Parkinson's Disease - Reduced Features

1. Dopaminergic System (Core Deficit)

2. Biochemical Reductions Within Nigral Neurons

3. Other Neurotransmitter / Neurochemical Reductions

4. Structural / Cellular Reductions

5. Functional / Pathway Reductions

Summary Table at a Glance

Clinical Case Answer: Parkinson's Disease

i. Probable Diagnosis (1 mark)

ii. Pathophysiology with Diagram (6 marks)

Core Lesion

Normal Basal Ganglia Circuit

Cortex → Striatum → GPi (inhibit) → Thalamus disinhibited → Cortex excited → Movement initiated

Cortex → Striatum → GPe (inhibit) → Subthalamic Nucleus disinhibited → GPi excited → Thalamus inhibited → Movement suppressed

• D1 receptors on direct pathway neurons → excites them (facilitates movement)
• D2 receptors on indirect pathway neurons → inhibits them (reduces suppression of movement)

In Parkinson's Disease - Loss of Dopamine

Summary Flow:

↓ Dopamine (SNpc degeneration)
       ↓
Direct pathway ↓ + Indirect pathway ↑
       ↓
GPi OVERACTIVATED
       ↓
VA/VL Thalamus OVER-INHIBITED
       ↓
Motor Cortex UNDER-STIMULATED
       ↓
HYPOKINESIA / AKINESIA / BRADYKINESIA

iii. Physiological Basis of Hyperkinesia (3 marks)

"Decreased basal ganglia output leads to hyperkinesia, an excess of movement." - Neuroscience: Exploring the Brain, 5th Ed.

iv. Two Drugs Used to Reduce Hypokinesia (2 marks)

1. Levodopa (L-DOPA) + Carbidopa

• Levodopa is the dopamine precursor that crosses the blood-brain barrier and is converted to dopamine in surviving nigral neurons and striatum.
• Carbidopa is a peripheral decarboxylase inhibitor - prevents peripheral conversion of L-DOPA, reducing side effects and increasing CNS bioavailability.
• Most effective drug for hypokinesia/bradykinesia in PD.

1. Dopamine Agonists (e.g., Pramipexole, Ropinirole, Bromocriptine)

• Directly stimulate D2 (and D1/D3) receptors in the striatum, bypassing degenerating neurons entirely.
• Used as monotherapy in early PD or as adjuncts to levodopa in later stages.
• Reduce "off" time and improve motor function.

v. Type of Rigidity in Parkinson's vs UMN Lesion Rigidity (3 marks)

In Parkinson's Disease: Cogwheel Rigidity (type of Lead-Pipe/Plastic Rigidity)

Comparison: Cogwheel (PD) vs Clasp-Knife (UMN) Rigidity

"Spasticity is velocity dependent, has a sudden release after reaching a maximum (the 'clasp-knife' phenomenon)... Rigidity is hypertonia that is present throughout the range of motion ('lead pipe' or 'plastic' stiffness) and affects flexors and extensors equally; it sometimes has a cogwheel quality." - Harrison's Principles of Internal Medicine, 22e

Clinical Case Answer: Left-Sided Stroke / UMN Lesion

i. Probable Diagnosis (1 mark)

• 60-year-old hypertensive male (major risk factor for stroke)
• Acute onset weakness of right upper and lower extremities (right hemiplegia) = contralateral to the lesion, since the corticospinal tract crosses at the pyramidal decussation
• Increased tone + exaggerated jerks + extensor plantar = classic upper motor neuron (UMN) syndrome
• Presentation within 2 hours = acute stroke

ii. Increased Muscle Tone and Exaggerated Tendon Jerks (4 marks)

Mechanism of Increased Muscle Tone (Spasticity)

"Spasticity is caused by damage to descending inhibitory pathways that travel closely with the corticospinal tract. Loss of these descending inhibitory influences may lead to increased excitability of motor neurons in the anterior horn, resulting in brisk reflexes and increased tone." - Neuroanatomy through Clinical Cases, 3rd Ed.

Mechanism of Exaggerated Tendon Jerks (Hyperreflexia)

• Muscle spindle → Ia afferent → Spinal cord → Alpha motor neuron → Muscle contraction

iii. Why the Plantar Response is Altered (Extensor Plantar / Babinski Sign) (3 marks)

Normal Plantar Response

Altered (Extensor) Plantar Response - Babinski Sign

1. The corticospinal tract normally exerts tonic inhibitory control over spinal flexor withdrawal (nocifensive) reflex programs in the spinal cord.
2. When the corticospinal tract is damaged, this inhibitory control is released (disinhibited).
3. The primitive nociceptive flexor withdrawal reflex (also called "triple flexion response") is unmasked - this is a phylogenetically ancient protective spinal reflex.
4. The hallmark of this reflex is that what appears to be "extension" of the great toe is actually part of a limb withdrawal pattern: the big toe dorsiflexes (extends) while the ankle dorsiflexes and hip/knee flex - this is the body withdrawing the limb from a noxious stimulus.
5. The other toes fan outward (abduct) - completing the Babinski sign.

"The extension movement of the great toe is a component of a larger synergistic flexion or shortening reflex of the leg... These spinal flexion reflexes, of which the Babinski sign is the most characteristic, are present because of disinhibition or release of motor programs of spinal origin." - Adams and Victor's Principles of Neurology, 12th Ed.

iv. Corticospinal Tract - Description with Diagrams (5 marks)

Definition

Origin - Upper Motor Neurons

• Neurons are large layer V pyramidal cells
• ~3% are giant Betz cells - the largest neurons in the human nervous system
• Somatotopic organization follows the motor homunculus: face lateral, hand/arm middle, trunk and leg medial (dipping into longitudinal fissure)

Course of the Corticospinal Tract

Key Points for This Case

LEFT Motor Cortex (Area 4)
        ↓
Left Corona Radiata
        ↓
LEFT Posterior Limb of Internal Capsule  ← LESION HERE (stroke)
        ↓
Left Cerebral Peduncle
        ↓
Left Medullary Pyramid
        ↓
Pyramidal Decussation (85% cross)
        ↓
RIGHT Lateral Corticospinal Tract
        ↓
RIGHT Anterior Horn LMNs
        ↓
RIGHT Upper + Lower Limb Muscles → WEAKNESS

Summary of UMN vs LMN Signs

Clinical Case Answer: Parkinson's Disease

a. Provisional Diagnosis

b. Pathophysiological Basis with Diagram

Primary Lesion

Normal Basal Ganglia Circuit

Cortex → Striatum (GABA/Substance P) → inhibits GPi → GPi releases thalamus → Thalamus (VA/VL) excites Cortex → Movement facilitated

Cortex → Striatum (GABA/enkephalin) → inhibits GPe → GPe releases STN → STN excites GPi → GPi inhibits thalamus → Movement suppressed

• Acts on D1 receptors on direct pathway neurons → excites them (↑ movement facilitation)
• Acts on D2 receptors on indirect pathway neurons → inhibits them (↓ movement suppression)
• Net result = dopamine promotes voluntary movement via both pathways

In Parkinson's Disease - Loss of Dopamine

↓ Dopamine (SNpc degeneration)
         ↓
Direct pathway ↓ + Indirect pathway ↑
         ↓
GPi (globus pallidus interna) OVERACTIVE
         ↓
VA/VL Thalamus OVER-INHIBITED
         ↓
Motor Cortex UNDER-STIMULATED (especially SMA)
         ↓
AKINESIA / BRADYKINESIA / HYPOKINESIA

"Depletion of dopamine in Parkinson's disease closes the funnel that feeds activity to cortical area SMA via the basal ganglia and VL thalamus." - Neuroscience: Exploring the Brain, 5th Ed.

c. Physiological Basis of Hypokinesia

Step-by-step mechanism:

• Dopamine normally stimulates D1 receptors on striatal neurons of the direct pathway
• Without dopamine, D1 stimulation ↓ → direct pathway neurons fire less
• Less GABA released onto GPi → GPi is less inhibited → GPi fires more

• Dopamine normally inhibits D2 receptors on indirect pathway striatal neurons
• Without dopamine, D2 inhibition is lost → indirect pathway neurons fire more
• More GABA released onto GPe → GPe is more inhibited → GPe fires less
• Less GPe inhibition on STN → STN fires more
• More STN excitation of GPi → GPi fires even more

• An overactive GPi sends excessive GABA-ergic inhibitory output to the VA/VL nuclei of the thalamus
• Thalamo-cortical relay neurons are suppressed

• The supplementary motor area (SMA) receives reduced thalamic input
• SMA is critically important for self-initiated (internally cued) movements - e.g., deciding to start walking or brushing teeth
• With reduced SMA activation, voluntary movement initiation fails → hypokinesia / akinesia

• The SMA is impaired for internally-generated, self-paced movement
• Externally-cued movements (responding to a visual cue on the floor, or marching to music) can be relatively preserved because they bypass the basal ganglia via the cerebellum
• Without proper stride length regulation, the patient takes increasingly rapid, short shuffling steps to compensate for a forward-displaced centre of gravity → festinant (hastening) gait

"Enhanced conduction through the indirect pathway leads to hypokinesia by increasing pallidothalamic inhibition... In Parkinson disease, a loss of dopaminergic input from the substantia nigra diminishes activity in the direct pathway and increases activity in the indirect pathway; the net effect is to increase inhibition of the thalamic nuclei and to reduce excitation of the cortical motor system." - Adams and Victor's Principles of Neurology, 12th Ed.

d. Physiological Basis of Tremor

Classic Features:

• "Pill-rolling" tremor of thumb and fingers
• Suppressed during voluntary movement (action)
• Worsens with stress or distraction
• Disappears during sleep

Mechanism - Oscillatory Loop Hypothesis:

Summary - Tremor Circuit:

↓ Dopamine
    ↓
STN overactive → rhythmic burst firing (4-6 Hz)
    ↓
GPi oscillates
    ↓
Thalamus (VA/VL) oscillates
    ↓
Motor cortex driven rhythmically
    ↓
Alternating agonist/antagonist contraction
    ↓
RESTING TREMOR (pill-rolling, 4-6 Hz)
    ↓
Stopped by voluntary movement (sensory feedback + cerebellar override)

Summary Table: Key Pathophysiological Mechanisms

Physiological Basis of Tremor in Parkinson's Disease (3 Marks)

Definition and Character

Physiological Mechanism

Step-by-Step Basis:

Why Tremor Stops During Voluntary Movement?

• The motor cortex generates a strong, purposeful command that overrides the oscillatory thalamic input
• Active limb movement generates sensory (proprioceptive) feedback that disrupts the re-entrant oscillatory loop
• The intact cerebellum provides real-time error correction and damping during movement

Summary Diagram:

↓ Dopamine (SNpc degeneration)
          ↓
STN overactive → synchronous rhythmic bursts (4-6 Hz)
          ↓
GPi oscillates (4-6 Hz)
          ↓
VA/VL Thalamus → rhythmic rebound firing
          ↓
Motor Cortex → pulsatile motor commands
          ↓
Alternating agonist/antagonist contractions
          ↓
RESTING TREMOR - "pill-rolling" (4-6 Hz)
          ↓ (voluntary movement)
Sensory feedback + cortical override → TREMOR STOPS

Types of Tremor - Comparison for Context