Part II · Chapter 7 · Lectures 5 & 6

Neurodegeneration & the basal ganglia

Cerebellar ataxia, Parkinson's, Huntington's and Alzheimer's — for each: cause, brain area, symptoms, and what it taught us about the healthy brain. The centrepiece is the go / no-go circuit, which you should be able to trace arrow by arrow.

1. Neural degeneration

Definition Neural degeneration — progressive loss of structure and function, and death, of neurons in the nervous system. Causes include genes, environmental toxins and autoimmune processes.

Disease	Where	Cause	Onset / course	Hallmark
Cerebellar degeneration	Cerebellum	Often hereditary (autosomal dominant & recessive; ~40 types)	—	Ataxia
Parkinson's	Dopamine neurons of the substantia nigra → basal ganglia "go" pathway	Not fully understood; mostly sporadic, not inherited; pesticides; multiple strokes	40–80 yrs; progresses over 10–20 yrs	Bradykinesia, rigidity, tremor at rest, loss of righting reflex
Huntington's	Striatum → "no-go" pathway	Genetic mutation	~40 yrs; 10–15 yrs	Chorea, dementia
Alzheimer's	Global; heavy hippocampal degeneration	Amyloid plaques + tau tangles	Gradual, 60–80 yrs	Dementia; can't form new memories

Heads-up — sources disagree The L5 study guide says Alzheimer's onset is "40–60 years old". Both lecture slide decks (L5 and L6) say gradual onset at 60–80. Go with the slides, and if an exam question hinges on it, it will almost certainly use the slides' number.

2. The cerebellum and ataxia

The cerebellum is often neglected, but it contains more than 80% of the neurons in the brain. Its degeneration (usually hereditary) causes ataxia: uncoordinated movement — under- and overshooting targets.

The lecture asks you to think at Marr's algorithmic level: what does the cerebellum compute, such that losing it produces overshooting? The answer: it generates sensory predictions — the predicted sensory outcome of a movement. Sensory feedback is slow; by the time you feel where your hand is, it has moved on. A prediction lets you plan the next correction without waiting.

Reaching with delayed feedback — with and without a cerebellum

Feedback delay (ms) Cerebellar prediction

What to notice: with prediction on, the hand glides to the target whatever the delay. Untick it, and the controller acts on where the hand was — it keeps pushing after it has arrived, overshoots, over-corrects, and oscillates. Drag the delay up to watch ataxia get worse; drag it to 0 and prediction stops mattering. Toy control model.

Two everyday demos You can't tickle yourself: your brain predicts the sensation from your own movement and cancels it. The heavy-object demo: when someone else lifts a heavy book off your hand, your hand jumps up; when you lift it off, your hand stays still — because you predicted the change.

3. The basal ganglia: go and no-go

The basal ganglia decide how vigorously to move. They do it with a chain of inhibitions, which is why the logic feels backwards. The one rule to hold on to: the GPi (globus pallidus internal) is a brake on the thalamus, and the thalamus excites the cortex to move. Everything else either presses or releases that brake.

Analogy The thalamus is a car that wants to go; the GPi is the handbrake, always partly on. The go pathway releases the handbrake. The no-go pathway pulls it harder. Dopamine is the driver's foot favouring "go". Where it leaks: a real handbrake isn't made of a chain of three inhibitory links — the double negatives are what you must trace by hand.

Basal-ganglia circuit simulator

Dopamine level Huntington's (lose no-go striatal neurons) DBS to GPi STN damage

Violet arrows excite; pink bar-ended lines inhibit. Box shading = activity relative to healthy (1.00). What to notice: Parkinson's and Huntington's end up at opposite ends of the movement meter by breaking different pathways that converge on the same GPi brake. Toy rate model; the dopamine → no-go (D2) link is standard textbook physiology that the slides don't draw.

Trace it by hand: Parkinson's

The lecture's chain, one arrow at a time:

Loss of dopamine neurons in the substantia nigra → less excitatory dopamine input to the striatum
→ striatum less activated
→ less inhibition of the GPi (so the GPi is more active)
→ more inhibition of the thalamus
→ less excitatory input to cortex → less vigorous movement.

PD cardinal symptom	What it looks like
Bradykinesia	Slowness of movement (extreme form: freezing of gait)
Rigidity	Stiffness
Tremor at rest	~3 Hz, goes away with purposeful movement
Loss of righting reflex	Can't recover balance when pushed

Two treatments and their problems

Solution 1 — L-dopa Adds dopamine to the system (a precursor the brain converts into dopamine). Problem: over time it causes dyskinesia — involuntary movements from irregular activity along the go pathway. Why (L6): (1) unnatural dopamine influx; (2) dopamine receptor sensitization — after excess L-dopa, receptors are over-stimulated/malfunction so that small amounts of dopamine now trigger involuntary movement. Try "Too much L-dopa" above.

Solution 2 — Deep brain stimulation (DBS) Stimulation to the GPi shuts off the GPi → less inhibition of the thalamus → more excitatory input to cortex → movement is invigorated. It skips the missing dopamine entirely by releasing the brake directly.

Huntington's: the no-go pathway breaks

The lecture's exercise: "What happens if I lesion the striatum — more or less movement?" In Huntington's, the striatal neurons lost are the ones driving the no-go (indirect) pathway, whose normal job is to inhibit movement. The chain:

Loss of striatal neurons → less inhibition of GPe (GPe more active)
→ STN more inhibited
→ less excitation of GPi
→ less inhibition of thalamus → more involuntary movement.

Result: chorea ("to dance") — involuntary, irregular muscle movements, a special type of dyskinesia — plus dementia (global cognitive deficits).

Common mistake Answering "less movement" because "damage = less". Here the damaged thing is a brake, so damage means more movement. Always count the inhibitory links: an even number of inhibitions between the lesion and the thalamus flips the sign an even number of times.

Hemiballismus Demyelination (loss of myelin) of basal-ganglia circuitry can cause severe dyskinesia: hemiballismus — a rare disorder of sudden, large-amplitude, flinging movements of one side of the body. going deeper Classically from damage to the STN; tick "STN damage" in the simulator — with its excitation of the GPi gone, the brake falls off.

Try itPredict a lesion you haven't seen

Suppose a drug selectively silences the GPe. More or less movement?

Step 1 — What does GPe normally do?

GPe inhibits the STN.

Step 2 — Follow the chain

GPe silenced → STN released (more active) → STN excites GPi more → GPi brakes the thalamus harder → less cortical excitation.

Answer & the takeaway

Less movement (Parkinson-like). The skill: find the GPi, then count signs. Anything that ends up raising GPi activity reduces movement; anything that lowers it increases movement.

4. Alzheimer's disease

Global neurodegeneration causing dementia (global cognitive deficits), gradual onset at 60–80. Two molecular culprits — learn which is between and which is inside neurons:

Plaques outside, tangles inside

Alzheimer's hits the hippocampus especially hard — and that tells us what the hippocampus is for. The lecture's question: what has Alzheimer's taught us about memory? Consider dissociations between impaired and intact abilities.

Memory type	In Alzheimer's	Definition & example
Working memory	✓ Intact	Temporarily hold and manipulate small amounts of info — a phone number long enough to dial it
Long-term memory	✓ Intact	Well-consolidated memories from the past — childhood events, family names
"Short-term" memory (course's term)	✗ Impaired	Forming and retaining new memories over minutes to hours — a recent conversation, where you put your keys

Watch the terminology In this course "short-term memory" means forming new memories over minutes–hours, which is what fails. Many textbooks use "short-term memory" to mean what this course calls working memory — which is intact. On the exam, use the course's definitions.

Try it"How do you rule out general effects of neurodegeneration?" (L6 asks, never answers)

Alzheimer's damages much of the brain. How can you claim the hippocampus is specifically for forming new memories, rather than the patients just being generally impaired?

Step 1 — Which weakness is this?

The "general impairment" weakness of a single measure (Ch. 5).

Step 2 — What rules it out?

The spared abilities. Working memory and old long-term memory are intact in the same patients — generally impaired patients wouldn't be fine on those. That's a dissociation.

Answer & the takeaway

Show intact performance on comparably demanding tasks (dissociation), and ideally find the reverse pattern elsewhere (double dissociation). Also match task difficulty so the spared tasks aren't just easier — avoid ceiling effects. The same logic from Ch. 5, applied to a disease.

The humanities side: philosopher Iris Murdoch described Alzheimer's as "an insidious fog, barely noticeable until everything around has disappeared." Artist William Utermohlen (diagnosed 1995) painted self-portraits that document the disease's gradual effects.

5. Check yourself

DBS of the GPi helps Parkinson's because it…

Why: PD's problem is a GPi that brakes the thalamus too hard; DBS takes the brake off. The second option is the disease, not the cure. L-dopa is the dopamine one.

Which disease is mostly sporadic, not inherited?

Why: Huntington's is a genetic mutation; cerebellar degeneration is often hereditary (~40 types). PD is mostly sporadic, linked to things like pesticides and multiple strokes.

A patient with a hereditary condition overshoots and undershoots when reaching and can't touch their nose smoothly. Most likely affected:

Why: Over/undershooting = ataxia = cerebellar degeneration (often hereditary). PD would be slow and small movements, not overshooting.

Tau tangles are found ___ neurons in Alzheimer's, and tau build-up in the frontal cortex also characterizes ___.

Why: Plaques (amyloid) are between; tangles (tau) are inside. CTE (Ch. 6) is the other tau disease in this course.

An Alzheimer's patient can repeat back a 7-digit number instantly and describe their wedding day, but can't remember what they ate an hour ago. This shows…

Why: Some memory abilities are spared while one fails — exactly the dissociation the lecture asks about. Spared abilities are what argue against general impairment.