Primatemodelsofmovementdisordersofbasalgangliaorigin
Mahlon R. DeLong
Movement disorders associated with basal ganglia
dysfunction comprise a spectrum of abnormalities that
rangefrom the hypokinetic disorders (of which Parkmson's
disease is the best-known example) at one extreme
to the hyperkinetic disorders (exemplified by Huntington's
disease and hemiballismus) at the other. Both
extremes of this movement disorder spectrum can be
accountedfor bypostulating specificdisturbances within
the basal ganglia-thalamocortical 'motor' circuit. In
this paper, Mahlon DeLong describes the changes in
neuronal activity in the motor circuit in animal models
of hypo- and hyperkinetic disorders.
Hypokinetic disorders are characterized by significant
impairments in movement initiation (akinesia) and
reductions in the amplitude and velocity of voluntary
movements (bradykinesia). Hypokinetic disorders are
usua!!y accompanied by muscular rigidity and tremor
at rest. By contrast, hyperkinetic disorders are
characterized by excessive motor activity in the form
of involuntary movements (dyskinesias) and varying
degrees of hypotonia. In recent years, the development
of primate models of these disorders (induced
by systemic or local administration of selective
neurotoxins) has made it possible to clarify some of
the pathophysiological mechanisms underlying such
diverse symptomatology as the hypokinesia of parkinsonism
and the involuntary, hyperkinetic movements
of hemiballismus and other dyskinesias. This range of
movement disorders can be explained using a functional
model of the basal ganglia-thalamocortical
'motor' circuit that incorporates current data from a
variety of experimental fields1-3.
Functional model of the 'motor' circuit
The main organizational features and postulated
mode of operation of the motor circuit are presented
elsewhere in this issue (see article by G. E. Alexander
and M. D. Crutcher). In brief, this circuit, like other
basal ganglia-thalamocortical circuits, represents a
re-entrant pathway through which influences emanating
from specific areas of cortex are returned to
certain of those same areas after intermediate processing
within the basal ganglia and thalamus4. The
'closed' portion of the motor circuit comprises (1)
several precentral motor areas [including the supplementary
motor area (SMA) and parts of the motor
and premotor cortex], (2) the putamen, which is part
of the striatum or 'input' stage of the basal ganglia and
receives projections from the precentral motor areas,
(3) the 'motor' portions of the internal segment of the
globus pallidus (GPi) and substantia nigra pars reticulata
(SNr), both of which receive projections from the
putamen and are considered output nuclei of the basal
ganglia, (4) portions of the external segment of the
globus pallidus (GPe) and the subthalamic nucleus
(STN), and (5) parts of the ventrolateral thalamus that
receive projections from the motor portions of GPi
and SNr and in turn project back to specific portions of
the precentral motor fields2.
Within the circuit are two projection systems that
arise from separate subpopulations of putamen
neurons and terminate within GPi and SNr (for
reviews, see Refs 1,2,5). The 'direct' pathway arises
from putamen neurons that contain both GABA and
substance P and project directly to the motor portions
of GPi and SNr. The 'indirect' pathway, on the other
hand, arises from putamen neurons that contain both
GABA and enkephalin and whose influences are
conveyed to the basal ganglia output nuclei only
indirectly, through a sequence of connections involving
GPe and the STN.
From the polarity of the sequential connections, it
would appear that under normal conditions the direct
pathway effectively provides positive feedback to the
precentral motor fields, from which much of the
movement-related activity within the circuit is thought
to arise (see Fig. 3 of G. E. Alexander and M. D.
Crutcher, this issue). In contrast, activity conducted
along the indirect pathway appears to provide negative
feedback to the precentral motor fields.
There is now considerable evidence indicating that
shifts in the balance between activity in the direct and
indirect pathways and the resulting alterations in GPi/
SNr output may account for the hypo- and hyperkinetic
features of basal ganglia disorders. Thus, in
general, it appears that enhanced conduction through
the indirect pathway leads to hypokinesia (by increasing
pallidothalamic inhibition), whereas reduced conduction
through the direct pathway results in hyperkinesia
(by reduction of pallidothalamic inhibition)1,3.
Hypokinetic disorders: experimental
parkinsonism
There have been numerous approaches to the
production of a suitable primate model of Parkinson's
disease, but parkinsonism induced by MPTP represents
the first model with features that closely
resemble the clinical, pathological and biochemical
characteristics of the human disorder6-s. MPTP is
converted in the brain to the toxin MPP+ by the
enzyme monoamine oxidase. MPP+ is then selectively
taken up into nigrostriatal neurons. How MPP +
destroys nigral neurons is still uncertain, but evidence
exists for interference with mitochondrial oxidation
and redox reactions9. Animals treated with MPTP
develop signs virtually identical to those in humans
with Parkinson's disease, including akinesia, bradyldnesia,
flexed posture, muscular rigidity, and postural
tremor. Not all primate species develop the
tremor characteristic of idiopathic Parkinson's
disease, but one species, the African green monkey,
does exhibit typical resting tremor in a high percentage
of cases. MPTP-treated animals exhibit the
pathological hallmark of Parkinson's disease, i.e. loss
of melanin-containing neurons of the pars compacta of
the substantia nigra (SNc) and resulting loss of
dopamine in the striatum and the substantia nigra
itself. Some degree of neuronal cell loss has also been
reported in the locus coeruleus and the raphe, as is
Mahlonft. DeLongis
attheDepartmentof
Neurology,TheJohns
HopkinsUniversity
SchoolofMedicine,
Meyer5-185,600
NorthWolfeStreet,
Baltimore,MD
21205,USA.
TINS, Vol. 13, No. 7, 1990 © 199o,ElsevierSciencePublishersLtd,(UK) 0166-22361901502.00 281
SMA/PMC/MC
Brainstem
Spinal cord
GPe
tSTN
GPi/SNr
VLo
VApc/mc
CM
Fig. 1. Schematic representation of neuronal activity in the 'motor' circuit in
hypokinetic disorders. Excessive inhibition of GPe within the indirect pathway
leads to disinhibition of the STN, which in turn provides excessive excitatory
drive to the basal ganglia output nuclei (GPi/SNr), thus leading to excessive
thalamic inhibition. This is reinforced by reduced inhibitory input to GPi/SNr
through the direct pathway. Overall, these effects are postulated to result in a
reduction in the usual reinforcing influence of the motor circuit upon cortically
initiated movements. In this figure and in Fig. 2, inhibitory neurons are
represented by filled symbols and excitatory neurons by open symbols. Both
figures should be compared with Fig. 3 in the article by G. E. Alexander and
M. D. Crutcher, this issue, which represents the operation of the motor circuit
under normal conditions. Abbreviations: CM, centromedian nucleus; GPe,
external segment of the globus pallidus; GPi, internal segment of the globus
pallidus; MC, primary motor cortex; PMC, premotor cortex; SMA, supplementary
motor area; SNr, substantia nigra pars reticulata: STN, subthalamic
nucleus; VAmc, nucleus ventralis anterior pars magnocellularis; VApc, nucleus
ventralis anterior pars parvocellularis; VLo, nucleus ventralis lateralis pars oralis.
the case in idiopathic Parkinson's diseasel°,n.
Studies of neuronal activity in MPTP-treated
animals have been directed primarily at the globus
pallidus since the major output from the basal ganglia
portions of the motor circuit arises from GPi. In
MPTP-treated monkeys, altered tonic neuronal activity
has been observed in both pallidal segments and
in the STN12,13.A major finding of these studies was a
significant increase in tonic neuronal discharge in GPi
and STN neurons after MPTP treatment. In GPe, by
contrast, the mean tonic discharge rate is significantly
decreased. These changes in tonic discharge are
consistent with the reported changes in metabolic
activity studied shortly (days) following MPTP treatment14-16.
However, they differ somewhat from
those reported in animals studied several weeks
following treatment 17,18. Such differences may reflect
various influences, including possible acute effects of
MPTP itself, damage to terminals and cell bodies and
changes in receptors. It should be emphasized that
regional metabolic activity reflects summed synaptic
activity of both afferents and local axon collaterals,
and therefore, may not be well correlated with local
neuronal activity. Such discrepancies underscore the
need for direct physiological measures of cellular
activity.
In addition to increases in tonic discharge, there is
evidence of enhanced phasic responses to proprioceptive
stimuli and voluntary movement in GPi
neurons19,2°.The responses of GP neurons to passive
manipulations of the extremities are increased in
MPTP-treated animals. Responses to passive displacement
of the limb are also detectable in a larger
percentage of pallidal neurons than normal and are
less specific, with loss of directional effects and
responses from multiple joints. Although phasic activity
during active movement or in more complex
tasks has not yet been studied in detail, in preliminary
studies an increase has been seen in GP neurons
during these tasks (Miller, W. C. and DeLong, M. R.,
unpublished observations). Together, these data
suggest that there is increased tonic output from the
basal ganglia (GPi) in animals rendered parkinsonian
with MPTP, and that phasic signals associated with
proprioceptive feedback and active movement are
increased in magnitude and decreased in selectivity.
By enhancing transmission through the direct pathway
and suppressing transmission through the indirect
pathway, the dopaminergic nigrostriatal inputs to the
motor circuit seem to have the net effect of augmenting
positive feedback to the precentral motor fields,
thereby facilitating cortically initiated movements.
The MPTP-induced changes in neuronal activity
observed in GPe, GPi and the STN are consistent
with the evidence indicating that a loss of striatal
dopamine results in an increase in transmission
through the indirect pathway and a reduction in
transmission through the direct pathway. The overall
effect of such imbalances would be to increase the
output from GPi/SNr, leading to excessive tonic and
phasic inhibition of thalamocortical neurons as indicated
in Fig. 1.
The changes in basal ganglia output observed in
experimental parkinsonism could produce the
observed behavioral disturbances by any of several
mechanisms. For example, the increased tonic output
from GPi, by reducing the tonic activity of thalamocortical
neurons, might lessen the responsiveness of
those precentral motor fields that are engaged by the
motor circuit. In addition, the increased gain and
decreased selectivity within the basal ganglia circuits
would be expected to disturb the normal processing of
phasic signals associated with proprioceptive inputs
and voluntary movement within the basal ganglia.
Bradykinesia
In normal individuals, rapid limb movements are
performed with a triphasic pattern of muscle activity
involving an initial agonist burst, an antagonist burst,
and a second agonist burst21. As movement amplitude
is increased, movement velocity is also increased.
The increase in movement velocity is produced by
282 TINS, Vol. 13, No. 7, 1990
generating a greater initial agonist burst. In parkinsonian
subjects, the normal amplitude-velocity relation
is disturbed and the large-amplitude movements
are performed at abnormally low velocities22. The
abnormal velocities are due to a failure to generate
adequate initial agonist bursts23. The resultant overall
movement is therefore discontinuous, with several
segmented, small-amplitude movements apparent in
the velocity tracing.
Recent studies24 have shown that while the magnitude
of the first agonist burst shows scaling in
parkinsonian subjects, the range over which the
scaling occurs is diminished. It should be noted as well
that bradykinesia may also result from additional
difficulties resulting from attempts to perform more
complex simultaneous and sequential motor acts2s-29.
In normal individuals, the simultaneous or sequential
performance of two simple motor acts does not
significantly affect the movement time of each act. In
parkinsonian subjects, however, movement times are
prolonged to a greater extent when simple movements
are performed sequentially or simultaneously
than when performed alone. In sequential movements,
the deficit arises from both a prolongation of
the individual movement times and an abnormal delay
between the movements.
Altered activity in the basal ganglia motor circuit in
parkinsonian subjects could result in bradykinesia by
several mechanisms. First, there may be relatively
less grading of phasic neuronal responses during
attempted movements of different amplitudes, which
would diminish the range of velocities permitted by
the basal ganglia output. Increased tonic inhibition of
thalamic neurons by excessive output from GPi could
simply reduce the overall responsiveness of cortical
mechanisms through a reduction of thalamocortical
activation. Also, with an excessively high level of tonic
discharge in GPi neurons, it is possible that the superimposed
phasic reductions in GPi activity that occur
during movement execution would not be transmitted
faithfully to the cortex, thereby resulting in a reduced
range of neuronal amplitude changes and scaling of
movement.
It is also conceivable that the linearly graded
neuronal responses observed in normal animals during
limb movement are not directly related to the scaling
of movement amplitude and velocity. If, instead, the
basal ganglia were involved in a monitoring or
comparator function (whereby motor commands are
compared with proprioceptive feedback), such neuronal
responses could reflect the feed-forward of
motor commands from the motor cortex and SMA.
Abnormally large phasic output from the motor circuit
during movement in the parkinsonian condition might
lead to misinterpretation of the command by the
cortex and thus to reduced output to the agonist
musculature3°. This type of feed-forward system
would be particularly important in movements performed
without visual feedback, the types of movements
most impaired in parkinsonian subjects.
Another possibility is that increased gain in the
feedback from proprioceptors might signal apparent
excessive movement or velocity, leading to a slowing
or premature arrest of ongoing movements.
In general, the available data from studies in normal
and MPTP-treated animals are consistent with the
view that voluntary movements are normally associated
with a graded phasic reduction of thalamic
inhibition mediated by the direct pathway. Bradykinesia
may be due to increased levels of inhibition in
the thalamic targets of basal ganglia output, resulting
from excessive tonic and phasic activity in the indirect
pathway and consequent increased negative feedback
conveyed to the precentral motor areas. In addition,
reduced activity in the direct pathway would result in
decreased positive feedback and thereby contribute to
the bradykinesia.
Akinesia
The term 'akinesia' is used in a variety of ways by
different authors. It may be taken to encompass the
multiple movement abnormalities seen in parkinsonism,
including difficulty initiating movements, difficulty
performing simultaneous and repeated motor acts and
even slowing of movement (i.e. bradykinesia). In its
SMAJPMC/MC
7
Brainstem
Spinal cord
STN
Putamen
'indirect'
~athway
®
GPi/SNr
direct"
pathway
VLo
VApc/mc
CM
Fig. 2. Schematicrepresentation of the 'motor' circuit in hyperkinetic disorders.
Reduced excitatory projections from the STN to GPi, due either to 5TN lesions
(as in hemiballismus) or reduced striatopallidal inhibitory influences along the
indirectpathway (asin Huntington's diseaseand L-DOPA-induced dyskinesias),
lead to reduced inhibitory outflow from GPi/SNr and excessivedisinhibition of
the thalamus. The overall effect is that of excessivepositive feedback to the
precentral motor fields engaged by the motor circuit (S/HA, PAAC,/HC), which
results in hyperkinetic movements. Abbreviations: CNI, centromedian nucleus;
GPe, external segment of the globus pallidus; GPi, internal segment of the
globus pallidus; IHC, primary motor cortex; P/HC, premotor cortex; S/HA,
supplementary motor area; SNr, substantia nigra pars reticulata; 5TN,
subthalamic nucleus; VAmc, nucleus ventralis anterior pars magnocellularis;
VApc, nucleus ventralis anterior pars parvocellularis; VLo, nucleus ventralis
lateralis pars oralis.
TIN& VoL 13, No. 7, 1990 283
simplest form, however, 'akinesia' refers to a relative
paucity of volitional movement, due to an impairment
of movement initiation.
The pathophysiological basis of akinesia remains
uncertain. Although classically attributed to loss of
nigrostriatal dopamine neurons with resultant dysfunction
in striopallidal mechanisms, it has also been
proposed that akinesia might be related to damage
that occurs outside the dopaminergic neurons of the
SNc, perhaps in the dopaminergic neurons of the
ventral tegmental area, which project to the nucleus
accumbens and frontal cortex (see Ref. 31 for
review). However, the MPTP model of parkinsonism
suggests that akinesia may be produced by damage
limited to the SNc and the nigrostriatal dopamine
system7,32. In these animals, akinesia appears to be a
relatively dramatic and early feature following administration
of the neurotoxin. Although large doses of
MPTP have been shown to produce damage outside
the SNc11,33, smaller doses with damage apparently
limited to the SNc appear sufficient for the production
of akinesia. Thus, it must be considered that akinesia
may be produced by dopamine depletion limited to the
neostriatum. In human Parkinson's disease and in the
primate MPTP model of parkinsonism, a large percentage
of the nigrostriatal dopaminergic projection,
especially that innervating the putamen, is lost34. It is
thus possible that akinesia results from selective
depletion of dopamine in the motor circuit at the
striatal (putamen) level. Akinesia might result simply
from increased tonic inhibition of thalamocortical
neurons that renders the conical projection areas less
responsive to other inputs normally involved in
initiating movements. A secondary factor may be the
lowered gain in the direct pathway of dopaminedepleted
animals, which would lead to decreased
phasic disinhibition of thalamocortical neurons during
attempted movements. It is conceivable, therefore,
that akinesia may represent an extreme form of
bradykinesia. Another possibility is that some aspects
of akinesia might result from a disturbance of 'set'
functions, which appear to be highly dependent upon
the integrity of basal ganglia pathways (see G. E.
Alexander and M. D. Crutcher, this issue).
Hyperkinetic disorders: experimental
hemiballismus
Apart from parkinsonism, the basal ganglia disorder
for which the neuropathological substratum has
seemed least in doubt, is hemiballismus. In humans,
vascular lesions restricted to the STN frequently
result in involuntary, often violent movements of the
contralateral limbs (termed 'hemiballismus' because of
the superficial resemblance of the movements to
throwing motions). This disorder provides one of the
clearest correlations in clinical neurology between
localized pathological change and movement abnormality.
In addition to the proximal ballistic movements,
these involuntary movements may take the
form of more distal, irregular (choreiform), or more
continuous writhing (athetoid) movements. Hemiballismus
has been produced in monkeys by experimental
lesions of the STN35-a7. This primate model
has provided new insights into the pathophysiology of
the hyperkinetic disorders.
Until recently, hemiballismus was generally thought
to result from a 'release' of GPi from an inhibitory
control from the STN. However, recent evidence
indicates that the projections from STN to GPi are
actually excitatory, and probably glutamatergica8,39.
Moreover, monkeys with hemiballismus secondary to
inactivation of the STN show decreased metabolic
activity both in GPi and in the ventrolateral thalamus,
suggesting that GPi output may be reduced in this
disorder14. The effect of STN lesions (produced by
the axon-sparing neurotoxin ibotenate) on GPi activity
was recently studied directly in the monkey4° and,
indeed, a significant reduction of GPi tonic discharge
was found. A decrease in the phasic responses of GPi
neurons to limb displacement was also found.
Together, these findings suggest that hemiballismus
results from a disinhibition of the thalamus due to a
reduction of tonic (and perhaps phasic) inhibitory
output from GPi. Conceivably, thalamocortical
neurons under such conditions might become increasingly
responsive to conical inputs or exhibit an
increased tendency to discharge spontaneously, thus
leading to involuntary movements.
It should be mentioned that there is now evidence
of a common mechanism underlying both the choreiform
movements of Huntington's disease and the
dyskinetic movements that are seen in hemiballismus.
It has been shown that early in the course of
Huntington's disease there is a selective loss of the
striatal GABA/enkephalin neurons that give rise to the
indirect pathway41. The consequent loss of inhibition
of GPe neurons would be expected to lead to
excessive inhibition of STN neurons, and this functional
inactivation of the STN could thus explain the
choreiform motor disturbances in Huntington's
disease that resemble those seen in hemiballismus
(Fig. 2). Most recently, these workers have found
that the rigid akinetic signs in advanced Huntington's
disease are associated with evidence of additional loss
of GABA/substance P-containing striatal neurons
projecting to GPi42. This would lead to increased
discharge of the partially deafferented GPi/SNr
neurons, by removal of inhibition.
The phenomenon of L-DOPA-induced dyskinesias
(which occur during periods of dopamine excess
associated with the pharmacological treatment of
Parkinson's disease) can be explained on a similar
basis. That is, excessive dopaminergic inhibition of
the striatal GABA/enkephalin neurons would lead to
reduced excitatory input to GPi/SNr via the indirect
pathway, and this effect could be compounded by
excessive dopaminergic stimulation of the striatal
GABA/substance P neurons that send inhibitory
projections to GPi/SNr via the direct pathway.
Effects of STN lesions in parkinsonian animals
According to the proposed functional model of the
motor circuit, the motor disturbances of Parkinson's
disease are postulated to result in large part from
increased thalamic inhibition due to excessive excitatory
drive from the STN to the output nuclei of the
basal ganglia (GPi/SNr). It is predicted, therefore,
that a lesion or inactivation of the STN in parkinsonian
subjects would ameliorate some of the motor impairments.
This has been tested recently by selective
lesioning of the STN with the fiber-sparing neurotoxin
ibotenate in MPTP-treated monkeys (Bergman, H.,
Wichmann, T. and DeLong, M. R., unpublished
observations). Such lesions produced an immediate
284 TINS, VoL 19, No. 7, 1990
and dramatic reduction of akinesia and bradykinesia
(as well as tremor and rigidity) in the contralateral
limbs. These results provide the first direct support
for the postulated 'positive' role of the STN (and the
indirect pathway) in the pathogenesis of hypokinetic
disorders. The fact that STN-lesioned animals also
showed a marked reduction in contralateral tremor
and rigidity suggests that the STN and the indirect
pathway may play a critical role in the pathogenesis of
these abnormalities as well. It is noteworthy that, as
expected, the animals exhibited dyskinesias of the
contralateral limbs, but that these were transient,
whereas the amelioration of the parkinsonian signs
persisted until the time of death.
Concluding remarks
There is now considerable evidence that the
respective pathophysiological mechanisms underlying
hypo- and hyperkinetic movement disorders (representing
both ends of the clinical spectrum of basal
ganglia-associated motor disturbances) involve
changes in the operational features of the basal
ganglia-thalamocortical motor circuit that are essentially
polar opposites. Thus, hypokinetic disorders
(e.g. Parkinson's disease) are thought to be associated
with excessive tonic and phasic inhibitory
output from the basal ganglia to the thalamus, and the
hyperkinetic disorders (e.g. hemiballismus) with an
abnormally low level of basal ganglia outflow. Future
studies are expected to reveal that the spectrum of
basal ganglia-associated movement disorders can be
accounted for by varying combinations of these two
pathophysiological extremes.
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Acknowledgement
Thisworkwas
supportedbya&rant
fromtheUSPHS(NIH
NS15417)andby
donationsfromthe
E.K.Dunnfamily.
Next Month
The August issue of TINSwill include the following articles:
Patch-clamping in slices of mammalian CNS, by A. Konnerth
Brief seizure episodes induce long-term potentiation and mossy
fibre sprouting in the hippocampus, by Y. Ben-Ari and A, Represa
Molecular approaches to the segmentation of the hindbrain,
by D. Wilkinson and R. Krumlauf
The cellular basis for segmentation in the developing hindbrain,
by A. Lumsden
Target regulation of neurotransmitter phenotype, by S. C. Landis
The Korsakoff syndrome: a neurochemical perspective,
by W. J. /VlcEntee and R. G. Mair
TINS, Vol. 13, No. 7, 1990 © 1990,ElsevierSciencePublishersttd,(UK) 0166-2236/90/$02.00 285