MOTOR
SYSTEM
TYPES OF NEUROTRANSMITTERS
• There are many different ways to classify neurotransmitters. Dividing them into amino
acids, peptides, and monoamines is sufficient for many purposes.
• Some more precise divisions are as follows:
• Around 10 "small-molecule neurotransmitters" are known:
• acetylcholine (Ach)
• monoamines (epinephrine (E), norepinephrine (NE), dopamine (DA), serotonin (5-HT) and
melatonin)
• 3 or 4 amino acids, depending on exact definition used: (primarily glutamic acid, gamma
aminobutyric acid (GABA), aspartic acid & glycine)
• Purines, (Adenosine, ATP, GTP and their derivatives)
• Fatty acids are also receiving attention as the potential endogenous cannabinoid.
• Over 50 neuroactive peptides (vasopressin, somatostatin, neurotensin, etc.) have been
found, among them hormones such as Luteinizing hormone (LH) or insulin that have
specific local actions in addition to their long-range signalling properties.
• Histamine
• Single ions, such as synaptically released zinc, are also considered neurotransmitters by
some.
• Gaseous, including nitric oxide (NO) and carbon monoxide (CO)
• The major "workhorse" neurotransmitters of the brain are glutamic acid and GABA.
WHAT’S THE MOTOR SYSTEM?
• Parts of CNS and PNS specialized for control
of limb, trunk, and eye movements
• Also holds us together
• From simple reflexes (knee jerk) to voluntary
movements (96mph fast ball)
PRIMARY MOTOR CORTEX
http://www.emunix.emich.edu
Primary somatomotor cortex
► precentral gyrus, (Brodmann 4 area)
► somatotopic arrangement
► agranular cortex (layer 2 and 4 are thin,
giant pyramidal cells - Betz cells in layer 5)
►Subcortical groups of neuronal cell bodies developing from the prosencephalic wall (dorsal
striatum constituted by the caudate nucleus and putamen, the ventral striatum formed by the
nucl. accumbens and the olfactory tubercle, the globus pallidus, the subthalamic nucleus,
claustrum, amygdaloid body (red and blue)…
►It is not correct anatomically, but in clinical practice red nucleus and substantia nigra are also
considered as basal ganglia (green)
Motor systems – basal ganglia
Motor systems – thalamus
Ventral-anterior (VA) and ventrolateral (VL) nuclei of the thalamus are considered
as motor nuclei and they are connected to different motor cortical areas.
Motor systems – cerebellum
archicerebellum
reciprocal connection with the
vestibular nuclei (body
balance posture)
paleocerebellum
epicritic and proprioceptive
sensory feed-back
(spinocerebellar and
cuneocerebellar tracts)
neocerebellum
descending information from
the motor cortical areas
(corticopontinepontocerebellar
indirect
pathways)
pontine nuclei,
inferior olivary nucl.
substantia nigra,
red nucleus,
reticular formation,
superior collicle
Motor systems – brainstem nuclei
HIERARCHIC ORGANIZATION OF
MOTOR SYSTEM
http://www.slideshare.net/drpsdeb/pres
entations
CORTEX
• Externally guided movements
– those requiring sensory
inputs
• Picking up objects, using
tools, moving eyes to explore
faces, making gestures etc.
Motor systems – cortical areas
► Many different cortical areas: mainly within the frontal lobe
MOTOR CORTEX
• Primary motor cortex (area 4)
• Somatotopic organization
• Control of lower motor neuron
• Premotor cortex (area 6 laterally)
• Preparation of strategy of movement
• Sensor motor transformation
• Movement patterns selection
• Supplementary motor cortex (area
6 medially)
• Involved in planning of complex movements
• Movement of both limbs
• Complex motion sequences
• Activated also by complex movement rehearsal
http://www.slideshare.net/CsillaEgri/prese
ntations
THE PRIMARY MOTOR CORTEX
• (or M1) works in association with pre-motor areas to plan
and execute movements.
• M1 contains large neurons known as Betz cells which send
long axons down the spinal cord to synapse onto alpha
motor neurons which connect to the muscles.
• Pre-motor areas are involved in planning actions (in concert
with the basal ganglia) and refining movements based
upon sensory input (this requires the cerebellum).
• The human primary motor cortex is located in the dorsal
part of the precentral gyrus and the anterior bank of the
central sulcus. The precentral gyrus is in front of the
postcentral gyrus from which it is separated by the central
sulcus. Its anterior border is the precentral sulcus, while
inferiorly it borders to the lateral fissure (Sylvian fissure).
Medially, it is contiguous with the paracentral lobule.
MOTORIC CONTROLLING
SYSTEMS
• The upper motor neurons
reside in the precentral gyrus
of the frontal lobe also called
the "motor strip". These upper
motor neurons are arranged in
a stereotypical fashion.
Neurons which control
movements of the face and
mouth are located near the
Sylvian or lateral fissue and
neurons which control the
muscles of the thighs and legs
are located near the medial
longitudinal fissure and within
the central sulcus.
STEPS IN MOTOR ACTION
INTRODUCTION
• Skeletal muscle contraction is initiated by
lower motor neuron
• Lower motor neuron is a part of local
reflex circuits
• The information from several sources is
integrated in the lower motor neuron
• Higher levels of CNS
Upper motor neuron, tectum, n. ruber, brain
stem
• Proprioception
http://www.frontiersin.org/files/Articles/42416/fnhum
HTML/image_m/fnhum-07-00085-g001.jpg
INTRODUCTION
• Skeletal muscle contraction is initiated
by lower motor neuron
• Lower motor neuron is a part of local
reflex circuits
• The information from several sources is
integrated in the lower motor neuron
• Higher levels of CNS
Upper motor neuron, tectum, n. ruber, brain
stem
• Proprioception
http://www.frontiersin.org/files/Articles/42416/fnhum
HTML/image_m/fnhum-07-00085-g001.jpg
18
INTRODUCTION
• Skeletal muscle contraction is initiated
by lower motor neuron
• Lower motor neuron is a part of local
reflex circuits
• The information from several sources is
integrated in the lower motor neuron
• Higher levels of CNS
Upper motor neuron, tectum, n. ruber, brain
stem
• Proprioception
http://www.frontiersin.org/files/Articles/42416/fnhum
HTML/image_m/fnhum-07-00085-g001.jpg
19
LOWER MOTOR NEURON
• α motoneuron
• Innervation of contractile
elements
• Extrafusal fibers
• Muscle contraction
• γ motoneuron
• Innervation of muscle spindles
• Intrafusal fibers
• Alignment of muscle spindles
• Gamma loop
• β motoneuron
http://epomedicine.com/wp-content/uploads/2016/07/gamm
ALPHA MOTOR NEURONS (Α-MNS)
• are large lower motor neurons of the brainstem and spinal
cord. They innervate extrafusal muscle fibers of skeletal
muscle and are directly responsible for initiating their
contraction.
• Alpha motor neurons are distinct from gamma motor
neurons, which innervate intrafusal muscle fibers of muscle
spindles.
• While their cell bodies are found in the central nervous
system (CNS), alpha motor neurons are also considered
part of the somatic nervous system—a branch of the
peripheral nervous system (PNS)—because their axons
extend into the periphery to innervate skeletal muscles.
MOTOR UNIT
• A typical muscle is innervated by
about 100 motoneurons which
are localized in motor nucleus
• Each motoneuron innervate from
100 to 1000 muscle fibers and
one muscle fiber is innervated by
a single motoneuron
• The ensemble of muscle fibers
innervated by a single neuron
and corresponding motoneuron
constitutes the motor unit
PROPRIOCEPTION
• Information about the position of body parts in relation to
each other
(The sum of information about lengths of particular muscles)
• Information about movement
(The force and speed of muscle contraction)
• Reflex regulation of muscle activity
• Muscle spindles
• Lie in parallel with extrafusal muscle fibers
• Golgi tendon organ
• Arranged in series with extrafusal muscles
http://www.slideshare.net/CsillaEgri/presentations
23
MUSCLE SPINDLE AND GOLGI
TENDON ORGAN
http://images.persianblog.ir/559630_iXFiuRo0.jpg
24
MUSCLE SPINDLES
• encapsulated structures within skeletal muscle,
containing intrafusal muscle fibers, in parallel with
extrafusal muscle fibers (normal skeletal muscle);
multiple nuclei in central region and intrafusal
fibers at each end; two morphological/functional
types of spindles
Muscle spindle
ABOUT THE GAMMA-LOOP
• Skeletal muscles can be activated directly, by the stimulation of
alpha-motoneurons or indirectly, via the gamma loop –
proprioceptive reflex arc.
• Stimulation of gamma-motoneurons results in the contraction of
intrafusal fibres of muscle spindles. Shorthening of the muscle
spindle (similarly to the stretching of the surrounding muscles)
activates the proprioceptive reflex arc. This results in the
indirect contraction of extrafusal („working”) muscle fibres.
gamma
motoneuron
Gamma-loop
alpha
motoneuron
STRETCH REFLEXES
• 1. passive stretch of muscle (e.g. by tapping tendon)
activates Ia afferents, which activate alpha motor
neurons, causing contraction of stretched muscle:
monosynaptic reflex
• 2. passive contraction of muscle (stimulation of alpha
motor neurons) causes decreased activity of muscle
spindles, leading to decreased activity of alpha motor
neurons
STRETCH REFLEXES
• 3. gamma loop: supraspinal input (e.g.
corticospinal) activates gamma motor neurons,
activating intrafusal fibers that stretch the
muscle spindle, activating Ia fibers, which
activate alpha motor neurons
• 4. voluntary muscle contraction against a load:
corticospinal fibers activate both alpha and
gamma motor neurons, allowing Ia fibers to
continue to sense muscle length while muscle is
contracting: alpha-gamma coactivation
HIERARCHIC ORGANIZATION OF
MOTOR SYSTEM
http://www.slideshare.net/drpsdeb/presentations
32
REFLEX
• Reflex movement
• Stereotype (predictable)
• Involuntary
• Proprioceptive
• Exteroceptive
• Monosynaptic
• Polysynaptic
• Monosegmental
• Polysegmental
http://www.slideshare.net/CsillaEgri/presentations
33
PROPRIOCEPTIVE REFLEX
• Myotatic reflex
• Monosynaptic
• Monosegmental
• Muscle spindle
• Homonymous muscle - activation
• Antagonist muscle - inhibition
• Phasic response (Ia)
• Protection against overstretch of
extrafusal fibrers
• Tonic response (Ia a II)
• Maintains muscle tone
http://www.slideshare.net/CsillaEgri/presentations
34
Motor systems – spinal cord
All kinds of spinal reflexes are automatic responses to a stimulus,
when the dicission is made by the spinal neuronal circuits without
major influence of higher centres of the nervous system!
Patellar reflex
STRETCH REFLEX
http://www.slideshare.net/ananthatiger/cns-4
http://www.slideshare.net/drpsdeb/presentations
38
EXTEROCEPTIVE REFLEX
• Polysynaptic
• Polysegmental
http://images.slideplayer.com/15/4638059/slides/slide_3
7.jpg
39
http://www.easynotecards.com/uploads/920/77/1c7a7974_150bb922c9b__8000_00004383.png
40
FLEXION WITHDRAWAL
REFLEX
 Polysynaptic reflex mediated by FRAs (flexion
reflex afferents: nociceptors, mechanoreceptors
etc.)
flexion in response to painful stimuli
 FRAs synapse on inhibitory and excitatory
interneurons which excite ipsilateral flexor
motorneurons & inhibit extensor motorneurons
 Physiological importance:
Rapid flexion away from painful stimuli
 Clinical importance: upper motor neuron lesion
impairs flexion reflex  pathalogical Babinski
sign 41
UPPER MOTOR NEURON LESION: BABINSKI
SIGN
(Type of flexion reflex) (pathological reflex)
PYRAMIDAL AND EXTRAPYRAMIDAL SYSTEMS
• Pyramidal system is the chief organizer and executor of voluntary movements.
• Extrapyramidal system includes all the motor centres and pathways that lie
outside the pyramidal system and are beyond voluntary control.
• Extrapyramidal system:
• coordinates movements of various groups of muscles both in space and time,
• regulates job- and sport-specific automatic movements consisting of periodic
elements (e.g. walking, running, riding a bike, dancing, driving a car, handwriting or
typing, etc.),
• controls emotional movements,
• helps to control posture and balance,
• regulates muscle tone.
Pyramidal and extrapyramidal systems can only be separated
anatomically but not functionally! None of the two systems can work
properly alone, they constitute one motor system together!!!
SUBCORTICAL (STEM) PATHWAYS
CONTROLLING LOWER MOTONEURONS
Medial system
• Axial muscle control
• Tr. Vestibulospinalis
• Reflex control of balance and
postural control
• Tr. Reticulospinalis
• Muscle tone regulation
(postural control)
• Tr. Tectospinalis
• Coordination of head and eyes
movements
Lateral system
• Distal muscle control
• „Reflex“ control of the
limbs
• Replaced by tr.
corticospinalis
• Tr. Rubrospinalis
• Tr. Rubrobulbaris
44
Just a sketch: only the principal components can be recognized.
PYRAMIDAL SYSTEM
Colours, beauty, harmony, regularity, but not more than an abstract art.
EXTRAPYRAMIDAL SYSTEM
Taken together: the real world.
CORTICAL CONTROL OF LOWER
MOTOR NEURON
Tractus corticospinalis
Tractus corticobulbaris
Voluntary motor activity
48
VOLUNTARY MOTOR ACTIVITY
Idea
Association
cortex
Premotor +
Motor cortex
Basal
Ganglia
Lateral
cerebellum
Movement
Intermediate
Cerebellum
ExecutionPlanning
http://www.slideshare.net/drpsdeb/pres
entations
VOLUNTARY MOTOR ACTIVITY
• Result of cooperation of upper and
lower motor neuron
• Basal ganglia
• Motor gating – initiation of wanted
and inhibition of unwanted movements
• Cerebellum
• Movement coordination
http://www.slideshare.net/drpsdeb/pres
PYRAMIDAL TRACT
• Upper motor neuron
• Primary motor cortex
• Lower motor neuron
• Anterior horn of spinal cord
• Tractus corticospinalis lateralis
• 90% of fibers
• Tractus corticospinalis anterior
• 10% of fibers
• Cervical and upper thoracic segments
• Tractus corticobulbaris
http://images.slideplayer.com/14/4330915/slides/slide_34.jpg
Sceletal
muscles of
the head
and neck
Sceletal muscles
of the trunk and
limbs
MAJOR MOTOR PATHWAYS
1. Corticospinal (cortex to spinal
cord)
a) Lateral – distal limb muscles
(fine manipulations)
b) Ventral – trunk and upper
leg muscles
(posture/locomotion)
2. Corticobulbar (cortex to pons,
5th, 7th, 10th and 12th cranial
nerves) – control of face and
tongue muscles; upper face
both contralateral, lower face
contralateral
MAJOR MOTOR PATHWAYS
3. Ventromedial (brain stem
to spinal cord) – trunk
and proximal limb muscles
(posture, sneezing,
breathing, muscle tone)
4. Rubrospinal (red nucleus
to spinal cord) –
modulation of motor
movement (limb movement
independent of trunk
movement)
PYRAMIDAL MOTOR SYSTEM
CORTICOBULBAR TRACT
• Upper motor neurons which innervate the muscles of the
face and head are located near the lateral fissure of the
brain.
• Their axons coalesce to form the corticobulbar tract.
• These axons then descend within the genu of the internal
capsule to the medial part of the cerebral peduncle.
• The upper motor neuron axons then synapse on lower
motor neurons of the cranial nerve nuclei which are
located in midbrain, pons and medulla.
MOTOR NEURON LESIONS
• Upper motor neuron lesion of the neural pathway inside the
CNS (not including the ventral horn of the spinal cord or motor
nuclei of the cranial nerves)
• stroke, traumatic brain injury or cerebral palsy
• Lower motor neuron lesion affects nerve fibers within the
ventral horn of the spinal cord travelling to the relevant
muscle(s)
• Nerve trauma
56
Upper motor neuron lesion Lower motor neuron
lesion
Reflexes Increased, may have
pathological reflex signs
(Babinski sign)
Decreased,
Muscle tone Increased, contralateral Decreased, ipsilateral
Weakness Yes, contralateral Yes, ipsilateral
PARAPLEGIA
• is an impairment in motor and/or sensory function of the
lower extremities. It is usually the result of spinal cord injury
or a congenital condition such as spina bifida which
affects the neural elements of the spinal canal.
• The area of the spinal canal which is affected in
paraplegia is either the thoracic, lumbar, or sacral regions.
If the arms are also affected by paralysis, tetraplegia is the
proper terminology.
• The causes range from trauma (acute spinal cord injury:
transsection or compression of the cord, usually by bone
fragments from vertebral fractures) to tumors (chronic
compression of the cord), myelitis transversa and multiple
sclerosis.
HEMIPLEGIA
• It can be congenital (occurring before, during, or soon after
birth) or acquired (as from illness or stroke).
• It is usually the result of a stroke, although disease processes
affecting the spinal cord and other diseases affecting the
hemispheres are equally capable of producing this clinical
state. Hemiplegia can be a more serious consequence of
stroke than spasticity.
• Other causes include Type 2 diabetes mellitus, which can
lead to transient hemiplegia, a type of spinal injury called
Brown-Sequard syndrome, and injections of local
anaesthetic given intra-arterially rapidly, instead of given in
a nerve branch.
• Lesions in the posterior limb of the internal capsule can also
lead to hemiplegia.
Peripheral and central facial palsy
EXTRAPYRAMIDAL MOTOR SYSTEM
• The extrapyramidal system dampens erratic motions, maintains muscle tone
and truncal stability. It is phylogenetically older that the pyramidal system
and thus plays a relatively more important role in lower animals. Many of its
synaptic connections are extremely complex and even today, poorly
understood. Neurodegenerative disorders which affect the extrapyramidal
system have yielded much of our knowledge about its normal function.
• The major parts of the extrapyramidal system are the "subcortical nuclei".
This includes the caudate, putamen, and globus pallidus which are also
known as the Basal ganglia. The caudate nucleus is especially affected in
Huntington's chorea.
• The substantia nigra, is located in the midbrain. It is particularly affected in
idiopathic Parkinson's disease.
cortical areas
caudate nucl.
putamen
globus pallidus
thalamus
cerebellum,
pontine nuclei,
inferior olivary nucl.
vestibular
apparatus
substantia nigra,
red nucleus,
reticular formation,
superior collicle
zona incerta,
subthalamic nucl.
Componentsoftheextrapyramidalsystem
Extrapyramidal system: synapses and neurotransmission
rubrospinal tr.
tectospinal tr.
reticulospinal tr.
vestibulospinal tr.
Efferentextrapyramidalpathways
olivospinal tr.
EXTRAPYRAMIDAL MOTOR SYSTEM
• The thalamus is a very complex structure with many functions
including cognition and pain perception, but parts of the thalamus
are also components of the extrapyramidal system.
• Other nuclei include the Subthalamic nucleus. Unilateral damage
to the subthalamic nucleus results in hemiballism.
• The final major nucleus is the Red Nucleus which is immediately
adjacent to the substantia nigra in the midbrain.
• To summarize, the extrapymidal nuclei include the substantia nigra,
caudate, putamen, globus pallidus, thalamus, red nucleus and
subthalamic nucleus. All of these nuclei are synaptically connected
to one another, the brainstem, cerebellum and the pyramidal
system.
BASAL GANGLIA
• Unlike the cerebellum, which plays a
role in rapid balistic movements, the
basal ganglia are more important
for the accomplishment of
movements that may take some time
to initiate or stop
• Important for internal guiding
(rather then external) of movement
• Dopamine – nigrostriatal pathway
BASAL GANGLIA
Damage to the basal ganglia:
• Produces either too much activation
(hyperkinetic) responses= twitches,
movements bursts, jarring, etc.
• Huntington’s Chorea-dominant gene based,
increases glutamate in striatum which
destroys GABA neurons in BG and loss of
inhibition
• No cure
• Tourette’s
OR
• Produces too little force
(hypokinetic)=rigidity
• Parkinson’s disease Pink=inhibition
Blue=excitation
DISORDERS OF THE BASAL GANGLIA
Parkinson’s Disease
• Parkinson's Disease is the second most
common age-related neuro- degenerative
disease, affecting approximately 1% of
population over 60.
• Characterized by resting tremor, slowed/absent
movement (hypokinesia), rigidity of the extremities
and neck, & reduced facial expressiveness
• Caused by the loss of the dopaminergic neurons in the
substantia nigra pars compacta
• Typically treated with L-Dopa
72
PARKINSON'S DISEASE (PD)
• Emerging evidence has provided support for the
hypothesis that PD is the result of complex interactions
between genetic abnormalities, environmental toxins,
mitochondrial dysfunction and other cellular
processes.
• Recently, epigenetic modifiers have been identified
as a potential mediators of environmental factors
participating in the pathogenesis of PD
PARKINSON'S DISEASE
• Although the exact cause of Parkinson's disease is
unknown, research has concentrated on genetics,
environmental toxins, endogenous toxins and viral
infection.
In Parkinson's, cells are destroyed in part of the brain
stem - the substantia nigra, which sends out fibers to
the corpus stratia, gray and white bands of tissue in
both sides of the brain. Cells there release dopamine,
one of three major neurotransmitters (chemical
messengers) which help the body respond to stress. By
the time symptoms develop, patients have lost 80 to
90 percent of their dopamine-producing cells.
PARKINSON’S DISEASE
76Increased output of indirect
pathway, decreased output of direct
pathway
PARKINSON'S DISEASE
• Symptoms include tremors, slowed
movement and postural instability.
• Other features include rigidity, flexed
posture, freezing phenomenon and loss of
postural reflexes.
• Patients can experience depression, sleep
disturbances, dizziness and problems with
speech, swallowing and sexual functioning.
PD PATHOGENESIS
• PD is characterized by accumulation of SNCA in the presynaptic
nerve terminals of dopaminergic neurons in the SN. The
neurotoxicity of SNCA might be mediated through interaction with
histone altering its acetylation.
• Hyperacetylation of H3 or H4 represents key epigenetic changes in
dopaminergic neurons. Some environmental toxins have been
found to induce a time-dependent increase or decrease of
histone acetylation of DNA (Dieldrin, paraquat).
• Dysregulation of acetylation of H3 or H4 is regarded as an
important mechanism underlying pesticide-induced neuron loss in
PD.
Journal of the Neurological Sciences 349 (2015) 3-9
Possible role of DNA methylation and
related factors in the pathogenesis
of PD.
One-carbon metabolic disturbance
results in decreased level of Sadenosylmethionine
(SAM), which
leads to hypomethylation of DNA.
The decreased methylation level of
specific PD-related genes changes
chromosome conformation and
makes much easier for transcription,
such as SNCA overexpression that
leads to α-synuclein accumulation
and subsequently dopaminergic
neurons degeneration. In addition,
high level of homocysteine (HCY)
can induce dopaminergic neuronal
apoptosis via impairment of
mitochondrial function and
apoptosis-related gene activation,
leading to caspase activation and
neuronal apoptosis. AIF, apoptosis
inducible factor; Met, methionine;
SAH, S-adenosylhomocysteine.
Journal of the Neurological Sciences 349 (2015) 3-9
The process of histone
acetylation and its effect on
gene transcription.
Two main enzymes termed
as acetylase (HATs) and
deacetylase (HDACs)
mediate the process of
acetylation/deacetylation,
respectively. The histone
acetylation produced a
more loosened chromatin
structure leading to
transcriptional activation,
whereas histone
deacetylation formed
heterochromatin and then
transcriptional repression.
TF, transcriptional factor;
RN-p, RNA polymerase.
Journal of the Neurological Sciences 349 (2015) 3-9
HUNTINGTON'S DISEASE
• Huntington's disease is caused by a trinucleotide repeat expansion in
the Huntingtin gene, which codes for Huntingtin protein, denoted
"Htt". Huntington's disease is one of several polyglutamine diseases.
This expansion produces an altered form of the Htt protein, called
mutant Huntingtin (mHtt), the misfunction of this protein increases
neuronal cell death in select areas of the brain. This damage itself
isn't fatal, but life expectancy is reduced due to complications
caused by its symptoms.
• Huntington's disease's most obvious symptoms are abnormal body
movements called chorea and a lack of coordination, but it also
affects a number of mental abilities and some aspects of behavior.
Physical symptoms occur in a large range of ages around a mean
occurrence of late forthies/early fifties, but if they occur before the
age of 20 then the condition is known as Juvenile HD. As there is
currently no proven cure, symptoms are managed with various
medications and supportive services.
HUNTINGTON'S DISEASE
• Huntington's disease is caused by a trinucleotide repeat expansion in
the Huntingtin gene, which codes for Huntingtin protein, denoted
"Htt". Huntington's disease is one of several polyglutamine diseases.
This expansion produces an altered form of the Htt protein, called
mutant Huntingtin (mHtt), the misfunction of this protein increases
neuronal cell death in select areas of the brain. This damage itself
isn't fatal, but life expectancy is reduced due to complications
caused by its symptoms.
• Huntington's disease's most obvious symptoms are abnormal body
movements called chorea and a lack of coordination, but it also
affects a number of mental abilities and some aspects of behavior.
Physical symptoms occur in a large range of ages around a mean
occurrence of late forties/early fifties, but if they occur before the
age of 20 then the condition is known as Juvenile HD. As there is
currently no proven cure, symptoms are managed with various
medications and supportive services.
HUNTINGTON´S DISEASE-GENETICS
• Normal state
• DNA
• ATGCAGGTGACCTCAGTG
• TACGTCCACTGGAGTCAC
• RNA
• AUGCAGGUGACCUCAGUG
• PROTEIN
• Met-Gln-Val-Thr-Ser-Val
• Trinucletide expansion mutation
• DNA
• ATG(CAGCAGCAG)20CAGGTGACCTCA
GTG
• TAC(GTCGTCGTC)20GTCCACTGGAGTCA
C
• RNA
• AUG
(CAGCAGCAG)20CAGGUGACCUCAGU
G
• PROTEIN
• Met-(Gln-Gln-Gln)20Gln-Val-Thr-Ser-Val
PATHOPHYSIOLOGY OF HD
• Degeneration of neuronal cells, especially in the frontal lobes and
caudate nucleus (the striatum) of the basal ganglia occurs. There is
also astrogliosis and loss of medium spiny neurons.
• In Huntington's disease the external globus pallidus over-inhibits the
flow of excitation from the subthalamic nuclei, which interferes with
the initiation of motion. The subthalamic nuclei also generate
reduced excitation to the internal globus pallidus, resulting in a
weak inhibitory signal to the thalamus. The thalamus in turn then
sends a strong excitatory signal to the putamen resulting in
unmodulated motion.
• Role of epigenetics still unclear (but probable)
CEREBELLUM
• The cerebellum, which located inferior to the tentorium,
coordinates muscle activity, equilibrium and tone.
• It is functionally and anatomically divided into three
lobes. The flocculonodular lobe or archicerebellum
maintains equilibrium.
• The anterior lobe or paleocerebellum maintains muscle
tone.
• The posterior lateral lobes or neocerebellum controls
coordination and allows us to perform intricate motor
tasks like playing the piano. Recent evidence suggests
that the neocerebellum also plays a role in memory,
especially memory of fine motor skills.
• Cebebellar motor tracts are uncrossed, so that
injuries on one side will cause difficulties on the
same side of the body.
• The major cerebellar tracts are the
• Spinocerebellar, connecting the spinal cord and the
cerebellum,
• Vestibulospinal, connecting the vestibular system and
the cerebellum,
• Corticopontocerebellar, connecting the cortex, pons
and cerebellum and the
• Dentatorubrothalamic connecting the dentate nucleus
of the cerebellum, the red nucleus and the thalamus.
CEREBELLUM:
INPUTS
89
Receive many inputs from
periphery, spinal cord and
brain regions
CEREBELLUM:
OUTPUTS
90
VESTIBULAR SYSTEM
• The vestibular system controls balance. It is synaptically linked to
the extrapyramidal system. So that persons with extrapyramidal
neurodenerative disorders frequently also have problems with
balance and may experience frequent falls.
• The semicircular canals are lined by hair cells and filled with
endolymph. The endolymph moves when the head moves and
thus stimulates the hair cells. The hair cells then project synaptically
to the Vestibular ganglion which is located within the bone of the
skull. The ganglion then sends projections to the Superior and
lateral vestibular nuclei which are located in the medulla adjacent
to the base of the fourth ventricle. These nuclei in turn send axons
via the Inferior cerebellar peduncle to the Flocculonodular lobe of
the cerebellum to maintain equilibrium.
VESTIBULAR SYSTEM
• The major tracts of the vestibular system include the
lateral vestibulospinal which maintains equilibrium,
the vestibuloocular which controls saccadic eye
movements and the vestibulocortical which causes
dizziness when stimulated.
• The practical implications are that diseases of the
inner ear cause loss of equilibrium, dizziness and
saccadic eye movements when the head is turned.
TREMOR
TREMOR
• is an unintentional, somewhat rhythmic, muscle
movement involving to-and-fro movements
(oscillations) of one or more parts of the body.
• It is the most common of all involuntary
movements and can affect the hands, arms,
head, face, vocal cords, trunk, and legs. Most
tremors occur in the hands. In some people,
tremor is a symptom of another neurological
disorder.
TREMOR
• is generally caused by problems in parts of the
brain or spinal cord that control muscles throughout
the body or in particular areas, such as the hands.
• Neurological disorders or conditions that can
produce tremor include multiple sclerosis, stroke,
traumatic brain injury and neurodegenerative
diseases that damage or destroy parts of the
brainstem or the cerebellum.
• Other causes include the use of some drugs (such
as amphetamines, caffeine, corticosteroids, and
drugs used for certain psychiatric disorders, alcohol
abuse or withdrawal, mercury poisoning,
overactive thyroid or liver failure.
TREMOR
• is generally caused by problems in parts of the
brain or spinal cord that control muscles throughout
the body or in particular areas, such as the hands.
• Neurological disorders or conditions that can
produce tremor include multiple sclerosis, stroke,
traumatic brain injury and neurodegenerative
diseases that damage or destroy parts of the
brainstem or the cerebellum.
• Other causes include the use of some drugs (such
as amphetamines, caffeine, corticosteroids, and
drugs used for certain psychiatric disorders), alcohol
abuse or withdrawal, mercury poisoning,
overactive thyroid or liver failure.
TREMOR
• Tremors can be an indication of hypoglycemia, along with
palpitations, sweating and anxiety. A magnesium and Vitamin
B1 deficency has also been known to cause a tremor or
shaking, soon resolved when the nutrients are taken.
• Tremor may occur at any age but is most common in middleaged
and older persons. It may be occasional, temporary, or
occur intermittently. Tremor affects men and women equally.
TREMOR CLASSIFICATION
• Tremor is most commonly classified by clinical features and cause or
origin. Some of the better known forms of tremor, with their symptoms,
include the following:
• Essential tremor (sometimes called benign essential tremor) is the most
common of the more than 20 types of tremor. The hands are most
often affected but the head, voice, tongue, legs, and trunk may also
be involved. Head tremor may be seen as a “yes-yes” or “no-no”
motion.
Essential tremor may be accompanied by mild gait disturbance.
Tremor frequency may decrease as the person ages, but the severity
may increase, affecting the person’s ability to perform certain tasks or
activities of daily living.
Heightened emotion, stress, fever, physical exhaustion, or low blood
sugar may trigger tremors and/or increase their severity. Onset is most
common after age 40, although symptoms can appear at any age. It
may occur in more than one family member. Children of a parent
who has essential tremor have a 50 percent chance of inheriting the
condition. Essential tremor is not associated with any known
pathology.
TREMOR CLASSIFICATION
• Parkinsonian tremor is caused by damage to
structures within the brain that control movement.
This resting tremor, which can occur as an isolated
symptom or be seen in other disorders, is often a
precursor to Parkinson's disease (more than 25
percent of patients with Parkinson’s disease have
an associated action tremor).
The tremor, which is classically seen as a “pill-rolling”
action of the hands that may also affect the chin,
lips, legs, and trunk, can be markedly increased by
stress or emotions. Onset of parkinsonian tremor is
generally after age 60. Movement starts in one limb
or on one side of the body and usually progresses
to include the other side.
TREMOR CLASSIFICATION
• Dystonic tremor occurs in individuals of all ages who
are affected by dystonia, a movement disorder in
which sustained involuntary muscle contractions
cause twisting and repetitive motions and/or painful
and abnormal postures or positions.
Dystonic tremor may affect any muscle in the body
and is seen most often when the patient is in a
certain position or moves a certain way. The
pattern of dystonic tremor may differ from essential
tremor. Dystonic tremors occur irregularly and often
can be relieved by complete rest. Touching the
affected body part or muscle may reduce tremor
severity (a geste antagoniste). The tremor may be
the initial sign of dystonia localized to a particular
part of the body.
TREMOR CLASSIFICATION
• Psychogenic tremor (also called hysterical tremor)
can occur at rest or during postural or kinetic
movement. The characteristics of this kind of tremor
may vary but generally include sudden onset and
remission, increased incidence with stress, change
in tremor direction and/or body part affected, and
greatly decreased or disappearing tremor activity
when the patient is distracted. Many patients with
psychogenic tremor have a conversion disorder or
another psychiatric disease.
TREMOR CLASSIFICATION
• Orthostatic tremor is characterized by fast (>12Hz)
rhythmic muscle contractions that occur in the legs
and trunk immediately after standing. Cramps are
felt in the thighs and legs and the patient may
shake uncontrollably when asked to stand in one
spot. No other clinical signs or symptoms are
present and the shaking ceases when the patient
sits or is lifted off the ground. The high frequency of
the tremor often makes the tremor look like rippling
of leg muscles while standing. Orthostatic tremor
may also occur in patients who have essential
tremor.
TREMOR CLASSIFICATION
• Physiologic tremor occurs in every normal individual and has
no clinical significance. It is rarely visible to the eye and may
be heightened by strong emotion (such as anxiety or fear),
physical exhaustion, hypoglycemia, hyperthyroidism, heavy
metal poisoning, stimulants, alcohol withdrawal or fever.
• It can be seen in all voluntary muscle groups and can be
detected by extending the arms and placing a piece of
paper on top of the hands. Enhanced physiologic tremor is a
strengthening of physiologic tremor to more visible levels. It is
generally not caused by a neurological disease but by
reaction to certain drugs, alcohol withdrawal, or medical
conditions including an overactive thyroid and
hypoglycemia. It is usually reversible once the cause is
corrected.
THE DEGREE OF TREMOR SHOULD BE ASSESSED IN FOUR POSITIONS. THE
TREMOR CAN THEN BE CLASSIFIED BY WHICH POSITION MOST ACCENTUATES
THE TREMOR:
Position Name Description
At rest Resting tremors Tremors that are worse at rest include
Parkinsonian syndromes and essential tremor if
severe. This includes drug-induced tremors
from blockers of dopamine receptors such as
haloperidol and other antipsychotic drugs.
During contraction (eg. a tight fist
while the arm is resting and
supported)
Contraction
tremors
Tremors that are worse during supported
contraction include essential tremor and also
cerebellar and exaggerated physiologic
tremors such as a hyperadrenergic state or
hyperthyroidism
[1]
. Drugs such as adrenergics,
anti-cholinergics, and xanthines can
exaggerate physiologic tremor.
During posture (eg with the arms
elevated against gravity such as in a
'bird-wing' position)
Posture tremors Tremors that are worse with posture against
gravity include essential tremor and
exaggerated physiologic tremors
[1]
.
During intention (eg finger to nose
test)
Intention tremors Intention tremors are tremors that are worse
during intention, e.g. as the patient's finger
approaches a target, including cerebellar
disorders
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