Module B - Motor control and movement disorders Flashcards
What type of movements are processed by the forebrain?
Voluntary
What type of movements are processed by the spinal cord and brainstem?
Reflex movements and rhythmic motor patterns
Where do motor outputs from the cerebral cortex innervate?
Brainstem (corticoreticular) Spinal cord (corticospinal tract) Brainstem to spinal cord (indirect) Brainstem to muscles (indirect) Spinal cord to muscles (indirect)
Where do sensory outputs from muscles innervate?
Brainstem
Spinal cord to brainstem
Brainstem to thalamus to motor regions of the cerebral cortex
Describe the components of the subcortical inner loop of movement in the forebrain:
Thalamus, basal ganglia, brain stem, cerebellum
Regulate fine movement and precision
Selective excitability of cortex (facilitation/inhibition)
Name the location and types of motoneurons:
Spinal cord
Brainstem
(motoneuron pools/nuclei)
Alpha motoneurons (final common path) Gamma motoneurons (innervate muscle spindles, send information back to brain about muscle stretching)
What are motor units?
The anatomical and functional elements of the ‘output’ stage of the motor system
FF (fast twitch, fatigable) and S (slow twitch)
Describe the synaptic inputs of alpha motoneurons as the final common path:
Descending tracts (corticospinal, rubrospinal, vestibulospinal, reticulospinal) Spinal (brainstem) interneurons Peripheral receptors (group 1a afferent fibres from muscle spindle)
List the most frequent types of movement disorders:
Paralysis
Abnormalities of muscle tone (hypertonia e.g. spasticity after stroke or rigidity in PD)
Ataxia (incoordination in cerebellar disorders)
Abnormal involuntary movements (epileptic fit, tremor in PD)
Describe the types of paralysis:
Monoplegia - one arm or one leg
Hemiplegia - one arm and one leg, same side
Parapelgia - both legs
Quadriplegia - all 4 limbs
Where is the location of damage/lesion in motor units to cause myopathies?
Muscle fibres
What are muscular dystrophies?
A group of inherited disorders characterised by progressive muscle wasting and weakness (without primary structural abnormality in the motoneuron)
What caused Duchenne muscular dystrophy?
Defective gene for dystrophin (a muscle protein)
Describe the features of myotonic muscular dystrophy:
Myotonia - muscle stiffness, due to very slow relaxation after contraction and failure of muscle to relax
Wasting and weakness of muscle including the heart
Describe the inheritance of myotonic muscular dystrophy:
Inherited dominantly, up to 2000 triple CTG repeats in chromosome 19 coding for a protein kinase (myotonin?)
Describe Myasthenia gravis:
Muscle weakness without wasting
Autoimmune disease
Fewer ACh binding sites leads to decreased EPPs and decreased synaptic transmission
Describe the production of botulism:
Botulinum toxins produced under anaerobic conditions, 1 microgram kills an adult human if injected
Describe the mechanism of action of botulinium toxins:
Muscle paralysis results from decreased ACh release
Toxins bind to nerve terminal and are internalised by endocytosis, cause proteolysis of several membrane proteins involved in vesicle docking and NT release (SNAP-25 and Syntaxin)
Describe the effects of botulinum toxins:
Striated and smooth muscles affected - disruptions in autonomic nervous system (dry mouth, postural hypotension, severe constipation)
Describe infant botulinism:
Constipation, lethargy, weakness, difficulty in feeding, can progress to flaccid paralysis and respiratory arrest
Describe the other applications of botulinum toxins:
Dystonias (persistent increase in muscle tone and involuntary movements such as in cerebral palsy)
Hyperhydrosis (excessive sweating)
GI and urinary disorders
Migrane
Describe the changes in the distal part of the axon in Wallerian degeneration:
Describe the changes in the distal part of the axon in Wallerian degeneration:
Loss of synaptic transmission (on electrical stimulation of the axon) within 24 hours
Degeneration within days (due to loss of the axon survival factor normally supplied by cell bodies NMNAT2)
Describe the changes in motoneuron cell body:
Chromatolysis, changes in biochemical and elecrophysiological properties
Describe axon regeneration in Wallerian degeneration:
1-4mm/day facilitated by arrays of Schwann cells
Re-innervation of muscles
Re-myelination of axons (partial) - functional recovery
Describe peripheral neuropathies:
Most common is demyelinating (MS)
Can affect both motor and sensory nerves
Can accompany other diseases (diabetes, chemotherapy-induced in treating cancer patients)
Describe the mechanism of action of peripheral neuropathies:
Exposed axolemma Na+ channels decrease K+ channels to increase Slowing or block of conduction Inability to conduct action potentials at high frequency
Where do diseases/disorders of motor units affect?
Cell body
Describe Poliomyelitis (Polio):
Acute degeneration of motoneurons resulting from a viral (oral) infection
Brought under control by vaccination
Describe the incidence of ALS:
~5/100,000 (200 in NZ)
90% have no family history of the illness
10% have rare familial form of ALS with dominant inheritance of mutation in superoxide dismutase
Average age of onset in 5th decade of life
Death usually within 2-3 years
Describe the main symptoms of ALS:
Progressive wasting, weakness and atrophy of muscles leading to paralysis
-Weakness of legs, arms and hands
-Difficulty with speech and swallowing
-Impairment of respiration
Muscle stretch reflexes exaggerated and muscle tone increased (spasticity)
Describe the other signs of ALS:
Signs of muscle denervation:
- Fasciculations (twitches of some motor units which survived atrophy)
- Fibrillations (spontaneous action potentials generated in individual muscle fibres in EMG)
No involvement of extraocular muscles
No involvement of anal and bladder sphincters
Usually no sensory or intellectual deficits
Describe the three main progressive degenerations (causes of the disease):
- Motoneurons in the spinal cord (exception of motoneurons controlling sphincters)
- Motoneurons in the brainstem (except III, IV, VI nuclei)
- Upper motoneurons (increased stretch reflexes and spasticity)
1+2 lower motoneurons
What is the neurotrophic hypothesis of ALS?
Reduction in the level of neurotrophic factors (BDNF, NT3) which promote motoneurons survival
What is the oxidative stress hypothesis of ALS?
Damage of neurons by free radicals (reactive oxygen and nitrogen species) when radical production exceeds the detoxification capacity of specific enzymes (glutathione oxidase, superoxide dismutase, catalase)
What is the excitotoxic hypothesis and its two components in ALS?
Excessive activation of AMPA/NMDA receptors by glutamate
(a) Increase EC glutamate due to decreased activity of astrocytic glutamate transporter GLT1
(b) Decrease GluR2 subunit expression (AMPA-R), predisposes motoneurons to higher calcium influx
What is the TDP-43/FUS mutation hypothesis of ALS?
TDP-42 and FUS (RNA processing proteins) normally found in nucleus
Genes coding for these proteins mutate in some forms of familial ALS, and the two proteins are shifted to the cytoplasm where they form insoluble aggregates affecting neuronal function
Describe the treatment options for ALS:
No effective drugs available to arrest or alter the course of the disease
Small beneficial effect of Riluzole (blocks glutamate release), slows disease process by a few months
Dexpramipexole (drug improving mitochondrial function), clinical trial
Baclophen (GABA-B agonist), reduce spasticity
Other symptomatic treatments (control of excessive salivation)
Experimental replacement or trophic therapy using genetically modified cells or stem cells
What type of injuries are the most frequent traumatic injuries of the CNS?
Spinal cord 10,000/year 50% quadriplegic 75% 16-30 years old 250,000 confides to wheelchairs
Describe the motor deficits associated with left hemisection of the spinal cord (Brown-Sequard syndrome) at Th8 level:
Monoplegia (no voluntary motor functions of the left leg)
Loss of excitatory inputs to motoneurons from the cortico-spinal and the rubro-spinal tracts
Describe the sensory deficits associated with left hemisection of the spinal cord (Brown-Sequard syndrome) at Th8 level:
Loss of pain and temperature sensation below Th8 on the right (spinothalamic tract crosses midline in spinal cord)
Fine tactile perception and proprioception lost below Th8; ipsilateral on the left side (dorsal columns remain ipsilateral throughout their course in the spinal cord)
Describe the spinal shock period of acute complete spinal cord lesion:
Period of areflexia lasts 1-3 days due to loss of excitatory inputs from descending tracs
What are the physiological symptoms after complete lesion at Th8 level during spinal shock:
Paraplegia
Total anaesthesia (in lower part of body)
Areflexia (in lower part of body)
Blood vessels dilated (decreased blood pressure) in lower part of body (role of RVL) (bigger in quadraplegic)
Sweating absent in lower body
Bladder and bowels atonic (continual seepage)
Dysfunction of sexual organs
Describe the symptoms of the recovery (partial) phase after an acute complete spinal cord lesion:
Hyperactive stretch reflexes Flexor (withdrawal) reflexes recover Reflex emptying of bladder and rectum Increased blood pressure Paresthesias (voluntary movements of legs remain absent)
Describe the mechanism of recovery after an acute complete spinal cord lesion:
Sprouting of axon terminals and formation of new synapses (reprogramming of remaining axon connections; synaptic plasticity) Denervation supersensitivity (increase receptor expression/trafficking)
What can be used as respiratory management in quadraplegic patients?
Artificial ventilation (including breathing pacemakers) but this is damaging over long term
What can be used as management in paraplegic patients?
Parastep - microcomputer controlled system for evoking coordinated muscle contraction in paraplegic patients
Rex bionics (exoskeleton) , pair of robotic legs that enables a paraplegic to stand up, walk, move sideways, turn around, go up and down steps etc.
Peripheral nerve grafted to the brain provides a permissive environment for axon regeneration
Describe regeneration in the spinal cord (in experimental animals):
Nerve grafts
Neutralising antibodies to growth-inhibiting myelin-associated glycoprotein (MAG) and NOGO-A secreted by oligodendrocytes
Trophic factors (NT3, GDNF)
Bridges with fetal spinal cord
Describe the potential for functional recovery after stem cell transplants following CNS damage:
Human embryonic stem cells
Bone marrow stem cell transplants
Adult olfactory enshaething cells (Schwann cell-like) present in the nasal epithelium and the optic nerve
