Basal Ganglia and Parkinsonism — 15 Marks

A. BASAL GANGLIA

1. Components (Anatomical Parts)

2. Connections (Circuitry)

• Direct pathway: Striatum ⊣(GABA) GPi/SNpr ⊣(GABA) Thalamus → Cortex. Net effect: disinhibits thalamus → excites motor cortex → facilitates movement.
• Indirect pathway: Striatum ⊣(GABA) GPe ⊣(GABA) STN →(glutamate, excitatory) GPi/SNpr ⊣(GABA) Thalamus → Cortex. Net effect: has an extra inhibitory relay → inhibits thalamus → suppresses movement.

3. Functions

• Planning and smooth execution of voluntary movement (working with the cortex and cerebellum)
• Regulation of muscle tone and posture
• Suppression of unwanted/competing movements
• Contribution to cognitive functions (procedural learning, working memory) and affective/limbic functions (via ventral striatum - nucleus accumbens)
• Contains no direct connection to lower motor neurons; it acts entirely by modulating cortical output through the thalamus.

B. PARKINSONISM

1. Definition

2. Pathophysiology

• Core lesion: progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, with loss of the nigrostriatal dopamine pathway. Motor symptoms appear once striatal dopamine falls by ~60-80%.
• Pathological hallmark: intracytoplasmic inclusions called Lewy bodies, composed of aggregated α-synuclein; PD is now regarded as a synucleinopathy. Braak staging shows pathology beginning in the olfactory bulb/medulla (stage 1-2, causing pre-motor hyposmia, constipation, REM sleep behaviour disorder), reaching the substantia nigra at stage 3 (onset of motor features), and later the cortex (stages 5-6, causing dementia) - Katzung's Basic and Clinical Pharmacology, p. 282-297.
• Etiology: mostly idiopathic; genetic forms involve SNCA (α-synuclein), PARK2 (parkin), LRRK2, PINK1 genes; secondary causes include drugs (dopamine receptor blockers/antipsychotics), toxins (MPTP, manganese, CO), post-encephalitic states, and vascular (multi-infarct) parkinsonism.
• Circuit consequence of dopamine loss: Loss of nigrostriatal dopamine removes the normal facilitation of the direct pathway (D1) and disinhibition of the indirect pathway (D2). Net result:
• Indirect pathway becomes overactive → excessive inhibition of thalamus.
• Direct pathway becomes underactive → reduced facilitation of thalamus.
• Both changes converge to excessively inhibit the thalamocortical projection, reducing excitatory drive to the motor cortex → bradykinesia/akinesia and rigidity.
• There is also a relative cholinergic excess in the striatum (since dopamine normally restrains striatal cholinergic interneurons), contributing to tremor and rigidity - hence anticholinergic drugs help.

3. Clinical Features

1. Tremor - 4-6 Hz "pill-rolling" rest tremor, decreases with voluntary movement
2. Rigidity - "lead-pipe" or "cogwheel" rigidity
3. Akinesia/Bradykinesia - slowness in initiation and execution of movement, micrographia, hypomimia (masked facies), hypophonia
4. Postural instability - stooped/flexed posture, shuffling festinant gait, loss of postural reflexes, freezing episodes

• Asymmetrical onset
• Reduced arm swing while walking
• Non-motor features: anosmia, constipation, REM sleep behaviour disorder, depression/anxiety, autonomic dysfunction (orthostatic hypotension, sialorrhea, sphincter disturbance), cognitive decline/dementia in advanced disease - Bradley and Daroff's Neurology in Clinical Practice, p. 2323-2424; Katzung's Basic and Clinical Pharmacology, p. 282.

4. Treatment

• Deep Brain Stimulation (DBS) of subthalamic nucleus or GPi - for advanced disease with motor fluctuations refractory to medical therapy, or disabling tremor
• Physiotherapy, speech therapy, occupational therapy, and exercise programs
• Supportive care for non-motor symptoms (antidepressants, management of autonomic dysfunction)
• Katzung's Basic and Clinical Pharmacology, p. 299-322.

Summary Diagram for Answer

Hypothalamus - Functions in Detail

Location and Overview

1. Autonomic Nervous System Regulation

• Posterior and lateral hypothalamus - stimulation raises heart rate and arterial blood pressure (sympathetic effects)
• Preoptic/anterior hypothalamus - stimulation lowers heart rate and blood pressure (parasympathetic effects)
• These effects act via cardiovascular centers in the pontine and medullary reticular formation - Guyton and Hall Textbook of Medical Physiology, p. 734.

2. Body Temperature Regulation

• Anterior hypothalamic-preoptic area contains heat-sensitive and cold-sensitive neurons that directly sense blood temperature. Heating this area triggers sweating and cutaneous vasodilation to lose heat; cooling triggers vasoconstriction and shivering to conserve/produce heat.
• Posterior hypothalamus integrates signals from peripheral skin thermoreceptors with the anterior hypothalamic thermostat and coordinates heat-conserving/heat-producing responses (shivering, vasoconstriction) - Guyton and Hall Textbook of Medical Physiology, p. 896.

3. Regulation of Water Balance and Thirst

• Osmoreceptors in the hypothalamus near the supraoptic nuclei detect plasma osmolality; increased osmolality stimulates ADH (vasopressin) synthesis in the supraoptic nucleus, transported down axons to the posterior pituitary for release, promoting renal water reabsorption.
• The hypothalamus also generates the thirst sensation, driving water-seeking behaviour.

4. Control of Feeding and Energy Balance

• Lateral hypothalamic area = "feeding/hunger center" - stimulation causes voracious appetite; bilateral destruction causes anorexia and starvation.
• Ventromedial nucleus = "satiety center" - stimulation abolishes hunger; bilateral destruction causes hyperphagia and obesity.
• Arcuate nucleus contains orexigenic (NPY/AgRP) and anorexigenic (POMC/CART) neurons that integrate leptin, ghrelin, and insulin signals to regulate appetite and energy expenditure.
• Mammillary bodies partially control feeding reflexes such as licking and swallowing - Guyton and Hall Textbook of Medical Physiology, p. 735.

5. Endocrine Control

• TRH → TSH; CRH → ACTH; GnRH → LH/FSH; GHRH and somatostatin → GH; dopamine (PIH) → inhibits prolactin.

• ADH (vasopressin) from the supraoptic nucleus - water reabsorption, vasoconstriction.
• Oxytocin from the paraventricular nucleus - uterine contraction during labor and milk ejection reflex during breastfeeding - Guyton and Hall Textbook of Medical Physiology, p. 735.

6. Circadian Rhythm Control

7. Emotional and Behavioral Responses

• Generates the visceral/somatic expressions of emotion - rage, fear, aggression, pleasure (stimulation of specific nuclei can provoke defensive/attack behaviour or reward-seeking behaviour).
• Regulates sexual behaviour and reproductive drive via connections with the anterior pituitary gonadotropins and limbic structures.
• Mammillary bodies form part of the Papez circuit, contributing to memory consolidation (their bilateral damage, as in Wernicke-Korsakoff syndrome, causes amnesia).

8. Regulation of Sexual and Reproductive Function

9. Gastrointestinal Regulation

Quick Summary Table

Anatomy of the Ear and Mechanism of Hearing - 15 Marks

A. PARTS OF THE EAR

1. External (Outer) Ear

• Pinna (auricle): cartilaginous flap that collects sound waves and funnels them into the canal
• External auditory meatus (canal): conducts sound to the tympanic membrane; outer 1/3 cartilaginous, inner 2/3 bony; lined by skin with ceruminous (wax) glands
• Tympanic membrane (eardrum): thin, cone-shaped membrane separating external from middle ear; vibrates in response to sound pressure waves

2. Middle Ear (Tympanic Cavity)

• Ossicles: malleus (attached to tympanic membrane), incus, and stapes (footplate fits into the oval window) - form a lever chain that transmits vibration from the eardrum to the inner ear fluid
• Muscles: tensor tympani (keeps tympanic membrane taut) and stapedius (dampens excessive ossicular movement - protective reflex)
• Eustachian (auditory) tube: connects middle ear to nasopharynx, equalizes air pressure across the tympanic membrane
• Oval window (receives stapes footplate) and round window (relieves fluid pressure)

3. Internal (Inner) Ear

• Cochlea - organ of hearing, a coiled tube of 2.5 turns divided into three fluid-filled scalae:
• Scala vestibuli (perilymph, continuous with oval window)
• Scala media/cochlear duct (endolymph, contains the organ of Corti)
• Scala tympani (perilymph, ends at round window)
• Separated by Reissner's membrane (between scala vestibuli and media) and basilar membrane (between scala media and tympani)
• Organ of Corti - the actual sensory receptor organ, sitting on the basilar membrane, containing:
• Inner hair cells (~3,500, single row) - primary sound transducers (90-95% of afferent auditory nerve fibers synapse here)
• Outer hair cells (~12,000, 3-4 rows) - mainly modulate/"tune" cochlear sensitivity
• Tectorial membrane overlying the stereocilia of hair cells
• Supporting (Deiters') cells, rods/pillars of Corti forming the reticular lamina
• Vestibular apparatus (semicircular canals, utricle, saccule) - balance, not hearing
• Guyton and Hall Textbook of Medical Physiology, p. 656-659.

B. MECHANISM OF HEARING

1. Conduction of Sound (External and Middle Ear)

• The pinna collects sound waves and channels them through the external auditory meatus to vibrate the tympanic membrane.
• The malleus, incus, and stapes act as a connected lever system: movement of the tympanic membrane moves the malleus, which moves the incus, which moves the stapes footplate against the oval window.

• The lever action of the malleus-incus increases force by about 1.3 times.
• The tympanic membrane's surface area (~55 mm²) is about 17 times larger than the stapes footplate (~3.2 mm²), concentrating the same total force onto a smaller area.
• Combined effect: about 22 times greater force is delivered to the cochlear fluid than would occur from sound striking fluid directly, giving 50-75% efficient impedance matching for frequencies between 300-3000 Hz - Guyton and Hall Textbook of Medical Physiology, p. 656.
• The tensor tympani and stapedius muscles contract reflexively (acoustic reflex) with loud sounds to reduce ossicular movement and protect the inner ear.

2. Cochlear Mechanics - the "Traveling Wave"

• Inward movement of the stapes at the oval window creates a pressure wave in the perilymph of the scala vestibuli.
• This pressure wave displaces the basilar membrane, creating a traveling wave that moves from the base toward the apex of the cochlea.
• The basilar membrane is narrow and stiff at the base (near the oval window) and wide and flexible at the apex - this graded stiffness means:
• High-frequency (high-pitch) sounds cause maximum vibration near the base
• Low-frequency (low-pitch) sounds cause maximum vibration near the apex
• This spatial separation of frequencies along the basilar membrane is called tonotopic organization, and it is the basis of place theory of pitch discrimination - Guyton and Hall Textbook of Medical Physiology, p. 656-658.
• Pressure is finally relieved through the round window, bulging into the middle ear.

3. Transduction by the Organ of Corti (Hair Cell Excitation)

• Vibration of the basilar membrane moves the rigid unit of basilar fibers, rods of Corti, and reticular lamina.
• This shears the stereocilia of the hair cells against the overlying tectorial membrane.
• Bending of stereocilia toward the modiolus (or in the excitatory direction) opens mechanically-gated ion channels, causing depolarization (K+/Ca2+ influx from endolymph, which has a high positive potential); bending in the opposite direction causes hyperpolarization.
• Depolarization of hair cells triggers neurotransmitter (glutamate) release at their base, generating action potentials in the afferent fibers of the cochlear nerve (CN VIII).
• About 90-95% of afferent fibers arise from inner hair cells (primary sound detection), while outer hair cells mostly receive efferent fibers and act as a "cochlear amplifier," fine-tuning sensitivity and frequency selectivity by actively changing their length/stiffness - Guyton and Hall Textbook of Medical Physiology, p. 659.

4. Neural Pathway (Central Processing)

Summary Flow Diagram (for exam)

Thalamus - Connections, Functions, and Thalamic Syndrome

A. Overview

B. Major Thalamic Nuclei and Their Connections

C. Functions of the Thalamus

1. Sensory relay station - relays and processes all somatosensory (touch, pain, temperature, proprioception via VPL/VPM), visual (LGB), and auditory (MGB) information en route to the cortex. Even after destruction of the somatosensory cortex, the thalamus retains a crude ability to perceive pain and temperature, showing it is not merely a passive relay but has an independent discriminative role, especially for pain and temperature sensation - Guyton and Hall Textbook of Medical Physiology, p. 606.
2. Motor relay - relays basal ganglia (globus pallidus) and cerebellar output to the motor and premotor cortex (VA/VL nuclei), essential for planning and coordination of movement.
3. Integration and association - the pulvinar and association nuclei integrate multimodal sensory information for higher cognitive processing (language, visuospatial function).
4. Consciousness and arousal - intralaminar and reticular nuclei are part of the ascending reticular activating system, maintaining wakefulness and attention; the reticular nucleus gates thalamocortical transmission.
5. Emotion and memory - anterior and dorsomedial nuclei connect the limbic system (mammillary bodies, hippocampus, amygdala) with the cingulate and prefrontal cortex, contributing to memory (Papez circuit) and emotional/behavioural regulation.
6. Pain perception - crude, poorly localized pain and temperature sensation is appreciated at thalamic level itself (hence the marked pain seen with thalamic lesions).
7. Coordination between cortical areas - via diffuse and specific thalamocortical projections, synchronizing activity across different cortical regions (thalamocortical oscillations relevant to sleep and consciousness).

D. Note on Thalamic Syndrome (Dejerine-Roussy Syndrome)

• Contralateral hemianesthesia - dense loss of all sensory modalities on the side of the body opposite the lesion; may be dissociated, i.e., pain/temperature and touch/vibration can be affected separately depending on which fiber tracts are involved
• Thalamic pain (central post-stroke pain) - severe, disagreeable, often burning or lancinating spontaneous pain, or pain evoked by minor stimuli (allodynia/hyperpathia), typically appearing weeks to months after the acute sensory loss resolves; classically resistant to standard analgesics
• Astereognosis and loss of proprioception due to involvement of deep sensory pathways
• Distorted taste sensation may occur
• A transient hemiparesis can occur if the lesion extends to affect adjacent internal capsule fibers
• Mild choreoathetoid movements or thalamic hand posturing may be seen in some cases (not always present)

• Bradley and Daroff's Neurology in Clinical Practice, p. 352.