Introduction to Movement Disorders

Question 1

which neurotransmitter is at the core of movement

Answer 1

dopamine

Question 2

what are movement disorders sub-divided into

Answer 2

hypokinetic - too little movement
hyperkinetic - too much movement

Question 3

what does multifocal degeneration often lead to

Answer 3

‘non-motor’ symptoms like in dementia, psychosis, sleep disorders and autonomic disorders

Question 4

outline parkinsons disease epidmeiology

Answer 4

1 in 350 will get parkinsons
costing £2.9 billion pounds

Question 5

outline the aetiology of parkinsons disease

Answer 5

hypokinetic neurodegenrative disease
cascade effect of dysfunctional proteins transferring onto neighbouring cells
alpha synuclein - begins in brain stem and substantia nigra, loss of core cells which project widely - mainly dopamine but also serotonin and adrenaline

Question 6

outline the clinical presentation of parkinsons disease

Answer 6

varies depending on where disease begins e.g if in cortex causes cognitive problems like lewy body dementia, or if in brainstem causes autonomic dysfunction through, occipital area = visual problems

Question 7

where does parkinsons manifest usually in the brain

Answer 7

parietal cortex - affects visuospatial functioning

Question 8

how much of the substantia nigra can be lost before symptoms begin

Answer 8

90%

Question 9

what is the main clinical feature of parkinsons

Answer 9

problem with initiating movement

Question 10

what are the main structures of the basal ganglia relevant in parkinsons

Answer 10

striatum - caudate nucleus + putamen
lentiform nucleus - external globus pallidus and internal globus pallidus

Question 11

outline the functional anatomy of the basal ganglia

Answer 11

four largely segregated parallel cortical loops
with some cross talk
link basal ganglia to the limbic system so movement selection is informed of emotional and motivational state to the frontal lobes involved in executive functioning and sensory cortex receiving proprioceptive feedback of motor activity

Question 12

outline the direct pathway of movement in the basal ganglia

Answer 12

striatum to GPi directly

Question 13

outline the indirect pathway of movement in the basal ganglia

Answer 13

striatum to Gpi indirectly via Gpe and STN (subthalamic nucleus)

Question 14

outline direct pathway activation

Answer 14

GPi inhibition -> thalamic disinhibition -> cortical activation

Question 15

outline indirect pathway activation

Answer 15

Gpi activation -> thalamic inhibition -> cortical inhibition

Question 16

what are these basal ganglia loops sometimes compared to?

Answer 16

center surround phenomenon in the visual cortex - try to sharpen image and cant , same with sharpening movement
cant make movement precise

Question 17

what does the direct pathway faciliate

Answer 17

it is the activation circuit, so faciliates the activation of desired movement pathways

Question 18

what does the indirect pathway inhibit

Answer 18

it is the inhibitory circuit, inhibits activation of inappropriate/conflicting movement pathways

Question 19

what does overactivity of the Gpi cause?

Answer 19

it’s preset mode is to inhibit, so it would be predicted to cause reduced activation of desired movements
BRADYKINESIA

Question 20

what would underactivity of the GPi cause?

Answer 20

it’s preset mode is to inhibit so its predicted to cause excessive activation of undesired movement
CHOREA

Question 21

what are the key features of parkinsonism

Answer 21

bradykinesia
associated with muscle ridgidity, asymmetric resting tremor, postural instability

Question 22

what are some causes of parkinsonism

Answer 22

parkinsons disease
drugs (anti-dopaminergics)
cerebrovascular disease
structural lesions of basal ganglia
‘parkinsons plus’ syndromes (MSA, PSP, DLB)

Question 23

outline the clinical signs of parkinsonism

Answer 23

tremor - rest tremor (rotary) or pill rolling (thumb and index)
bradykinesia = slow movement
problem with initiating movement -> basal ganglia doesnt allow initial release of movement
re-emerging tremor - they can extend hand with no tremor but complex after a while

Question 24

outline the epidemiology of tremor

Answer 24

80% of patients experience tremor
most commonly affects hands and arms
may become severe with strong emotions
generally most severe when limb is at rest and improves with movement

Question 25

outline postural instability

Answer 25

appendicular (limb related) symptoms dont respond well to medication balance excerises are key - yoga, pilates, kick boxing - need to build a reserve early on so less likely to reach critical threshold e.g build up reactive movement physical exercise is. akey disease modifier - aerobic and strength training

Question 26

outline dopaminergic fibres in bradykinesia in the basal ganglia

Answer 26

- dopaminergic fibres stimulate the direct pathway - D1 receptors - dopaminergic fibres inhibit the indirect pathway - D2 receptors

Question 27

outline the pathways through which reduced cortical activity results in bradykinesia

Answer 27

direct pathway (activating) becomes underactive -> overactive Gpi indirect pathway (inhibitory) becomes overactive ->overactive Gpi overactive Gpi (inhibitory) inhibits motor thalamus and cortex = bradykinesia

Question 28

why does giving dopamine drugs to parkinsonism patients not work?

Answer 28

as dopamine is involved in other things like vomiting response and peripheral gut movement - unwanted side effects and not desired ones

Question 29

what is the first drug given to parkinsonism patients

Answer 29

LEVO-DOPA can cross BBB taken up into nigral nuerones decarboxylated into dopamine released into synaptic cleft activates post striatal dopamine receptors really effective - patients start to walk again as replacing lost dopamine in substantia nigra but DOSE is important

Question 30

what is the problem with administering levo dopa

Answer 30

acts on circuit so if it is degenerating, no matter how much dopamine you give it wont work

Question 31

what is the see saw effect in neurology

Answer 31

dopamine can override the circuits going through the basal ganglia/cortex, so side effects can be psychosis and cognitive effects as they use dopamine antagonist

Question 32

what are some dopamine agonists

Answer 32

ropinirole pramipexole

Question 33

outline deep brain stimulation for treatment of parkinsonism

Answer 33

stimulation frequency and amplitude titrated against clinical imapairment stimulating electrode blocks firing of neurons in its vicinity DBS of the STN and GPi is a very effective treatment for advanced parkinsons disease

Question 34

outline how deep brain stimulation works on the basal ganglia cortical circuit that causes bradykinesia

Answer 34

parkinsonism is caused by over-inhibition of motor thalamus using DBS blocks output of STN or Gpi and reduces level of inhibition which improves bradykinesia

Question 35

outline oscillatory activity in the basal ganglia of parkinsonism patients

Answer 35

excessive beta oscillations (10-30Hz) seen in PD patients measured by DBS electrode drug induced improvement correlates with degree of synchronisation suppression stimulation of STN at non-therapeutic 10-20Hz frequencies WORSENS bradykinesia

Question 36

what does strong extensive synchronisation of beta band oscillations prevent

Answer 36

neurons coding information in time and space, both adjacent and spatially distributed neurons are locked into beta rhythm oscillations cause disturbed cortical activation that degrades movement

Question 37

what are problems with the standard model of the basal ganglia

Answer 37

direct and indirect pathways are far less distinct than originally believed - lot of COLLATERALISATION - lesion of motor thalamus doesnt lead to parkinsonism - lesion of Gpe predicted to cause chorea, but doesnt - evidence shows basal ganglia could be more active during motor learning than motor activation

Question 38

outline chorea

Answer 38

unpatterned, excessive movement caused by dopamine

Question 38

what is a myoclonus

Answer 38

sudden jerks of movement e,g like when we are falling asleep

Question 39

what is the prototypical form of chorea

Answer 39

huntingtons chorea genetic condition excess of huntington gene leading to accumulation of huntington protein on caudate nucleus - results in chorea anterior caudate nucleus function is thinking and behaviour so huntingtons patients usually demented

Question 40

whats another way you can develop chorea?

Answer 40

sydenhams chorea from streptococcus - different time course e.g someone has sore throat and then has abnormal movement

Question 41

outline huntingtons disease

Answer 41

autosomal dominant neurodegenerative disorder symptom onset is midle age clinical features: - chorea - dementia - anxiety and depression

Question 42

outline the genetics of huntingtons disease

Answer 42

gene - Chr 4p CAG (polyglutamine) repeat at N-terminus = explains 60% of onset age variability , more repeats = younger onset <36 repeats = unaffected > 40 = full penetrance

Question 43

what is the aetiology of huntingtons disease

Answer 43

intranuclear inclusions increased inclusion length promotes proteolysis and aggregation of huntington fragments exceeds capacity of cell to clear via autphagy and proteasomes inclusions are seen but small aggregates may be more pathological

Question 44

outline the brain pathology of huntingtons disease

Answer 44

atrophy of striatum (caudate and putamen) particularly affects spiny neurones projecting from putamen to GPe

Question 45

outline the mechanism of chorea in the basal ganglia striatum circuit

Answer 45

degeneration of indirect pathway leads to disinhibition of motor thalamus and overactivation of inappropriate motor programs

Question 46

what is dystonia

Answer 46

precision of movement is LOST non-degenerative just happens and manifests = involuntary sustained muscle contractions leading to abnormal postures and repetitive movements

Question 47

what are some examples of dystonia?

Answer 47

writing e.g writers cramp spasmodic torticollis - neck muscles, cant move neck in one direction BUT if person touches face it gives sensory feedback, and forces basal ganglia to generate new circuit - neck moves head around

Question 48

what are primary dystonias

Answer 48

genetic young onset = generalised late onset = usually focal

Question 49

what are secondary dystonia

Answer 49

structural lesions metabolic diseases hereditary degenerative diseases

Question 50

what % of dystonias are associated with degenerative diseases

Answer 50

25%

Question 51

outline primary torsion dystonia

Answer 51

intially mapped to DYTI locus on Chr 8 gene codes for Torsin A - heat shock protein only 30% penetrance presents in childhood with lower limb dystonia subsequent generalisation

Question 52

what is the role of the basal ganglia in dystonia?

Answer 52

almost all lesions causing dystonia are in basal ganglia or thalamus reduced functional activity and grey matter volume on MRI neuronal activity in Gpi correlated with dystonic EMG activity DBS of basal Gpi is an effective treatment

Question 53

what is paired associative stimulation

Answer 53

pulses from median nerve stimulation timed to reach cortex 25ms before TMS pulse to thumb after 90 pairs of pulses, cortical stimulation leads to enhanced thumb contractions lasts for one hour and is specific to thumb

Question 54

outline excessive neuroplasticity in dystonia patients

Answer 54

excessive plasticity could drive maladaptive reorganisation of cortical sensorimotor maps

Question 55

so what is the mechanism of dystonia

Answer 55

excessive neuroplasticity : - abnormal basal ganglia activity - impaired surround inhibition - dystonic movements = supposedly