Lecture 4: Motor Disorders

motor control

-cortex issues commands based on integration of sensory inputs

-a copy is sent to basal ganglia and cerebellum

-these feedback to cortex via thalamus

-command that reaches lower motor neurons is continually modulated by basal ganglia and cerebellum

motor cortex

-issues descending motor commands for muscle activation

-regulates activity levels in spinal cord circuits

-where the upper motor neuron begins

motor cortex damage symptoms

-impaired voluntary movement

-poor high level coordination 

-weakness of voluntary movement

-upper motor neuron syndrome 

cerebral palsy (damage to motor cortex)

-result of damage to motor control structures of the brain 

-injury often occurs pre or peri natally 

-stiffness and weakness of muscles 

-poor coordination 

-affects upper motor neurons 

-varied effects on different people

stroke (damage to motor cortex)

-interruption of blood supply to cortex

-upper motor neurons affected

-symptoms depend on extent and location but usually typical of motor cortex damage

cerebral haemorrhage (main cause of stroke)

-often results from an aneurism

-blood is toxic to neural tissue

-if an aneurism can be spotted before rupture can sometimes be treated

cerebral ischaemia (main cause of stroke)

-caused interruption of blood supply to part of the brain due to blockage of a blood vessel 

-lack of oxygen/glucose leads to excitotoxicity and neuronal cell death 

-can be caused by thrombus or emboli or cardiovascular disease 

core region (cerebral ischaemia)

-the region most severely impacted by loss of blood supply

-hard to salvage

penumbra region (cerebral ischaemia)

-around core area where interruption to blood supply may not be total due to overlapping blood supplies

-key for treatment as has not fully lost blood supply and if can remove cause of stroke then potential for good recovery

fine motor control (damage to motor cortex)

-most prominent and widespread symptoms of motor cortex damage relate to fine motor control

-homunculus → there are large representations for these activities and unlikely to be missed by damage, so require coordination across sub-regions

upper motor neuron syndrome 

-collection of symptoms that result from damage to UMNS or their pathways 

-leads to lack of voluntary control of muscles via lower motor neurons

-lack of regulation of lower motor neurons and spinal reflex circuits 

-reflexes become abnormal 

babinski reflex (upper motor neuron syndrome)

-stimulate inside of foot arch and move to ball of foot

• positive response → toes curl upwards, implies an issue with UMNs

• normal response → toes curl downwards

-indicates cortical damage or issues with spinal cord

difficulties separating impact on cognitive and motor function

-people are often perceived to have cognitive impairments but this can simply just be the effect of damage on motor control of speech

-can have nothing wrong cognitively and expression of speech be impaired due to motor issues

conditions implicated in basal ganglia dysfunction

• Parkinson’s disease

• Huntington’s disease

• Tourette’s syndrome

• tardive dyskinesia

• hemiballismus

→ all linked by impaired selection of appropriate sequences of movements

Parkinson’s disease (basal ganglia)

-involuntary tremor, slowness of movement, rigidity

-difficulty initiating voluntary movements

Huntington’s disease (basal ganglia)

-sudden, jerky, involuntary movements with no purpose

-no weakness, ataxia or sensory deficit

Tourette’s syndrome (basal ganglia)

-sudden repetitive, involuntary movements or utterances

tardive dyskinesia (basal ganglia)

-repetitive, involuntary, purposeless movements

-difficulty in stopping movements

hemiballismus (basal ganglia)

-violent, involuntary movements 

-ballistic movements 

monogenic Parkinson’s disease

-around 10% of cases occur due to mutation of one or several genes

sporadic Parkinson’s disease

-around 90% of cases don’t seem to be linked to genetic change

-do not know cause of disease

importance of studying monogenic forms of diseases

-makes it easier to unpick the causes and risk factors for these conditions

-have a pathway of change from simple levels (genes) to complicated levels (the condition)

-helps develop treatments for all population with condition and not just monogenic patients

genetic causes of primarily non-genetic diseases

-if a gene mutation is reliably associated with the common clinical phenotype it may tell us about the downstream cellular/molecular events responsible for the condition overall

• gene → protein → cell behaviour → CNS pathway → Parkinson’s disease

-can make the puzzle more tractable, gives clues for developing drugs to target affected proteins

-develop gene therapy techniques to alter the faulty genetic messages

-easier to do this in genetic cases than sporadic cases

symptoms of Parkinson’s disease

• all underlined by impaired selection of movement

-paucity of spontaneous movement → insufficiency of movement

-bradykinesia → very slow movements

-akinesia → no movements

-increased muscle tone

-resting tremor → pill rolling

-shuffling gait and flexed posture, impaired balance

-mask-like expression

basal ganglia and Parkinson’s disease

-nigrostriatal dopamine neurons degenerate and die

-so don’t get release of dopamine → no excitatory output 

-basal ganglia still inhibits excitatory output 

-can give drugs that act as building blocks of dopamine (L-dopa) → helps remaining neurons build dopamine to create excitatory output 

limits of L-dopa

-PD arises following degeneration of nigrostriatal neurons

-so increasing dopamine availability using drugs stops being effective if there are too few functioning cells left to release dopamine

-doesn’t address non-motor symptoms of PD

non-motor symptoms (Parkinson’s disease)

-lots of severe non-motor symptoms associated with PD 

-depression, anxiety, regulating sw cycle, pain, dysphagia, hypotension, dementia and cognitive impairment 

-underrecognized, underdiagnosed and undertreated as motor symptoms are dominant

deep brain stimulation (Parkinson’s disease)

-electrical stimulation of specific basal ganglia structures to counteract excessive inhibitory output

-blocks and reduced excessive inhibition which allows for return of functions

-allows excitation so people can perform motor programmes

limits of deep brain stimulation

-side effects

-not similarly effective for all

-fails to deal with non-motor symptoms

-confounded by DBS typically being used in later stages

-may make some non-motor symptoms worse

alpha-synuclein (Parkinson’s disease explanation)

-protein 

-misfolding and aggregation into Lewy bodies is a hallmark of PD 

-impair normal neuronic function

alpha-synuclein and lewy bodies (Parkinson’s disease explanation)

-happens throughout the brain → tends to start in olfactory bulb and spreads as disease progresses

-dopamine neurons in substantia nigra may be particularly vulnerable

-accounts for non-motor symptoms

cerebellum damage

-results in ataxia

-two types of impairment:

1. disturbances of posture or gait

2. decomposition of movement

-voluntary movement loses fluidity and appears mechanical, slow and robotic

intention tremor (cerebellum damage)

-when go to move/make action have tremor

-no tremor when resting

dysarthria (cerebellum damage)

-disruption of fine control of speech, slurring

-speech is a fine and controlled process of muscles and cerebellum damage impairs these muscle movements

ataxia (cerebellum damage)

-collection of disorder, unified by their symptoms rather than their causes

-loss of voluntary coordination of muscles → neurological finding in a patient and not a disease

types of ataxia (cerebellum damage)

• focussing on types of symptom → cerebellar, sensory, vestibular

• focussing on type of cause → acquired, hereditary, late onset cerebellar dysfunction

• focussing on more detailed diagnosis

motor neuron disease (MND)

-disease of motor neurons 

-leads to degeneration of direct motor control pathway 

-execution of motor plan through motor neurons is impacted

-degeneration of motor neurons and muscle wasting 

• degenerative 

• progressive 

• incurable 

causes of MND

~10% of cases have genetic component

-90% have environmental, toxic, viral and other factors implicated

types of MND

-ALS is most common subtype of MND 

-general distinction of subtypes is related to effects on either upper or lower motor neurons 

-ALS affects both types 

symptoms of MND

-often altered cognitive function, ability to communicate and affective changes 

-complications arising due to impaired respiratory function is often cause of death → affects muscles in chest relating to breathing

treatment and recent research

• identifying biomarkers for early diagnosis

• identify risk factors

• novel neuroprotective drugs

• gene therapies

• drug to cure and slow progression

• clinical and technological interventions to improve and prolong life

SOD1 gene (MND)

-mutations cause genetic form of MND (ALS)

-new drug tofersen prevents SOD1 production

-CSF biomarkers indicated early effects but no benefit at 6 months

-at 12 months there was patient benefit

-SOD1 ALS is rare but major breakthrough in treatment

• genetic drug targeting is effective

• CSF biomarkers are reliable