L29 Motor Control and Disease II (Imported from Quizlet)

Indirectly, upper, lower

The basal ganglia and cerebellum influence movement ______________ by regulating the function of ________ motor neurons (i.e. they have no direct connections to _________ motor neurons)

Neurodegenerative

What style of diseases affect both the basal ganglia and cerebellum?

Movement

The basal ganglia plays a role in the initiation of ...?

Motor cortex (telencephalon)

Basal ganglia (forebrain)

- Caudate

- Putamen

- Globus Pallidus

- Subthalamic nucleus

Ventral lateral nucleus of thalamus (diencephalon)

Substantia nigra (midbrain)

What are the key components in the initiation of movement?

Basal ganglia, Area 6, VLo, motor loop

The motor cortex connects to the ________ _________, which in turn feedback to the premotor area (______ _) via the ventrolateral complex of the thalamus (____) to control the initiation of movement - this is known as the _________ ______

Direct and indirect

The motor loop consists of 2 pathways, what are they?

With no initiating cortical input, the Globus pallid us internal segment (GPi) tonically inhibits the VLo

Basal ganglia in the initiation of movement - the direct pathway

Describe (1) in the image

Producing continuous stimulation or inhibition

What is meant by tonically?

Input from many cortical regions converges on the striatum

Basal ganglia in the initiation of movement - the direct pathway

Describe (2) in the image

When activated by this input, the striatum inhibits, the inhibitory activity of the GPi, releasing the VLo to activate Area 6 and initiate movement

Basal ganglia in the initiation of movement - the direct pathway

Describe (3) in the image

Integration of cortical inputs to trigger a response

Rapidity of response - "engine is running"; inhibition of inhibition releases the "brake"

Why set it up like this?

Indirect pathway, substantial nigra, GPe

Basal ganglia - the indirect pathway

The direct pathway is modulated by a complex ___________ __________ which involves the ____________ _______ (SN) and GP external segment (___)

Substantia nigra, activation, direct, indirect, GPe, inhibited, decreases, activation

Basal ganglia - the indirect pathway

The _____________ _______ has a complex role and acts via the striatum (CP) to maintain the balance between inhibition and activation of the VLo

--> Excitatory input from the SN stimulates VLo ___________, by activating the inhibition of the GPi through the _________ pathway --> In the ___________ pathway, inhibition of GPi by _____ is inhibited by the CP and so the VLo is ___________

--> However, inhibitory input from the SN ___________ CP inhibition of the GPe, which then inhibits the GPi allowing __________ of the VLo

VLo

Basal ganglia - the indirect pathway

So the SN is balancing/tuning the activation of the ______

Parkinson's, Huntington's

Degeneration of neurons in different parts of this circuit leads to ______________ or ______________ disease

James Parkinson in 1817

Who and when was Parkinson's disease first described?

Essay on the Shaking Palsy

What was the essay James Parkinson wrote in 1817 called?

1, 100, 85, 90, 10, 15

Parkinson's is the second most common degenerative disorder (_:___ people over the age of 60)

Sporadic cases (__-__%)

Familial cases (__-__%) caused by genetic mutations

Hypokinesia - paucity/insufficiency of movement

Bradykinesia - very slow movements

Akinesia - no movements

Increased muscle tone - rigidity

Resting tremor - at 4-5Hz - 'pill rolling'

Shuffling gait and flexed posture, impaired balance

Mask-like expression

What are the motor symptoms of Parkinson's disease?

Mood disorders, loss of sense of smell

What are the non-motor symptoms of Parkinson's?

Loss of Dopamine (DA)

What is Parkinson's caused by?

A brain disorder resulting from deficiency of a single neurotransmitter

Parkinson's is the first example of what?

Basal ganglia, substantia nigra

80% of the brain's dopamine is found in the ________ ________, specifically the _____________ ______ (SN)

Loss of dopaminergic (DA-ergic) neurons in the substantial nigra

Loss of dopamine in PD patients is due to what?

Loss of dopamine (DA-erguc)

Loss of dopaminergic (DA-ergic) neurons in the substantial nigra

Loss of dopamine in PD patients is due to what?

That intravenous L-dihydroxyphenylalanine (L-DOPA - a dopamine precursor) provided a dramatic though brief reversal of symptoms in PD patients

What did Oleh Horyenkiewicz (early 1960s) find out?

That gradual increases in oral L-DOPA provided significanct and longer benefits

What did Cotzias show later on?

5

Beneficial effects of L-DOPA only last for around how many years?

By boosting capacity of surviving DA-ergic neurons in substantial nigra (SN) to make dopamine (DA)

Does not stop the degeneration of SN neurons

Eventually there are insufficient SN neurons left to make DA

How does L-DOPA work?

Increase in motor response fluctuations and drug related dyskinesias

What are the side effects of L-DOPA?

Increased activity of the indirect pathway and decreased activity of the direct pathway

Reduced dopaminergic input from substantial nigra to striatum leads to both ...?

Less inhibition of the GPi and so its inhibitory activity is increased

This leads to decreased activity of the VLo and so less motor cortex activation

--> Hypokinesis - reduced movement

(L-DOPA reverses this effect, but only as long as some DA-ergic neurons survive)

What does it mean if there's an increased activity of the indirect pathway and decreased activity of the direct pathway?

GPi, Parkinsonian

In severe PD cases, surgical removal of the ____ ('pallidotomy') can be effective in reversing the _______________ effects

Deep brain stimulation

What has been used recently to inhibit GPi hyperactivity?

3, 7

Huntington's disease is rare, hereditary, progressive, fatal - _-_ people per 100,000 with European ancestry, less in other ethnic groups

George Huntington (1851-1916)

Who discovered Huntington's disease?

Hyperkinesia or dyskinesia, 'chorea' (involuntary jerking or twitching movements)

What are the early symptoms of Huntington's disease?

Akinesia and dystonia (muscle spasms), dementia, personality disorder (psychosis)

What are the late symptoms of Huntington's disease?

Autosomal dominant genetic disease resulting in neuronal degeneration:

--> Initially in the indirect pathway components of the striatum

--> Subsequently in the direct pathway components and in the GPe

What is the cause of Huntington's disease?

Degeneration in the striatum reduces (X) the indirect path inputs to the GPe

This increases the inhibition of the GPi with the result that the VLo is dis-inhibited and there is inappropriate initiation of movement

--> Hyperkinesis, chorea

What happens early on in Huntington's in the basal ganglia?

The striatal direct path and GPe neurons also degenerate, releasing the GPi to over-inhibit the VLo

--> Akinesia

What happens later on in Huntington's in the basal ganglia?

Caudate, putamen, globus pallidus

The basal ganglia include the ________, ___________ and __________ __________ and are regulated by the substantial nigra

Striatum, hyperkinesis, akinesis

HD is due to degeneration of the __________ and leads initially to ______________ and then to _________

Substantia nigra, hypokinesis

PD is due to degeneration of the ______________ _______ and leads to _____________

Inherited, genetic

Both PD and HD have an ______________, _________ element

Sporadic/idiopathic

Most cases of PD are __________/___________ but the disease is common (1% in >60s), only 10-15% are inherited

Specific to an individual, cause unknown

What is idiopathic?

Sporadic, 0.005

HD is rarely __________ (therefore mainly inherited) but rare (_____%)

If you have the mutation you are very likely to get the disease

Mutations in multiple genes 'predispose' you to getting PD: some are rare but with high 'penetrance' (e.g. SNCA) others are common but have low penetrance (e.g. GBA1) - what is meant by high penetrance?

HTT

Only mutations in _____ (encoding 'Huntingtin' protein) cause HD, but if you have the specific mutation you are certain to get the disease at some point (onset varies)

Protein degredation, mitochondrial function

PD genes encode proteins involved either in _________ ______________ pathways (e.g. Parkin, SNCA; hence Lewy body protein aggregates) or in _______________ __________ (e.g. PINK1, DJ-1)

Intracellular transport, poly-glutamine

The function of HTT protein remains unclear but its feature suggest it is involved in _______________ _________ - mutant HTT protein contains extended stretches of ______-____________ (polyQ) which contributes to aggregation of protein in 'inclusion bodies' in affected neurons

Funnel, filter

The basal ganglia act as a kind of. _________, to collect information from the prefrontal and motor cortices, and then as a _______ to decide which information to act upon, balancing the different inputs

5, 7

There is substantial input from many cortical areas, notably Areas _ and _, areas thought to be involved in perceptions of the body in space and time

That the 'decision to act' integrates sensory information about the body in the environment with planning information (Area 6 and Prefrontal) in course of initiating movement

What does the substantial input from many cortical areas suggest?

Upper motor neurons - no direct connections to spinal cord

What does the cerebellum modulate?

Learned execution of planned, voluntary, multijoint movements

What is the cerebellum required for?

Direction, timing, force, predictions, past experiences, motor learning

In ball throwing (ballistics):

Cerebellum appears to instruct motor cortex with respect to __________, _________ and _______ of movement

This is based on _____________ of outcomes (movements are usually too fast for fed back sensory information to be of immediate use)

Predictions are based on _____ ______________ of movements

Cerebellum also compares what is intended with what actually happens - ________ ____________

Cortex, corticopontocerebellar, sensory

The cerebellum receives massive input from many areas of the _________, ___________________ projection, and ___________ information from the spinal cord and vestibular system

Thalamus

In turn the cerebellum projects back to the motor cortex via the ______________ (VLc) but it has no direct output to the spinal cord

Detect and correct differences between the intended movement and the actual movement - the so-called motor error (it records the motor error detected and build it into its prediction for the next time you make the movement)

What is the primary function of the cerebellum?

Cerebellar ataxia

Lesions in the cerebellum result in _______________ __________, a condition characterised by poorly integrated movement

Dyssynergia

Even a simple task like touching your nose requires co-ordination of multiple muscles and joints in sequence - In ataxia this ability is lost, what is this called?

Alcohol intoxication

What has a similar affect to dyssynergia because it depressed cerebellar circuits?

Cerebellar ataxia, neuronal degeneration, Creutzfeld-Jacob Disease

The cerebellum is a major target in BSE (bovine spongiform encephalitis) which is characterised by _____________ _________

BSE is caused by __________ ______________ caused by a self-replicating protein called a prion

In humans this is called ____________-__________ ___________ (CJD)

Spinal motor units

The brain exerts control over ...?

Lower

Spinal motor neurons = _______ motor neurons

In brainstem and cortex

Where do upper motor neurons reside?

Motor neuron

________ _________ disease can affect either upper or lower motor neurons

Movement

Postural control is integrated with ...?

Anticipation

Different regions of the motor cortex initiate ____________

The basal ganglia

What initiates movement?

Neuronal degeneration

Huntington's chorea and Parkinson's disease result when ____________ _______________ affects different parts of the basal ganglia system

Motor actions

What is the cerebellum involved in perfecting?

Lewy bodies (intracellular protein aggregates)

Degeneration of dopaminergic neurons is marked by the presence of what?

The neurons that make it are dying

Dopamine loss here means reduction - DA levels fall over time because of what?