B7.037 Motor Control Systems Flashcards
major descending motor systems
corticospinal
corticobulbar
2 motor control systems
basal ganglia (magnitude) cerebellar (correction)
function of motor control systems
modulate outputs of corticospinal and corticobulbar systems
NO direct motor outputs
modulation via the thalamus
features of akinetic rigid syndrome
slowness of movement (bradykinesia) velocity independent increased tone (rigidity) postural instability rest tremor bilateral, mildly asymmetrical chronic
movement disorders
a group of disorders affecting the ability to produce and prevent movement
difficulty not caused by weakness
hypo-kinetic movement
move too little
akinetic-rigid syndromes
parkinsonism
hyperkinetic movement
move too much
abnormal involuntary movements
primary clinical signs of parkinsonism
bradykinesia/akinesia
increased tone: rigidity
postural instability
general orientation of basal ganglia system
follows lateral ventricles
subcortical gray structure (contains a lot of neurons)
components of the basal ganglia
striatum: -caudate -putamen globus pallidus -interna -externa subthalamic nucleus substantia nigra
major inputs of basal ganglia
cortico-striate
from cortex into either caudate or putamen portion of striatum (both work as one unit)
major output of basal ganglia
globus pallidus interna
direct path in basal ganglia
cortex > striatum > GPi > thalamus
inhibitory to thalamus (decreases magnitude of movement)
indirect path in basal ganglia
cortex > striatum > GPe > subthalamic nucleus > GPi > thalamus
path through subthalamic nucleus increases inhibitory effect even more (upregulates pathway which downregulates movement)
how is the basal ganglia system modulated
through the substantia nigra (dopaminergic)
input from the substantia nigra inhibits output from the GPi, leading to more movement
more dopaminergic activity
more modulation from substantia nigra
less output from GPi
more movement
less dopaminergic activity
less modulation from substantia nigra
more output from GPi
less movement
type of neurotransmission from GPi to thalamus
GABA = inhibitory
type of neurotransmission from subthalamic nucleus to GPi
glutamate = excitatory
hypokinetic movement disorders etiology
too much GPi activity (more inhibitory)
hyperkinetic movement disorders etiology
too little GPi activity (less inhibition)
types of conditions that cause parkinsonism
Parkinson's Disease - most common drugs vascular encephalitis multi systems atrophy toxins (MPTP, MN, CO)
brain pathology of Parkinson’s disease
idiopathic neurodegenerative disease of the substantia nigra
less dopaminergic input to the striatum
more output from the GPi, more inhibition of the thalamus
not enough movement
clinical features of Parkinson’s
rest tremor, rigidity, bradykinesia and postural instability in later stages of disease
autonomic dysfunction
neuropsychiatric disturbances
epidemiology of parkinson’s
1 mil in US
0.3% of US population (3% of people over 65 and 10% over 80)
50,000-60,000 new diagnoses per year
age of onset of Parkinson’s
typically between 40-70
- avg is 60
- 4-10% before 40
risk factors for Parkinson’s
increasing age family history male gender Caucasian environmental (chemical based industries)
genetic causes of parkinsons
uncommon for parkinson’s to be an inherited form
a-synuclein
parkin
UCH-L1
autonomic manifestations of parkinson’s
orthostatic hypotension constipation dysphagia heartburn excessive sweating, heat intolerance urinary disturbances male sexual dysfunction
cognitive manifestations of Parkinson’s
apathy
dysexecutive
dementia (15-40%)
cortical targets of the basal ganglia
limbic channel - apathy
oculomotor channel - hypsometric saccades
prefrontal channel - dysexecutive
motor channel - akinesia
current method of pharmacotherapy for Parkinson’s
repair the dopamine deficiency
pharmacotherapeutic options
Levodopa
MAO-B inhibitors
dopamine agonists
COMT inhibitors
how does levodopa work
crosses the BBB and is converted to dopamine in remaining neurons in the substantia nigra
can be stored as well
combo therapy with levodopa
carbidopa used to block peripheral decarboxylase
peripheral decarboxylase breaks down levodopa outside of CNS, blocking this allows levodopa to be used in smaller doses to decrease adverse effects (nausea and vomiting)
efficacy of levodopa
most effective agent
if patients don’t improve, they probably don’t have parkinson’s
pharmacokinetics of carbidopa/levodopa
half life is 90 min
5-10% enters brain w carbidopa
immediate and extended release options available
long term complications of levodopa
motor fluctuations -wearing off phenomenon -on/off phenomenon dyskinesia (overshooting) -chorea -dystonia
why are there long term complications of levodopa
short half life
decreasing ability of nigral neurons to store dopamine over time (remaining cells still dying away as time progresses)
mechanism of action of MAO-B and COMT inhibitors
MAO-B and COMT break dopamine down into biproducts
inhibiting these makes dopamine’s effects last longer
MAO-B inhibitors
selegiline & rasagiline
- minimal effect when used alone
- reduces motor fluctuations and increases on time as an adjunct to levodopa
COMT inhibitors
entacapone & tolcapone
extends half life of levodopa from 1.5 to 2.5 hours
no role as monotherapy
no
function of dopamine agonists in Parkinson’s
stimulate postsynaptic dopamine receptors directly
do not require metabolic conversion
half life longer than levodopa
indication for dopamine agonists
initial monotherapy or as an adjunct to levodopa (after motor fluctuations begin)
effectiveness of dopamine agonists
effective for tremor, bradykinesia, and rigidity
not as effective for motor symptoms as levodopa
dopamine agonists
pramipexole
ropinirole
targets of deep brain stimulation in parkinson’s
subthalamic nucleus or GPi
stimulation shuts off these areas briefly, decreasing inhibition of the thalamus and increasing movement
effectiveness of deep brain stimulation in Parkinson’s
only effective in patients with Parkinson’s responsive to levodopa with motor fluctuations (well into course of disease)
features suggesting non-Parkinson’s disease cause of parkinsonism
symmetry at onset absence of rest tremor early dementia abrupt onset rapid progression supranuclear gaze palsy early or severe autonomic dysfunction UMN or cerebellar signs early falling **poor response to levodopa**
characterize multiple systems atrophy
degeneration of cells in the striatum parkinsonian features early postural instability early speech difficulties pyramidal tract signs cerebellar signs peripheral neuropathy
pathogenesis of multiple systems atrophy
pathology in striatum itself
INCREASES output from GPi
decreases movement
characterize vascular parkinsonism
caused by ischemia / strokes to the striatum
history of HTN and strokes
MRI white matter changes
agents causing drug induced parkinsonism
phenothiazines
metoclopramide
thioxanthenes
characterize drug induced parkinsonism
postural tremor greater than resting tremor
reversible (may take 6 months)
MPTP induced parkinsonism
causes death of substantia nigra neurons
signs and symptoms similar to Parkinson’s, but motor fluctuations occur right away
characterize hyper kinetic movement disorders
heterogenous group of disorders
abnormal involuntary movements
classification based upon phenomenology
pathophysiology and etiology of most unknown
well established empiric treatments for most
rhythmic involuntary movements
tremor
tremor
postural, action, rest common disease -essential tremor -familial tremor -Parkinson's unknown cause
treatment of tremor
essential: primidone, propranolol
PD associated: levodopa
suppressible abnormal involuntary movements
tics
tics
suppressible and associated with an urge to move
common disease
-Tourette’s
-adult onset tic disorder
treatments for tics
neuroleptics
pimozide
sustained abnormal involuntary movements
dystonia
dystonia
common diseases
-focal dystonias (blepharospasm, torticollis, writer’s cramp)
-generalized
unknown cause, but due to a lack of reciprocal inhibition
segawa genetic variant
treatment for dystonia
focal: botulinum toxin anticholinergics levodopa (segawa variant) neuroleptics pimozide
ballistic abnormal involuntary movements
chorea
chorea
ballistic movement: agonist, antagonist, agonist common diseases -hemi-ballismus -essential chorea -Huntingtons -post-strep
treatment of chorea
dopamine blockers
anticholinergics
abnormal involuntary movements that are not rhythmic, suppressible, sustained, or ballistic
myoclonus
myoclonus
brief, shock like movements common diseases -idiopathic -primary generalized epilepsies -post anoxic
treatment of myoclonus
anti-seizure meds (valproic acid)
long acting benzos
tardive dyskinesia
abnormal involuntary movements after use of dopamine blocking agents
can result in any type of movement previously described
-dystonia and chorea most common
-typically oral, lingual, buccal
treatment of tardive dyskinesia
difficult
most effective in short term: increase dopamine blocker, worsens in long term
anticholinergics to prevent
