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PY10.1-20 | Central Nervous System Physiology — Part 1

Foundations — CNS Organisation, Synapses, Neurotransmitters, Reflexes, and Receptors (PY10.1–PY10.6)

The central nervous system consists of the brain (cerebrum, diencephalon, brainstem, cerebellum) and the spinal cord. The peripheral nervous system includes all nerves and ganglia outside the CNS. Functionally, the PNS is divided into the somatic nervous system (voluntary, skeletal muscle) and the autonomic nervous system (involuntary, smooth muscle, cardiac muscle, glands). The ANS has two divisions: the sympathetic (thoracolumbar outflow, T1-L2) and parasympathetic (craniosacral outflow, CN III, VII, IX, X + S2-S4). A third division, the enteric nervous system (Meissner's and Auerbach's plexuses in the gut wall), operates semi-independently.

Figure: Foundations — CNS Organisation, Synapses, Neurotransmitters, Reflexes, and Receptors (PY10.1–PY10.6)

The sympathetic system uses short preganglionic fibres (cholinergic, nicotinic) and long postganglionic fibres (adrenergic, releasing noradrenaline). The parasympathetic system uses long preganglionic fibres (cholinergic, nicotinic) and short postganglionic fibres (cholinergic, muscarinic). The adrenal medulla is a modified sympathetic ganglion that releases adrenaline (80%) and noradrenaline (20%) directly into the blood — the basis of the fight-or-flight response.

Neurotransmitters (PY10.3) are classified by chemical structure into several groups. Acetylcholine (ACh) is the transmitter at all preganglionic autonomic synapses, the neuromuscular junction, and parasympathetic postganglionic endings. It is synthesised from choline and acetyl-CoA by choline acetyltransferase and degraded by acetylcholinesterase. Catecholamines — dopamine, noradrenaline, and adrenaline — share a common synthetic pathway: tyrosine is converted to DOPA by tyrosine hydroxylase (rate-limiting step), then to dopamine by DOPA decarboxylase, then to noradrenaline by dopamine beta-hydroxylase, and finally to adrenaline by PNMT (only in the adrenal medulla). Serotonin (5-HT) is derived from tryptophan. GABA is the principal inhibitory transmitter of the brain (synthesised from glutamate by GAD). Glutamate is the principal excitatory transmitter. Glycine is the main inhibitory transmitter in the spinal cord and brainstem. Other transmitters include histamine, neuropeptides (substance P, endorphins, enkephalins), nitric oxide, and purines (ATP, adenosine).

The synapse (PY10.4) is the junction between two neurons (or a neuron and an effector). Synapses are classified anatomically as axo-dendritic, axo-somatic, or axo-axonic. Functionally, they are excitatory or inhibitory. Electrically, they can be chemical (majority, unidirectional, synaptic delay of 0.5 ms, modifiable) or electrical (gap junctions, bidirectional, no delay, found in cardiac muscle and some brain circuits). Chemical synaptic transmission follows a sequence: action potential arrives at the presynaptic terminal, voltage-gated Ca2+ channels open, Ca2+ influx triggers vesicle fusion (SNARE proteins), neurotransmitter is released into the cleft, binds to postsynaptic receptors, and generates a postsynaptic potential. EPSPs depolarise toward threshold; IPSPs hyperpolarise away from threshold. Spatial summation (multiple synapses firing simultaneously) and temporal summation (one synapse firing rapidly) determine whether the postsynaptic neuron fires. This is the basis of neural integration.

Reflexes (PY10.5) are involuntary, stereotyped responses to stimuli. The basic unit is the reflex arc: receptor, afferent neuron, integration centre (spinal cord or brainstem), efferent neuron, and effector. Reflexes are classified as monosynaptic (stretch reflex — only one synapse, e.g., knee jerk) or polysynaptic (withdrawal reflex — multiple interneurons). They can be somatic (skeletal muscle) or autonomic (visceral). They can be superficial (plantar reflex), deep (tendon jerks), or visceral (pupillary light reflex). The stretch reflex (myotatic reflex) is clinically the most important: tapping the tendon stretches the muscle spindle, the Ia afferent fires, the alpha motor neuron is excited monosynaptically, and the muscle contracts. Simultaneously, the antagonist is inhibited via an inhibitory interneuron (reciprocal inhibition). The Golgi tendon reflex (inverse myotatic reflex) uses Ib afferents from Golgi tendon organs: when tension is excessive, the agonist is inhibited and the antagonist is facilitated — a protective mechanism against muscle tear. The withdrawal (flexor) reflex is polysynaptic and involves crossed extension: the stimulated limb flexes (withdrawal) while the opposite limb extends (to maintain balance).

Receptors (PY10.6) are specialised structures that convert stimuli into nerve impulses (transduction). They are classified by stimulus type: mechanoreceptors (touch, pressure, vibration, proprioception), thermoreceptors (warmth, cold), nociceptors (pain), photoreceptors (light), and chemoreceptors (taste, smell, blood gas). By location: exteroceptors (skin surface), proprioceptors (muscles, joints, inner ear), and interoceptors (viscera). By adaptation: rapidly adapting (Meissner's corpuscles — detect change) and slowly adapting (Merkel's discs — detect sustained pressure). The adequate stimulus is the form of energy to which a receptor has the lowest threshold. Receptors encode stimulus intensity by frequency coding (stronger stimulus = higher firing rate) and population coding (stronger stimulus = more receptors recruited). The generator potential (or receptor potential) is a graded, non-propagating depolarisation at the receptor ending — when it reaches threshold, it triggers action potentials in the afferent nerve.

Sensory Pathways — Ascending Tracts and Their Clinical Correlates (PY10.7)

Somatic sensation is carried from the body to the cerebral cortex by two major ascending systems. Understanding these two pathways is one of the most clinically powerful skills you will learn — it allows you to localise spinal cord lesions from the bedside examination alone.

Figure: Sensory Pathways — Ascending Tracts and Their Clinical Correlates (PY10.7)

The Dorsal Column-Medial Lemniscus (DCML) Pathway carries fine touch, vibration, two-point discrimination, and conscious proprioception (position sense). The pathway has three neurons. The first-order neuron has its cell body in the dorsal root ganglion (DRG). Its peripheral process receives stimuli from mechanoreceptors (Meissner's corpuscles, Pacinian corpuscles, Merkel's discs, Ruffini endings, muscle spindles, joint receptors). Its central process enters the spinal cord and ascends ipsilaterally in the dorsal columns — fibres from the lower limb travel in the fasciculus gracilis (medial), while fibres from the upper limb travel in the fasciculus cuneatus (lateral). The first-order neuron synapses in the nucleus gracilis or nucleus cuneatus in the lower medulla. The second-order neuron arises here, crosses the midline as the internal arcuate fibres (decussation of the medial lemniscus), and ascends through the brainstem as the medial lemniscus to synapse in the ventral posterolateral (VPL) nucleus of the thalamus. The third-order neuron projects from VPL through the posterior limb of the internal capsule to the primary somatosensory cortex (postcentral gyrus, Brodmann areas 3, 1, 2).

Key clinical point: DCML fibres ascend ipsilaterally before crossing in the medulla. Therefore, a spinal cord lesion affecting the dorsal column causes ipsilateral loss of fine touch and proprioception below the level of the lesion.

The Anterolateral System (Spinothalamic Tracts) carries pain, temperature, and crude (non-discriminative) touch. Again, three neurons. The first-order neuron (DRG) enters the spinal cord and synapses in the dorsal horn (substantia gelatinosa, Rexed laminae I, II, V). The second-order neuron crosses the midline within one or two segments via the anterior white commissure and ascends in the anterolateral white matter. The lateral spinothalamic tract carries pain and temperature; the anterior spinothalamic tract carries crude touch and pressure. The second-order neuron synapses in VPL of the thalamus (and also in the posterior group and intralaminar nuclei for the affective component of pain). The third-order neuron projects to the somatosensory cortex.

Key clinical point: Spinothalamic fibres cross within the spinal cord near their level of entry. Therefore, a spinal cord lesion affecting the anterolateral column causes contralateral loss of pain and temperature beginning one or two segments below the lesion.

This difference in crossing levels is the entire basis of Brown-Sequard syndrome (PY10.10). In a hemisection of the spinal cord, you get ipsilateral loss of DCML modalities (fine touch, proprioception, vibration) and contralateral loss of pain and temperature — because the two pathways cross at different levels.

Other ascending tracts worth knowing include the dorsal spinocerebellar tract (unconscious proprioception from the lower limb via Clarke's column, enters the cerebellum through the inferior cerebellar peduncle) and the ventral spinocerebellar tract (crosses twice, enters via the superior cerebellar peduncle). These tracts do not reach consciousness — they provide proprioceptive data to the cerebellum for coordination.

The somatosensory cortex has a somatotopic map (sensory homunculus) where the size of each body region's representation is proportional to its sensory receptor density — the lips, tongue, and fingertips have disproportionately large representations. The primary somatosensory cortex (S1) identifies the location and modality of sensation. The somatosensory association cortex (areas 5, 7) integrates this information for complex perception — recognising an object by touch (stereognosis), for example.

Pain Physiology — Pathways, Modulation, and Gate Control Theory (PY10.8)

Pain is not simply the detection of tissue damage. It is a complex experience shaped by sensory, emotional, and cognitive factors. Understanding pain physiology is critical for every doctor, because pain is the most common reason patients seek medical help.

Figure: Pain Physiology — Pathways, Modulation, and Gate Control Theory (PY10.8)

Types of pain. Acute pain is brief, well-localised, and serves a protective function (e.g., pulling your hand from a flame). Chronic pain persists beyond the expected healing time (more than 3-6 months) and often loses its protective value — it becomes a disease in itself. Fast pain (sharp, pricking) is carried by A-delta fibres (small, myelinated, conduction velocity 5-30 m/s). Slow pain (burning, aching, throbbing) is carried by C fibres (unmyelinated, conduction velocity 0.5-2 m/s). This is why a pinprick gives a double sensation — a quick sharp pain followed by a slower burning pain.

Pain receptors (nociceptors) are free nerve endings found in almost every tissue except the brain parenchyma itself (which is why brain surgery can be done under local anaesthesia). They respond to mechanical damage, extreme temperature, and chemical mediators released during tissue injury — bradykinin (the most potent pain-producing substance), prostaglandins, histamine, serotonin, potassium ions, and substance P. Prostaglandins do not directly cause pain but sensitise nociceptors, lowering their threshold — this is why aspirin and NSAIDs (which inhibit cyclooxygenase and reduce prostaglandin synthesis) are effective analgesics.

Pain pathways. The first-order neuron (DRG) releases substance P and glutamate at its synapse in the dorsal horn (laminae I, II, V). The second-order neuron crosses via the anterior white commissure and ascends in the lateral spinothalamic tract. This tract has two functional components: the neospinothalamic tract (direct to VPL thalamus, then to somatosensory cortex — mediates the discriminative aspect: where does it hurt? how intense is it?) and the paleospinothalamic tract (projects to reticular formation, periaqueductal grey, and medial thalamic nuclei, then to the cingulate and insular cortex — mediates the affective-motivational aspect: suffering, unpleasantness). This is why pain has both a sensory and an emotional dimension.

Referred pain is pain perceived at a site distant from the actual source of pathology. Classic examples: cardiac ischaemia (heart) referred to the left arm and jaw; appendicitis (visceral) referred to the periumbilical region (T10 dermatome) before localising to the right iliac fossa; diaphragmatic irritation referred to the shoulder tip (C3-C5, phrenic nerve). The mechanism involves convergence — visceral and somatic afferents from the same dermatome synapse on the same second-order neuron in the dorsal horn. The brain, accustomed to receiving pain signals from the skin (which is much more common), "misinterprets" the visceral input as coming from the corresponding somatic area.

Gate Control Theory of Pain (Melzack and Wall, 1965) is one of the most important concepts in pain physiology. The theory proposes that a "gate" mechanism in the substantia gelatinosa (lamina II) of the dorsal horn modulates pain transmission. Large-diameter A-beta fibres (carrying touch and pressure) activate inhibitory interneurons that "close the gate" — reducing the transmission of pain signals from C fibres to the second-order neuron (the projection neuron, or T cell). When only small-diameter C fibres are active (pain without touch), the gate is "open" and pain is transmitted. This explains why rubbing a painful area reduces pain — the touch input through A-beta fibres closes the gate.

This theory also explains the mechanism of TENS (Transcutaneous Electrical Nerve Stimulation) — electrical stimulation of A-beta fibres at the surface to close the gate and reduce pain perception.

Descending pain modulation. The brain does not passively receive pain — it actively controls it. The periaqueductal grey (PAG) in the midbrain is the command centre. When activated (by stress, fear, or opioid drugs), it sends signals to the nucleus raphe magnus in the medulla, which projects serotonergic fibres down to the dorsal horn, where they inhibit pain transmission. A parallel noradrenergic pathway from the locus coeruleus does the same. Both pathways activate enkephalin-releasing interneurons in the dorsal horn that presynaptically inhibit the primary afferent (reducing substance P release) and postsynaptically inhibit the projection neuron. This is the endogenous opioid system — the reason soldiers in battle may not feel severe injuries until after the danger has passed.

The three families of endogenous opioids are: endorphins (from pro-opiomelanocortin, the most potent), enkephalins (met-enkephalin and leu-enkephalin, found in the dorsal horn), and dynorphins (from pro-dynorphin). All bind to opioid receptors (mu, delta, kappa). Morphine and other opioid analgesics work by mimicking these endogenous peptides.