ERP recorded in the parietal or temporal lobes. A temporal
hierarchy within the network for directed attention was suggested, with a key role played by
the prefrontal cortex (Halgren et al. 1995a, Halgren et al. 1995b, Baudena et al. 1995). The
central role of the prefrontal cortex in directing attention to novel events was also confirmed
by other studies (Daffner et al. 2000, Bledowski et al. 2004, Kiehl et al. 2005, Strobel et al.
2008). The prefrontal cortex can have both an excitatory and inhibitory influence on the neural
148
generators of early ERP components and is involved in early attentional processing stages
(Herrmann and Knight 2001).
In our study, as the first step in the analysis, we analysed the ERPs from the STN and Gpi. We
observed a late positive potential in the latency range around 500 ms linked to the target
stimuli processing. The distractor stimuli were accompanied by a specific short positive peak
in the latency range around 200 ms. ERP latency depends on the classification speed, which is
proportional to the time required to detect and evaluate the stimulus (Kutas et al. 1997,
Magliero et al. 1984, Polich 2007). The latency of this early distractor-specific potential might
indicate a fast evaluation and categorisation of the distractor stimuli in the basal ganglia. The
nearly simultaneous appearance of the early distractor-specific potentials in the two
structures forming consecutive parts of the cortico-basal ganglia-thalamocortical circuitry, i.e.
GPi and STN, may be interpreted as a sign of the specific involvement of the basal ganglia in
orienting and attentional processes. Local field generation of this early distractor related
activity was confirmed using the bipolar montage analysis. The only patient with GPi
electrodes also displayed a short latency distractor- evoked potential. Unfortunately, we had
to exclude other dystonia Gpi patients because of severe abnormal movement- related
artefacts. We decided to present the data from the only analysable subject because the results
were interesting in the context of the STN recordings and because technically correct
recordings from Gpi in dystonia are rare. We are aware that data obtained from only one
subject must be further verified by recordings in more subjects.
Event-related cerebral activity may be evoked or induced. Evoked potentials (ERP) are time
and phase locked to the stimuli. Induced changes (ERD/S) are time locked, but not phase
locked to the stimuli. As the second step, we were interested in the relationship of the ERP to
the ERD/S, especially in the lower and higher alpha frequency range, as it is known that alpha
band spectral power co-varies with P300. Other frequency ranges demonstrate similar
associations, but slow alpha activity yields the strongest correlation (Intriligator and Polich
1995, Polich 1997). Alpha ERD occurs during cognitive processing; target related P3 potential
is clearly related to the desynchronization of late alpha frequency EEG (Boiten et al. 1992,
Pfurtscheller and Klimesch 1991, Klimesch 1997, Pfurtscheller and Klimesch 1992, Polich 2007,
Sergeant et al. 1987, Yordanova et al. 2001). We have observed ERD in higher alpha
frequencies following the late positive response in the ERP (latency 500-1500ms) induced by
the target stimuli. This probably represents the performance of the target-related cognitive-
149
motor response. An early lower alpha frequency band ERS was observed exclusively after the
distractor stimuli. There was a temporal overlap of the distractor specific ERS and ERP. As the
ERS in the alpha band is considered as a correlate of an active inhibition, this reaction probably
represents suppression of an involuntary shift of attention and then inhibition of further
cognitive processing of the distractor stimuli. Both early distractor related ERS and ERP may
share common mechanism with the N200 response in the scalp recordings. The amplitude of
N200 is higher in stop trials than in go trials in go/no and stop-signal tasks (Enriquez-Geppert
et al. 2010). The inferior-frontal cortex (IFC) plays an inhibitory role in motor control. It was
demonstrated that the IFC may modulate various cognitive functions of the basal ganglia and
specifically of the STN via a direct functional projection between the IFC and the STN (a
"hyperdirect" pathway) (Aron and Poldrack 2006, Aron et al. 2007, Balaz et al 2010). Apart
from the striatum, the subthalamic nucleus (STN) is the only structure in the basal ganglia that
receives a direct cortical projection (Albin et al. 1989; Parent and Hazrati). For this reason, we
would expect a later latency of the attentional phenomena in the Gpi. An early positive peak
was present in the Gpi at around 200 ms after the distractor stimuli. In the Gpi, a slow wave
with a latency around 800 ms following the distractors was also observed. The early activation
of the STN may lead to response suppression (in our case, inhibition of further cognitive
processing of the distractor stimuli and suppression of the motor response). The co-activation
of the Gpi (Mink 1996) may lead to subsequent inhibition of the thalamo-cortical motor
program (Coxon et al. 2006, Aron et al. 2007).
We evaluated the human event-related EEG signal recorded via intracerebral depth
electrodes. The main disadvantage of all intracerebral recordings is that they are performed
in structures that could be modified by pathological processes (in this case by Parkinson's
disease and generalized dystonia) and that the results could be influenced by medication. The
other limitation of this study is the absence of simultaneous scalp recordings (Fz, Cz, Pz), which
could not be placed because of the sterile bandaging over the parietally localized electrode
extensions as we respected the patients safety and the prevention from infectious
complications. On the other hand, as the depth electrodes are submerged directly into the
brain tissues and record from their immediate vicinity, the results are obtained directly from
cerebral structures. Some of them are almost inaccessible by scalp measurements, so the data
measured by the depth recordings provide important information about the function of the
subcortical structures. We performed simultaneous scalp recordings (Fz, Cz, Pz- in this case
150
they could be placed because of other electrode trajectory) using the same experimental
paradigm in an epilepsy surgery group of patients with implanted deep brain electrodes. We
did not observe the distractor- related early short positive peak on the scalp.
Acknowledgements:
The study was supported by MSMT CR research project: MSM0021622404. The technical part
of this study was supported by grant GA AV IAA 200650801. The technical part of the study
was also supported by project: Application laboratories of advanced microtechnologies and
nanotechnologies, CZ.1.05/2.1.00/01.0017, co-funded by the Operational Programme
'Research and Development for Innovations', the European regional development fund and
state budget.
We wish to thank Drs Novak and Chrastina (neurosurgery).
References:
Akay M (2000) Time Frequency and Wavelets in Biomedical Signal Processing, Wiley.
Albin RL, Young AB, Penny JB (1989) The functional anatomy of basal ganglia disorders. Trends
in Neuroscience 12:366–375.
Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP (2005) Pallidal vs subthalamic
nucleus deep brain stimulation in Parkinson disease. Archives of Neurology 62:554-60.
Aron AR, Poldrack RA (2006) Cortical and subcortical contributions to Stop signal response
inhibition: role of the subthalamic nucleus. The Journal of neuroscience 26:2424-33.
Aron AR, Behrens TE, Smith S, Frank MJ, Poldrack RA (2007) Triangulating a cognitive control
network using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI.
Journal of Neuroscience 27:3743-52.
Baláž M, Rektor I, Pulkrábek J (2008) Participation of the subthalamic nucleus in executive
functions: An intracerebral recording study. Movement disorders 23:553-557.
151
Baláž M, Srovnalová H, Rektorová I, Rektor I (2010) The effect of cortical repetitive transcranial
magnetic stimulation on cognitive event-related potentials recorded in the subthalamic
nucleus. Experimental Brain Research 203:317-27.
Baudena P, Halgren E, Heit G, Clarke JM (1995) Intracerebral potentials to rare target and
distractor auditory and visual stimuli. III. Frontal cortex. Electroencephalography and Clinical
Neurophysiology 94:251-264.
Baunez C, Robbins TW (1997) Bilateral lesions of the subthalamic nucleus induce multiple
deficits in an attentional task in rats. European Journal of Neuroscience 9:2086-99.
Baunez C, Robbins TW (1999a) Effects of dopamine depletion of the dorsal striatum and
further interaction with subthalamic nucleus lesions in an attentional task in the rat.
Neuroscience 92:1343-56.
Baunez C, Robbins TW (1999b) Effects of transient inactivation of the subthalamic nucleus by
local muscimol and APV infusions on performance on the five-choice serial reaction time task
in rats. Psychopharmacology 141:57-65.
Baunez C, Amalric M, Robbins TW (2002) Enhanced food-related motivation after bilateral
lesions of the subthalamic nucleus. Journal of Neuroscience 22:562-8.
Baunez C, Dias C, Cador M, Amalric M (2005) The subthalamic nucleus exerts opposite control
on cocaine and 'natural' rewards. Nature Neuroscience 8:484-9
Baunez C, Christakou A, Chudasama Y, Forni C, Robbins TW (2007) Bilateral high-frequency
stimulation of the subthalamic nucleus on attentional performance: transient deleterious
effects and enhanced motivation in both intact and parkinsonian rats. European Journal of
Neuroscience 25:1187-94.
152
Ballanger B, van Eimeren T, Moro E, Lozano AM, Hamani C, Boulinguez P, Pellecchia G, Houle
S, Poon YY, Lang AE, Strafella AP (2009) Stimulation of the subthalamic nucleus and
impulsivity: release your horses. Annals of Neurology 66:817-24.
Benarroch EE (2008) Subthalamic nucleus and its connections: Anatomic substrate for the
network effects of deep brain stimulation. Neurology 70:1991-5.
Bledowski C, Prvulovic D, Hoechstetter K, Scherg M, Wibral M, Goebel R, Linden DE (2004)
Localizing P300 generators in visual target and distractor processing: a combined eventrelated
potential and functional magnetic resonance imaging study. The Journal of
Neuroscience 24:9353-9360.
Boiten F, Sergeant J, Geuze R (1992) Event- related desynchronization: the effects of energic
and computational demands. Electroencephalography and Clinical Neurophysiology 82: 302-
309.
Brown P, Williams D (2005) Basal ganglia local field potential activity: character and functional
significance in the human. Clinical Neurophysiology 116:2510-2519.
Christakou A, Robbins TW, Everitt BJ (2001) Functional disconnection of a prefrontal corticaldorsal
striatal system disrupts choice reaction time performance: implications for attentional
function. Behavioral Neuroscience 115:812-25.
Conroy MA, Polich J (2007) Normative variation of P3a and P3b from a large sample (N= 120):
gender, topography, and response time. Journal of Psychophysiology21:22-32.
Courchesne E, Hillyard SA, Galambos R (1975) Stimulus novelty, task relevance, and visual
evoked- potential in man. Electroencephalography and Clinical Neurophysiology 39: 131-143.
Coxon JP, Stinear CM, Byblow WD (2006) Intracortical inhibition during volitional inhibition of
prepared action. J Neurophysiol 95:3371–3383.
153
Daffner KR, Mesulam MM, Scinto LF, Acar D, Calvo V, Faust R, Chabrerie A, Kennedy B,
Holcomb P (2000) The central role of the prefrontal cortex in directing attention to novel
events. Brain 123:927-939.
Desmedt JE (1981) Scalp-recorded event-related potentials in man as point of entry into the
analysis of cognitive processing. In: F.O. Schmitt, F.G. Worden, G. Edelmann and S.D. Dennis
(Eds.), The Organization of the Cerebral Cortex. MIT, Cambridge, MA, pp. 441-473.
Enriquez-Geppert S, Konrad C, Pantev C, Huster RJ (2010) Conflict and inhibition differentially
affect the N200/P300 complex in a combined go/nogo and stop-signal task. Neuroimage
51(2):877-87
Friedman D, Cycowicz YM, Gaeta H (2001) The novelty P3: an event-related brain potential
(ERP) sign of the brain's evaluation of novelty. Neuroscience and biobehavioral reviews
25:355-373.
Graybiel AM (1997) The basal ganglia and cognitive pattern generators. Schizophrenia
Bulletin23:459-469.
Grunwald T, Lehnertz K, Heinze HJ, Helmstaedter C, Elger CE (1998) Verbal novelty detection
within the human hippocampus proper. Proceedings of the National Academy of Sciences of
the United States of America 95:3193-7.
Halgren E, Baudena P, Clarke JM, Heit G, Liégeois C, Chauvel P, Musolino A (1995a)
Intracerebral potentials to rare target and distractor auditory and visual stimuli. I. Superior
temporal plane and parietal lobe. Electroencephalography and Clinical Neurophysiology
94:191-220.
154
Halgren E, Baudena P, Clarke JM, Heit G, Marinkovic K, Devaux B, Vignal JP, Biraben A (1995b)
Intracerebral potentials to rare target and distractor auditory and visual stimuli. II. Medial,
lateral and posterior temporal lobe. Electroencephalography and Clinical Neurophysiology
94:229-250.
Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM (2004) The subthalamic nucleus in the
context of movement disorders. Brain 127:4-20.
Herrmann CS, Knight RT (2001) Mechanisms of human attention: event-related potentials and
oscillations. Neuroscience and Biobehavioral Reviews 25:465-76.
Herzog J, Reiff J, Krack P, Witt K, Schrader B, Müller D, Deuschl G (2003) Manic episode with
psychotic symptoms induced by subthalamic nucleus stimulation in a patient with Parkinson's
disease. Movement Disorders 18:1382-4.
Intriligator J, Polich J (1995) On the relationship between EEG an P300 variability. Intenational
Journal of Psychophysiology 20: 59-74.
Kaipio ML, Cheour M, Ceponiene R, Ohman J, Alku P, Näätänen R (2000) Increased
distractibility in closed head injury as revealed by event-related potentials. Neuroreport
11:1463-1468.
Kiehl KA, Stevens MC, Laurens KR, Pearlson G, Calhoun VD, Liddle PF (2005) An adaptive
reflexive processing model of neurocognitive function: supporting evidence from a large scale
(n = 100) fMRI study of an auditory oddball task. Neuroimage 25:899-915.
Klimesch W (1997) EEG-alpha rhythms and memory processes. International Journal of
psychophysiology 26:319-340.
Knight RT (1984) Decreased response to novel stimuli after prefrontal lesions in man.
Electroencephalography and Clinical Neurophysiology 59:9-20.
155
Knight RT (1997) Distributed cortical networkfor visual attention. Journal of cognitive
neuroscience 9:75-91.
Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD,
Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five-year follow-up of bilateral stimulation
of the subthalamic nucleus in advanced Parkinson's disease. The New England Journal of
Medicine 349:1925-34.
Kutas M, McCarthy G, Donchin E (1997) Augmenting mental chronometry: the P300 as a
measure of stimulus evaluation time. Science 197:792-5.
Magliero A, Bashore TR, Coles MG, Donchin E (1984) On the dependence of P300 latency on
stimulus evaluation processes. Psychophysiology 21:171-86.
Mink JW (1996) The basal ganglia: focused selection and inhibition of competing motor
programs. Progress in Neurobiology 50:381–425.
Nambu A, Tokuno H, Takada M (2002) Functional significance of the cortico-subthalamopallidal
'hyperdirect' pathway. Neuroscience Research 43:111-7.
Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M, Jacobson CE
4th, Wang X, Gordon CW Jr, Zeilman P, Romrell J, Martin P, Ward H, Rodriguez RL, Foote KD
(2009) Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus
pallidus interna deep brain stimulation: the COMPARE trial. Annals of Neurology 65:586-95.
Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. II. The place of
subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Research Reviews
20:128-54.
Pfurtscheller G, Aranibar A (1977) Event- related cortical desynchronization detected by
power measurements of scalp EEG. Electroenceph clin Neurophysiol 42:817-826.
156
Pfurtscheller G, Klimesch W (1991) Event- related desynchronization during motor behavior
and visual information processing. Electroencephalography and Clinical Neurophysiology
Suppl 42:58-65.
Pfurtscheller G, Klimesch W (1992) Functional topography during a visuoverbal judgment task
studied with event- related desynchronization mapping. Journal of Clinical Neurophysiology
9:120-131.
Pfurtscheller G (2001) Functional brain imaging based on ERD/ERS. Vision Research 41: 1257-
1260.
Polich J (1997) On the relationship between EEG and P300: individual differences, aging and
ultradian rhythms. Internation Journal of Psychophysiology 26:299-317.
Polich J (2007) Updating P300: An integrative theory of P3a and P3b. Clinical Neurophysiology
118:2128-2148.
Rektor I, Kaňovský P, Bareš M, Brázdil M, Streitová H, Klajblová H, Kuba R, Daniel P (2003) A
SEEG study of ERP in motor and premotor cortices and in the basal ganglia. Clinical
Neurophysiology 114:463-471.
Rektor I, Bareš M, Brázdil M, Kaňovský P, Rektorová I, Sochůrková D, Kubová D, Kuba R, Daniel
P (2005) Cognitive-and movement-related potentials recorded in the human basal ganglia.
Movement Disorders 20:62-568.
Rektor I, Brázdil M, Nestrasil I, Bareš M, Daniel P (2007) Modifications of cognitive and motor
tasks affect the occurrence of event-related potentials in the human cortex. The European
Journal of Neuroscience 26:1371-1380.
Rogers RD, Baunez C, Everitt BJ, Robbins TW (2001) Lesions of the medial and lateral striatum
in the rat produce differential deficits in attentional performance. Behavioral Neuroscience
115:799-811.
157
Saint-Cyr JA, Trépanier LL, Kumar R, Lozano AM, Lang AE (2000) Neuropsychological
consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's
disease. Brain123:2091-108.
Schröger E, Wolff C (1998) Behavioral and electrophysiological effects of task-irrelevant sound
change: a new distraction paradigm. Cognitive Brain Research 7:71-87.
Sergeant J, Geuze R, van Winsum W (1987) Event- related desynchronization and P300.
Psychophysiology 24:272-277.
Squires NK, Squires KC, Hillyard SA (1975) Two varieties of long-latency positive waves evoked
by unpredictable auditory stimuli in man. Electroencephalography and Clinical
Neurophysiology 38:387-401.
Strobel A, Debener S, Sorger B, Peters JC, Kranczioch C, Hoechstetter K, Engel AK, Brocke B,
Goebel R (2008) Novelty and target processing during an auditory novelty oddball: a
simultaneous event-related potential and functional magnetic resonance imaging study.
Neuroimage 40:869-883.
Temel Y, Blokland A, Steinbusch HW, Visser-Vandewalle V (2005) The functional role of the
subthalamic nucleus in cognitive and limbic circuits. Progress in Neurobiology 76:393-413
Temel Y, Kessels A, Tan S, Topdag A, Boon P, Visser-Vandewalle V (2006) Behavioural changes
after bilateral subthalamic stimulation in advanced Parkinson disease: a systematic review.
Parkinsonism and Related Disorders 12:265-72
Voon V, Kubu C, Krack P, Houeto JL, Tröster AI (2006) Deep brain stimulation:
neuropsychological and neuropsychiatric issues. Movement Disorders Suppl 14:S305-27.
158
Wennberg RA, Lozano AM. Intracranial volume conduction of cortical spikes and sleep
potentials recorded with deep brain stimulating electrodes (2003) Clinical Neurophysiology
114:1403-1418.
Witt K Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO, Krause M, Tronnier V, Kloss M,
Schnitzler A, Wojtecki L, Bötzel K, Danek A, Hilker R, Sturm V, Kupsch A, Karner E, Deuschl G
(2008) Neuropsychological and psychiatric changes after deep brain stimulation for
Parkinson's disease: a randomised, multicentre study. Lancet Neurology 7:605-14
Yordanova J, Kolev V, Polich J (2001) P300 and alpha event- related desynchronization (ERD).
Psychophysiology 38:143-152.
159
3.9 Cognitive Event-Related Potentials and Oscillations in the Subthalamic Nucleus
Published in: Neurodegener Diseases 2010 Mar 3;7(1-3):160-162. IF: 3.5
Commentary:
The review article presented below corroborated our previous papers on STN recordings that
were commented on above.
According to our earlier studies based on intracerebral recordings of cognitive event-related
potentials (ERPs) in epilepsy surgery candidates, the cognitive activities in the
basal ganglia (BG) are organized in some way other than the well-known organization of the
cortico-BG-thalamocortical circuits (Rektor et al. 2005) . We report the results of three
substudies here. In the first two, the auditory oddball ERPs were recorded from the area of
the subthalamic nucleus (STN). Finally, a cognitive event-related desynchronization/
synchronization (ERD/S) study in α- and β-frequency bands was performed. Our results
indicate a specific, task-related involvement of STN in the cognitive activities. Cognitive
processing in STN is possibly processed via hyperdirect cortico-STN pathway. Certain effects
of deep brain stimulation surgery on cognitive performance could be explained by a direct
effect on ‘cognitive’ parts of the STN.
As a co-author I participated in conception of idea for an article, was a first author of two out
of three articles reviewed in the following article.
Cognitive Event-Related Potentials and Oscillations in the Subthalamic Nucleus
Ivan Rektor, Marek Baláž, Martina Bočková
First Department of Neurology, Masaryk University, St. Anne’s Hospital, Brno , Czech Republic
Prof. Dr. Ivan Rektor, CSc
First Department of Neurology, Masaryk University
St. Anne’s Hospital, Pekarska 53
160
CZ–656 91 Brno (Czech Republic)
Tel. +420 543 182 623, Fax +420 543 182 624, E-Mail irektor @ med.muni.cz
Key Words
Cognitive activities; Subthalamic nucleus; Basal ganglia; P3-like potential; Event-related
desynchronization/synchronization
Abstract
Background: The cognitive role of the subthalamic nucleus (STN) remains largely unknown.
Methods/Results: A modified protocol with a dual task elicited local field event-related
potentials (ERPs) within the STN. No generators of ERPs were elicited by the standard oddball
protocol in the STN (at variance with recordings from the putamen, caudate and
pallidum). Repetitive transcranial magnetic stimulation (rTMS) over the right inferior frontal
cortex caused a shortening of latencies of ERPs in standard and dual protocols. No
changes were observable after the rTMS over the dorsolateral prefrontal cortex and sham
stimulation. In the STN, only the tasks with an increased demand on executive functions
produced the α -/β -event-related desynchronization/synchronization in visuomotor tasks
with single letters writing.
Conclusion: Our results indicate a specific, task-related involvement of the STN in the cognitive
activities. Cognitive processing in the STN is possibly processed via hyperdirect
cortico-STN pathway. Certain effects of deep brain stimulation surgery on cognitive
performance could be explained by a direct effect on ‘cognitive’ parts of the STN.
According to our earlier studies based on intracerebral recordings of cognitive event-related
potentials (ERPs) in epilepsy surgery candidates, the cognitive activities in the
basal ganglia (BG) are organized in some way other than the well-known organization of the
cortico-BG-thalamocortical circuits [1] . We report the results of three substudies
here. In the first two, the auditory oddball ERPs were recorded from the area of the
subthalamic nucleus (STN). Finally, a cognitive event-related desynchronization/
synchronization (ERD/S) study in α- and β-frequency bands was performed.
161
Methods
Recordings were obtained from patients with Parkinson’s disease from externalized fourcontact
deep brain stimulation (DBS) electrodes implanted in the STN. Usually, two of the four
contacts of each electrode (0.5-mm intercontact distance and 1.5 mm electrode
contact width) were positioned inside the STN according to clinical effect, perioperative
microrecording and stimulation. The recording of bioelectrical activity was performed during
the interoperative period (before battery implantation). Recordings were performed using the
8-channel Nihon Kohden Neuropack 4200EP/EMG device, and later using the 32-channel EEG
system TruScan Alien. The signal was filtered in the range 1–200 Hz, time base 1,200 ms; a
biauricular reference electrode was used. The sampling rate was 256 Hz.
In 10 patients, involvement of STN in executive functions was tested by an auditory oddball
paradigm [2] . Tones were delivered through earphones, at a 2-Hz frequency: frequent tones
were delivered at 1,000 Hz and 70 dB, for 0.1 s; rare (target) tones were delivered at 2,000 Hz
and 70 dB, for 0.1 s. The tones were randomly generated at a 5: 1 ratio. The subjects were
instructed to recognize the target tones and to silently count them in the standard protocol.
A modified paradigm increased demands on executive functions.
The tasks consisted of silently changing a date upon each target presentation. The subjects
were given a two-item date which included the day of the week and the ordinal date (e.g.
Monday the 19th). The date had to be updated after each target stimulus [2] .
We found a local source, a steep rise in amplitude, in the ERPs (P3-like potential) recorded
during the dual task protocol within the STN in 8 of the 14 electrodes. In the remaining 6
electrodes, there were no ERP generators present. The occurrence of generator activity in STN
was significant (p ! 0.0001; test of homogeneity of binomial distribution). We did not observe
a voltage change in the ERPs recorded during the standard protocol. ERP latencies
were significantly longer in the modified protocol in the contacts with the best motor response
(Wilcoxon matched pairs test). In the second study, we raised the question whether the STN
connections with cortical structures influence its participation in
cognitive functions and examined two possible candidates for such a cooperation – the
dorsolateral prefrontal cortex (DLPFC) and the inferior frontal cortex (IFC).
The repetitive transcranial magnetic stimulation (rTMS) modifies the cortical excitability. One
rTMS session (600 pulses) of 1-Hz stimulation was delivered to each patient over the right IFC
(BA 44) or over the right DLPFC (BA 9, 46). The DLPFC has been associated with executive
162
functions and with higher cognitive functions, while the IFC was shown to be important for
the executive functions as well. The direct connection between the IFC and
the STN – the ‘hyperdirect’ pathway and its putative influence on motor aspects of STN activity
has been described earlier. The ERPs were recorded using the same method and technique as
described above. rTMS over the right IFC caused a statistically significant shortening of
latencies of ERPs in both protocols in all patients. No such changes were observable either
after the sham rTMS of IFC or after the active rTMS of the DLPFC area.
There was again a voltage change present in the STN with a modified protocol.
The aim of this work was to examine the involvement of the STN in the neurocognitive
networks in four visuomotor cognitive tasks with single letters writing. The α- and β-ERD/S
was used as the method of the EEG signal analysis. The ERD of the α - and β - bands is
interpreted as a correlate of an activated cortical area, and the ERS correlate of a cortical
deactivation.
The EEG signal was recorded from the STN in 5 patients. The used experimental protocol was
previously tested in a SEEG study in epilepsy surgery patients and showed a specific activation
of the prefrontal and lateral temporal neocortex [3] . The letters of the alphabet, presented in
a random order on a monitor, served as the visual stimuli. The duration of the stimulus
exposure was 200 ms, of the interstimulus interval 16 s; the mean number of trials
was 50. Subjects performed four visuomotor cognitive tasks: (1) single letter counting, (2)
copying, (3) writing another letter (planning, inhibition of automatic responses) and (4) writing
another letter inversed (planning, inhibition of automatic responses, mental inversion). Data
were first segmented according to the stimulation trigger onset. The individual frequency
windows were determined in the α -band (7–14 Hz) and the β -band (16–30 Hz) using time
frequency analysis (TFA). The trials were processed by a complex demodulation technique to
ascertain the envelope of power in the individual frequency bands and averaged. A decrease
in band power indicates induced (nonphase-locked,
noncoherent) ERD, and an increase in band power indicates event-related synchronization
ERS. The significance of the differences between the mean power observed during the
baseline and that measured inside evaluated interval was expressed as a probability
value (p) using a nonparametric Wilcoxon rank sum (signed rank) test for paired samples.
163
Results
The α - and β-ERD were expressed during the two more complex tasks with increased demand
on the executive functions: task 3 (in 3 of 5 subjects) and task 4 (in
4 of 5 subjects; table 1 ). No significant changes were detected during the first two tasks.
The results demonstrated specific and selective activation in the STN evoked by complex
cognitive tasks.
Discussion
The role of the BG in cognitive processing is largely unknown. An integrative role of the BG,
with subsequent modulation of cortical cognitive processing has been suggested [1] . In some
cases, direct connections with the cortex that bypass the circuitries might underlie the
processing of specific cognitive functions. This might be the case of STN. The standard oddball
ERP (P3-like potentials) was recorded in the putamen, caudate and pallidum [1]
but not in the STN. STN seems to be specifically involved in the processing of some cognitive
activities, e.g. of the executive functions. A modified protocol with a dual task elicited localfield
ERPs within the STN. rTMS 1 Hz over the right IFC caused a significant shortening of
latencies of ERPs in both protocols. No such changes were observable either after the sham
rTMS or after the active rTMS over the DLPFC. In the STN, only the tasks with an increased
demand on executive functions produced the α - and β -ERD/S. ERD/S was tested in
visuomotor tasks with single letters writing. Our results indicate a specific, taskrelated
involvement of the STN in the cognitive activities. Cognitive processing in the STN is possibly
processed via a hyperdirect pathway. These findings are more intriguing if we consider that
164
our target was either directly in the motor part of the STN or in its immediate vicinity,
according to the perioperation microrecording results and the effect of the DBS procedure on
the motor performance of the patients. The neuronal pools involved in cognitive activities may
be located in close vicinity to, or even overlap with, the neurons active in motor functions.
Certain effects of DBS surgery on cognitive performance could be explained by a direct effect
on ‘cognitive’ parts of the STN.
Acknowledgement
Supported by MŠMT ČR research project No. MSM 0021622404.
References
1 Rektor I, Bareš M, Brázdil M, Kaňovský P, Rektorová I, Sochůrková D, Kubová D, Kuba R,
Daniel P: Cognitive and movement-related potentials recorded in the human basal ganglia.
Mov Disord 2005; 20: 562–568.
2 Baláž M, Rektor I, Pulkrábek J: Participation of the subthalamic nucleus in executive
functions: an intracerebral recording study. Mov Disord 2008; 23: 553–557.
3 Bočková M, Chládek J, Jurák P, Halámek J, Rektor I: Executive functions processed in
the frontal and lateral temporal cortices: intracerebral study. Clin Neurophysiol 2007;
118: 2625–2636.
165
4 Conclusion
STN occupies an influential position within BG structure. Despite being primarily a motor
structure, results of our research indicate that STN takes active part in cognitive and non-motor
activities. Its participation in these activities is conditioned by the difficulty of the task, i.e. it
participates in more demanding cognitive tasks.
With growing numbers of procedures and centers involved in deep brain stimulation for
treatment of movement disorders and other conditions, interest in various aspects of
stimulation keeps growing.
It seems that STN cooperates directly with the inferior frontal cortex in its cognitive-related
performance. The connection of subthalamic nucleus with the dorsolateral prefrontal cortex
seems to be at best indirect. Modulation of STN activity by continuous DBS can influence wide
array of non-motor function in addition to its well described and usual effect on motor
symptoms of PD.
From its subcortical position it has a potential to influence cortical structures via direct
connections with IFC. Our findings are in line with a concept of BG having potential to modulate
the cortical cognitive processing.
We have also described improvement of some non-motor aspects by increasing the amplitude
of DBS STN.
The proof of participation of subthalamic nucleus in executive functioning underlines the need
of meticulous selection of candidates for deep brain stimulation surgery of this target in PD.
We plan to develop a new application for evaluation of cognitive status prior to DBS in order
to further refine candidate selection process.
166
5 Acknowledgements
I would like to express my sincere and deep thanks to Professor Ivan Rektor for his enlightened
leadership, intriguing discussions and brilliant suggestions. He always showed me a way and
led me to right sources both in science and in medicine.
Further thanks belong especially to members of the Movement Disorders Centre Brno
(Professor Martin Bareš, Professor Irena Rektorová and assistant professor Dr. Martina
Bočková) and our stereotactic neurosurgeons (Professor Zdeněk Novák, Associated professor
Jan Chrastina). Without continuous help and supportive attitude of these people my research
would not be possible at all. I also thank professor Milan Brázdil and late professor Robert
Kuba for showing their confidence in my work and exemplary behavior as scientists, teachers
and humans.
I also want to thank to all my other co-authors namely S.Goldemundová, Š.Aulická, V.Dírerová
and V. Pulkrábková
Last, but not least, I want to express thanks to my family and loved ones for their ongoing
encouragement and care. Especially I want to mention my late mother Dr. Eliška Balážová who
encouraged my interst in science and teaching, and my wife Dr. Zuzana Balážová, who keeps
supporting me lovingly in my work and life.
167
6 References
Aron AR, Behrens TE, Smith S, Frank MJ, Poldrack RA. Triangulating a cognitive control network
using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI. J Neurosci.
2007;27(14):3743-52.
Baláž M, Rektor I. Neurologické a kognitivní vlivy hluboké mozkové stimulace subtalamického
jádra u pacientů s Parkinsonovou nemocí. Neurol. pro praxi, 2008; 9(5): 305–307
Baláz M, Srovnalová H, Rektorová I, Rektor I. The effect of cortical repetitive transcranial
magnetic stimulation on cognitive event-related potentials recorded in the subthalamic
nucleus. Exp Brain Res. 2010;203(2):317-27.
Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic
nucleus for the treatment of Parkinson’s disease Lancet Neurol 2009; 8: 67–81
Benabid AL, Chabardes S, Seigneuret E, et al. Surgical complications in 526 DBS patients
operated over 20 years. 75th Annual Meeting of the American Association of NeuroSurgeons;
Washington DC, USA; April 2007. http://www.aans.org/library/ article.aspx?ArticleId=40839
(Nov 16, 2008 ).
Bergman H, Wichmann T, DeLong MR (1990) Reversal of experimental parkinsonism by lesions
of the subthalamic nucleus. Science 249:1436–1438
Bower JH, Maraganore DM, McDonnell SK, et al. Incidence and distribution of parkinsonism in
Olmsted County, Minnesota, 1976–1990. Neurology. 1999:1214–1220
Cavanagh JF, Wiecki TV, Cohen MX, Figueroa CM, Samanta J, Sherman SJ, Frank
MJ.Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold.
Nat Neurosci. 2011 Sep 25;14 (11):1462-7.
Castrioto A, Moro E. New targets for deep brain stimulation treatment of Parkinson's disease.
Expert Rev Neurother. 2013 Dec;13(12):1319-28.
168
Chrastina J, Novák Z, Rektor I, Baláž, M. Surgical complications of DBS. Journal fur Neurologie,
Neurochirurgie und Psychiatrie, Wien, Verlag fur Medizin und Wirtschaft, Austria. ISSN 1608-
1587, 2008, vol. 9, no. 1, p. 31 - 31.
Daniele A, Albanese A, Contarino MF et al. Cognitive and behavioural effects of chronic
stimulation of the subthalamic nucleus in patients with Parkinson´s disease. J Neurol
Neurosurg Psychiatry 2003, 74: 175-182
Daniels C, Krack P, Volkmann J, Pinsker MO, Krause M, Tronnier V, Kloss M, Schnitzler A,
Wojtecki L, Bötzel K, Danek A, Hilker R, Sturm V, Kupsch A, Karner E, Deuschl G, Witt K.
Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's
disease. Mov Disord. 2010 Aug 15;25(11):1583-9.
Deuschl G, Schüpbach M, Knudsen K, Pinsker MO, Cornu P, Rau J, Agid Y, Schade-Brittinger C.
Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease:
concept and standards of the EARLYSTIM-study. Parkinsonism Relat Disord. 2013 Jan;19(1):56-
61.
Dujardin K, Defebvre L, Krystkowiak P, Blond S, Destee A. Influence of chronic bilateral
stimulation of the subthalamic nucleus on cognitive function in Parkinson´s disease. J Neurol
2001, 248: 603-611.
Evans AH, Lees AJ. Dopamine dysregulation syndrome in Parkinson's disease. Curr Opin
Neurol. 2004 Aug;17(4):393-8. Review).
Fanfrdlová Z. Role neuropsychologického vyšetření v rámci péče o pacienty s Parkinsonovou
nemocí léčených metodou hluboké mozkové stimulace, Neurol. pro praxi, 2005: (5)4: 221–
224.
García-Larrea L, Cézanne-Bert G (1998) P3, Positive slow wave and working memory load: a
study on the functional correlates of slow wave activity. Electroencephalography and Clinical
Neurophysiology 108:260-73
169
Gironell A, Kulisevsky J, Rami L et al. Effects of pallidotomy and bilateral subthalamic
stimulation on cognitive function in Parkinson disease: a controlled comparative study, J
Neurol 2003:250:917-923
Goldenberg MM, Medical Management of Parkinson’s Disease P T. Oct 2008; 33(10): 590-594,
599-606.
Hariz ML, Johansson F, Shamsgovara P et al. Bilateral subthalamic nucleus stimulation in a
parkinsonian patient with preoperative deficits in speech and cognition: persistent
improvement in mobility but increased dependency – a case study. Mov Disord 2000, 15: 136-
139
Hikosaka O, Sakamoto M, Miyashita N. (1993) Effects of caudate nucleus stimulation on
substantia nigra cell activity in monkey. Exp Brain Res 95:457–472
Houeto JL, Damier P, Bejjani BP et al. Subthalamic stimulation in Parkinson´s disease: a
multidisciplinary approach. Arch Neurol 2000;57:461-5.Houeto JL, Mesnage V, Welter ML et
al. Subthalamic DBS replaces levodopa in Parkinson´s disease, two years follow-up. Neurology
2003;60:154-5
Houeto JL, Mesnage V, Welter ML et al. Subthalamic DBS replaces levodopa in Parkinson´s
disease, two years follow-up. Neurology 2003;60:154-5
Isoda M and Hikosaka O. Role for Subthalamic Nucleus Neurons in Switching from Automatic
to Controlled Eye Movement. The Journal of Neuroscience, 9 July 2008, 28(28): 7209-7218;
doi: 10.1523/JNEUROSCI.0487-08.200
Jahanshahi M, Ardouin CM, Brown RG et al. The impact of deep brain stimulation executive
function in Parkinson´s disease. Brain 2000, 123 (Pt 6):1142-1154
Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation:
summary and meta-analysis of outcomes. Mov Disord 2006; 21 (suppl 14): S290–304
170
Koppel BH, Rezai AR, Chang JW, Vitek JL: Anatomy and Physiology of the Basal Ganglia:
Implications for Deep Brain Stimulation for Parkinson´s Disease, Mov Disord, Vol. 21, Suppl.
14, 2006, S238-246
Krack P, Batir A, Van Blercom N et al. Five-year follow up of bilateral stimulation of subthalamic
nucleus in advanced Parkinson´s disease. N Engl J Med 2003,349:1925 – 1934
Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD,
Benazzouz A, LeBas JF, Benabid AL, Pollak P. Five-year follow-up of bilateral stimulation of the
subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 2003;349:1925-34
Krack P, Hariz MI, Baunez C, Guridi J, Obeso JA. Deep brain stimulation: from neurology to
psychiatry? Trends Neurosci. 2010; 33(10):474-84.
Lang AE, Lozano AM. Parkinson's disease. N Engl J Med 1998;339:1044-1053
Lang AE, Houeto JL, Krack P, Kubu C, Lyons KE, Moro E, Ondo W, Pahwa R, Poewe W, Tröster
AI, Uitti R, Voon V. Deep brain stimulation: preoperative issues.Mov Disord. 2006 Jun;21 Suppl
14:S171-96.
Lezcano E, Gomez-Esteban JC, Zarranz JJ, et al. Improvement in quality of life in patients with
advanced Parkinson’s disease following bilateral deep-brain stimulation in subthalamic
nucleus. Eur J Neurol 2004; 11: 451–54).
Lim SY, O'Sullivan SS, Kotschet K, Gallagher DA, Lacey C, Lawrence AD, Lees AJ, O'Sullivan DJ,
Peppard RF, Rodrigues JP, Schrag A, Silberstein P, Tisch S, Evans AH. Dopamine dysregulation
syndrome, impulse control disorders and punding after deep brain stimulation surgery for
Parkinson's disease. J Clin Neurosci 2009; 16(9):1148-52.
Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL
(1995) Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation.
Lancet 345:91–95.
171
Macia F, Perlemoine C, Coman I et al. Parkinson’s disease patients with bilateral subthalamic
deep brain stimulation gain weight. Mov Disord 2004; 19: 206–12).
Mallet, L., Schüpbach, M., N'Diaye, K., Remy, P., Bardinet, E., Czernecki, V., Welter, M.L.,
Pelissolo, A., Ruberg, M., Agid, Y., and Yelnik, J. Stimulation of subterritories of the subthalamic
nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc
Natl Acad Sci USA 2007; 104 (25): 10661-10666.
Mandat TS, Hurwitz T, Honey CR. Hypomania as an adverse effect of subthalamic nucleus
stimulation: report of two cases. Acta Neurochir (Wien) 2006;148(8):895-7.
Monakow KH, Akert K, Künzle H. Projections of the precentral motor cortex and other cortical
areas of the frontal lobe to the subthalamic nucleus in the monkey. Exp Brain Res. 1978 Nov
15;33(3-4):395-403.
Morgante L, Morgante F, Moro E, Epifanio A, Girlanda P, Ragonese P et al. How many
parkinsonian patiens are suitable candidates for deep brain stimulation of subthalamic
nucleus? Results of a questionnaire. Correspondence. Parkinsonism Relat Disord 14 (2008)
266-267
Morrison CE, Borod JC, Perrine K et al. Neuropsychological functioning following bilateral
subthalamic nucleus stimulation in Parkinson´s Disease. Arch Clin Neuropsychol 2004, 19:165-
181
Nambu A, Takada M, Inase M, Tokuno H (1996) Dual somatotopical representations in the
primate subthalamic nucleus: evidence for ordered but reversed body-map transformations
from the primary motor cortex and the supplementary motor area. J Neurosci 16:2671–2683.
Nambu A, Tokuno H, Inase M, Takada M. Corticosubthalamic input zones from forelimb
representations of the dorsal and ventral divisions of the premotor cortex in the macaque
monkey: comparison with the input zones from the primary motor cortex and the
supplementary motor area. Neurosci Lett. 1997;239(1):13-6.
172
Nambu A, Tokuno H, Hamada I, Kita H, Imanishi M, Akazawa T, Ikeuchi Y, Hasegawa N(2000)
Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey. J
Neurophysiol 84:289–300
Obeso JA, Rodriguez MC, DeLong MR. Basal ganglia pathophysiology. A critical review. Adv
Neurol. 1997;74:3-18.
Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of
Parkinson's disease (2001): treatment guidelines. Neurology 2001;56:Suppl 5:S1-S88
Ossig C, Reichmann H. Treatment of Parkinson’s Disease in Advanced Stages J Neural Transm
(2013) 120:523–529
Péron J, Frühholz S, Vérin M, Grandjean D. Subthalamic nucleus: a key structure for emotional
component synchronization in humans. Neurosci Biobehav Rev. 2013; 37(3):358-73.
Perriol M-P, Krystkowiak P, Defebvre L et al. Stimulation of the subthalamic nucleus in
Parkinson´s disease: Cognitive and affective changes are not linked to the motor outcome,
Parkinson Relat Disord 12 (2006) 205-210
Pfurtscheller G (2001) Functional brain imaging based on ERD/ERS. Vision Research 41: 1257-
1260.
Pollak P, Krack P, Fraix V, Mendes A, Moro E, Chabardes S, Benabid AL. Intraoperative microand
macrostimulation of the subthalamic nucleus in Parkinson's disease. Mov Disord. 2002;17
Suppl 3:S155-61. Review
Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F. Manic episode with psychotic
symptoms in a patient with Parkinson's disease treated by subthalamic nucleus stimulation:
improvement on switching the target. J Neurol Sci. 2008; 273(1-2):116-7.
173
Rektor I, Bares M, Brazdil M, Kanovsky P, Rektorova I, Sochurkova D, Kubova D, Kuba R, Daniel
P. Cognitive- and movement-related potentials recorded in the human basal ganglia. Mov
Disord. 2005 May;20(5):562-8.
Rektor I, Bočková M, Chrastina J, Rektorová I, Baláž M. The modulatory role of subthalamic
nucleus in cognitive functions – a viewpoint. Clinical Neurophys 2014. Accepted for
publication.
Rodriguez-Oroz MC, Moro E, Krack P. Long-term outcomes of surgical therapies for Parkinson's
disease. Mov Disord. 2012; 27(14):1718-28.
Saint-Cyr JA, Trepanier LL, Kumar R, Lozano A, Lang AE. Neuropsychological consequencies of
chronic bilateral stimulation of the subthalamic nucleus in Parkinson‘s disease. Brain 2000,
123, 2091-2108
Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into
representational cortical plasticity. Exp Brain Res 148(1):1-16
Smeding HM, Speelman JD, Huizenga HM, Schuurman PR, Schmand B. Predictors of cognitive
and psychosocial outcome after STN DBS in Parkinson's Disease. J Neurol Neurosurg
Psychiatry. 2011 Jul;82(7):754-60
Spottke EA, Volkmann J, Lorenz D, Krack P, Smala AM, Sturm V, Gerstner A, Berger K, Hellwig
D, Deuschl G, Freund HJ, Oertel WH & Dodel RC (2002) Evaluation of healthcare utilization
and health status of patients with Parkinson's disease treated with deep brain stimulation of
the subthalamic nucleus. J Neurol 249:759-66
Strafella AP, Vanderwerf Y, Sadikot AF. Transcranial magnetic stimulation of the human motor
cortex influences the neuronal activity of subthalamic nucleus. Eur J Neurosci. 2004
Oct;20(8):2245-9.
Telecká, S., Baláž, M., Rektorová, I., Fanfrdlová, Z., Rektor, I.: Jeden rok po hluboké mozkové
stimulaci pacientů s Parkinsonovou nemocí - neuropsycholgické výsledky. Česká a slovenská
neurologie a neurochirurgie 2010; 73/106(1): 57-61.
174
Temel Y, Blokland A, Steinbusch HW, Visser-Vandewalle V. The functional role of the
subthalamic nucleus in cognitive and limbic circuits. Prog Neurobiol. 2005 Aug;76(6):393-413.
Temel Y, Kessels A, Tan S, Topdag A, Boon P, Visser-Vandewalle V. Behavioural changes after
bilateral subthalamic stimulation in advanced Parkinson disease: a systematic review.
Parkinsonism Relat Disord. 2006 Jun;12(5):265-72
The Deep-Brain Stimulation for Parkinson's Disease Study Group. Deep-Brain Stimulation of
the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson's Disease. N
Engl J Med 2001; 345:956-963
Thobois S, Ardouin C, Lhommée E, Klinger H, Lagrange C, Xie J, Fraix V, Coelho Braga MC,
Hassani R, Kistner A, Juphard A, Seigneuret E, Chabardes S, Mertens P, Polo G, Reilhac A,
Costes N, LeBars D, Savasta M, Tremblay L, Quesada JL, Bosson JL, Benabid AL, Broussolle E,
Pollak P, Krack P. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's
disease: predictors and underlying mesolimbic denervation. Brain 2010; 133(Pt 4):1111-27
Umemura, A. , Oka, Y. , Tsuboi, R. , Fujii, S. , Shimizu, Y. , Okita, K. , Matsukawa, N. and Yamada,
K. (2013) Factors affecting early decline of executive function after subthalamic nucleus
stimulation in Parkinson’s disease.Advances in Parkinson's Disease, 2, 75-80.
Volkmann J, Albanese A, Kulisevsky J, Tornqvist AL, Houeto JL, Pidoux B et al. Long-Term Effects
of Pallidal or Subthalamic Deep BrainStimulation on Quality of Life in Parkinson’s Disease
Movement Disorders Vol. 24, No. 8, 2009, pp. 1154–1161
Voon V, Kubu C. Krack P, Houeto JL, Tröster AI. Deep brain stimulation: neuropsychological
and neuropsychiatric issues. Mov Disord, 2006 Jun; 21; Suppl.14: S305-S327.
Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schüpbach M, D'Ambrosia J, Thobois S,
Tamma F, Herzog J, Speelman JD, Samanta J, Kubu C, Rossignol H, Poon YY, Saint-Cyr JA,
Ardouin C, Moro E. A multicentre study on suicide outcomes following subthalamic
stimulation for Parkinson's disease. Brain. 2008 ;131(Pt 10):2720-8.
175
Witt K, Pulkowski U, Herzog J et al. Deep brain stimulation of the subthalamic nucleus
improves cognitive flexibility but impairs response inhibition in Parkinson´s disease.. Arch
Neurol 2004:61:697-700.)
Witt K, Granert O, Daniels C, Volkmann J, Falk D, van Eimeren T, et al. Relation of lead
trajectory and electrode position to neuropsychological outcomes of subthalamic
neurostimulation in Parkinson's disease: results from a randomized trial. Brain.
2013;136:2109-19.
Yoshida M, Precht W (1971) Monosynaptic inhibition of neurons of the substantia nigra by
caudato-nigral fibers. Brain Res 32:225–228.