Movement Disorders

A gentleman otherwise well had the idea his brain was rotten. He went to the king, begging him to command M. le Grand, Physician, M. Pegray, King's Surgeon-in-Ordinary and myself to open his head, remove his diseased brain and replace it with another. We did many things to him but it was impossible for us to restore his brain. -- Ambroise Pare (1526)

History

Edwin Smith papyrus

John Hughlings Jackson

General introduction

Lower motor neuron signs

fasciculation and atrophy, decreased tone and reduced or absent tendon reflexes

Upper motor neuron signs

groups of muscles (synergists) are invariably all affected, atrophy is rare and there are no fasciculations, but there is spasticity in which muscle tone and deep tendon reflexes are both increased

Basal ganglia

Common symptoms

tremors - involuntary oscillatory movements
athetosis - slow, writhing movements of fingers & hand
chorea - abrupt movements of limb and facial muscles
ballism - violent, flailing movements
dystonia - persistent abnormal posture

Details on organization and function of basal ganglia

This link as the wiring diagrams

Parkinson's disease

Described as syndrome in 1817 by James Parkinson

0.1-1% of population (this considered fairly common); it is the third most common neurological disease
degeneration of SNpc

symptoms only evident after 80% of cells die
cell death occurs during normal aging

degeneration also of raphe nuclei (serotonin) and locus coeruleus (norepinephrine)
Symptoms

Much variety in different patients
Appear after age 50 or so
Positive symptoms - behaviors manifest that are normally inhibited

Tremor at rest
Muscular rigidity, cogwheel rigidity
Involuntary movements

Negative symptoms

Disorders of posture

Disorders of fixation - inability to maintain a part of body in normal position
Disorders of equilibrium - difficulty in standing or sitting

Disorders of righting - inability to get up
Disorders of locomotion

Go from walking to running
Stopping in doorway

Disorders of speech
Akinesia - delayed & slowed movements

Facial mask
Bradykinesia

During ballistic movements, unlike normal triphasic agonist-antagonist-agonist activation, patients have delayed, prolonged and multiple EMG bursts

Insidious onset, often hand tremor and distal stiffness
10-20 years to incapacitation
symptoms can disappear for periods, often evoked by strong stimulus
Cognitive

Parkinson's originally stated that "the senses and the intellect remain uninjured".
Recent studies document cognitive deficits in some patients, especially as disorder progresses.
impaired ability to spontaneously generate efficient strategies when relying on self-directed, task-specific planning

e.g., Wisconsin card sorting

deficits associated with frontal lobe damage

remember prefrontal caudate circuit
also frontal cortex receives direct dopaminergic input from basal forebrain

motor planning deficits

increased response time in choice response tasks relative to controls, even accounting for initial difference in simple response time

MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

1982, drug addicts in San Francisco who came to hospital with Parkinson's symptoms. Period of confusion about how such young individuals could have Parkinson's disease. Finally discovered that a contaminant in synthetic heroin was the cause - MPTP. When taken it is converted to MPP⁺ which is toxic to DA cells. SNpc cells killed by MPTP.
MPTP now used to make animal model of Parkinson's disease

Initially used in rats but with no ill effects because brain organization different, e.g., no corticospinal tract
MPTP treated macaque monkeys develop symptoms of hypokinesia/bradykinesia, rigidity, tremor that are reversed with L-DOPA
DA cells in ventral tegmentum & NE cells in locus coeruleus also destroyed - further resembling human

physiological studies in MPTP-treated monkeys reveal circuits responsible for certain symptoms (review DeLong et al ideas)

recording in MPTP-treated monkeys showed elevated levels of activity in GPi & STN and reduced activity in GPe
hypokinetic disorder circuit - excessive inhibitory feedback due to excessive basal ganglia output

excessive inhibition of GPe in indirect pathway
disinhibition of STN
excessive excitatory drive to GPi/SNpr
excessive thalamic inhibition
reduced cortical production of movements
reinforced by reduced inhibitory input to GPi/SNpr through direct dircuit

if excessive activation of GPi by STN causes symptoms, treat by lesioning or inactivating STN

in MPTP treated monkeys, lesions of STN result in immediate, dramatic reduction of akinesia and bradykinesia as well as tremor and rigidity in contralateral limbs

Treatments

Increase effective dopaminergic transmission pharmacologically

Symptoms do not manifest until DA levels reduced 80%. Brain compensates for reduced DA transmission by producing more DA receptors - denervation supersensitivity
L-DOPA

metabolic precursor of DA that passes blood-brain barrier
dosage must be titrated for each patient and vary with course of disease because SNpc neuron death continues
denervation supersensitivity makes dosage of L-DOPA difficult without producing side effects
thought disorder side effects due to mesolimbic dopamine system

other drugs that increase DA transmission can also be effective, e.g., amphetamine, monoamine oxidase inhibitors, tricyclic antidepressants

Increase effective dopaminergic transmission through implants

embryonic dopaminergic cells
adrenal medulla

Pallidotomy

Eliminate neural circuits responsible for positive symptoms

Deep brain stimulation

subthalamic nucleus

Neurotrophic factors may prevent or delay death of SN neurons

Glial cell line-derived neurotrophic factor that enhances survival and growth of midbrain dopaminergic neurons

Tardive dyskinesia

caused by long-term use of antipsychotic drugs (phenothiazines and butyrophenones) that block DA neurotransmission
excess motor activity, especially of face & tongue
difficult to treat; reducing or eliminating antipsychotic drug can exacerbate symptoms

Huntington's disease

George Huntington systematically studied, publishing in 1872
degeneration of caudate nucleus

first cells to die are those that project to GPe, the indirect pathway through STN

Known that lesions of STN (either by stroke or experimental) cause hemiballismus - a very clear correlation

later intrinsic cholinergic cells in striatum die

symptoms

chorea (from Greek, dance)
dementia
death after 15-20 years
onset after age 40-50
progress of disorder

subtle onset: absentminded, irritable, depressed, fidgeting, clumsiness
uncontrolled movement become prominent until individual confined to bed
speech becomes slurred, then incomprehensible and finally stops
cognitive abilities impaired, ability to reason goes

rare in general population, 1.6 per million per year death rate; more common in caucasian European; rare in asian or african descendents

no effective treatment
genetic disease

Nancy Wexler

autosomal dominant 50% chance of having it if parent does
Traced to village of Bures in England in 1630

Afflicted individuals thought to be witches
Disease brought to US in 1630 among passengers of John Winthrop fleet
The large incidence around Lake Maracaibo can be traced to one women whose father, an English sailor, carried the gene

3000 decendents, 100 with Huntington's disease, 1,100 children with 50% chance of having it!

genetic mapping studies show that mutation is on chromosome 4
in 1993 the exact gene was identified

authorship was "Huntington's Disease Collaborative Research Group" - representing 6 labs around the world
nature of the mutation is that a CAG triplet that occurs 11-34 times in the normal gene, occurs from 35 to 100 or more times in mutant

studying 75 families, there is evidence that the age of onset is predicted by the number of excess triplets

thus genetic counseling may be able not only to specify whether individual will develop symptoms but also when!

now determine what protein is coded and what that protein does normally. determine whether protein is absent or dysfunctional in Huntington's disease

symptoms can be produced in nonhuman primates by excitatory neurotoxins injected in striatum

hyperkinetic disorder circuit - excessive positive feedback due to reduced basal ganglia output

reduced striatopallidal inhibition along indirect pathway
reduced excitatory projection from STN to GPi/SNpr
reduced inhibition on thalamus
more cortical activation leading to movements

Hemiplegia

unilateral loss of voluntary movement
changes in postural tone
changes in reflexes
usually caused by vascular disease affecting middle cerebral artery which supplies motor areas (among many other brain regions)
Primary motor cortex (area 4)

paresis (paralysis)
loss of fractionation (fine distal control of fingers)
spasticity

most pronounced in anti-gravity muscles

e.g., usually arm flexors hold against gravity, but when person takes quadrupedal position, the arms become spastic in extended position
thus, spasticity is not property of independent muscles but occurs in groups of muscles in purposeful way

abnormal reflexes

Babinski sign, extensor plantar response

Apraxia

described most thoroughly by Liepmann around 1900
inability to produce a movement that is not due to paresis (paralysis) - specific loss of skill
various forms depending on site of damage (not complete agreement on designations and criteria)

ideational apraxia

misuse of objects due to disturbance of identification (agnosia)

ideomotor apraxia

simple movements can be executed, but complex movements cannot

limb kinetic apraxia

inability to make movements or use objects or the purpose intended by the will

clinical / experimental testing necessary to distinguish damage to a motor system from damage to areas that control it

some tests with no bilateral impairment

finger-tapping speed
movement steadiness
repetitive screw rotation
imitation of single hand posture
imitation of single face posture

some tests with bilateral impairment

finger tapping on 2 keys
finger tapping with rhythm
manual sequence box
imitation of multiple hand movements
imitation of multiple face movements

Premotor cortex (area 6 - lateral)

inability to produce indirect trajectories
Ablation of premotor cortex impairs conditional motor behavior

Supplementary motor area (area 6 - medial)

Brinkman, bimanual coordination deficit
absence of speech

Prefrontal

deficits in delayed response tasks

dorsolateral - spatial
ventral - object

Posterior parietal cortex (areas 5, 7)

Gerstmann's syndrome

Following left parietal (in normal right hand dominant)
left-right confusion
finger agnosia
dysgraphia
dyscalculia
apraxia

Balint's syndrome

Following bilateral damage
unable to make voluntary eye movements into affected hemifield
optic ataxia - deficit in visually guided reaching
deficit in visual attention

Neglect

Following right (nondominant) hemisphere damage
Constructional apraxia

Last edited 21 Sep 2009, JDS