Nervous System Physiology

Every thought, sensation and movement is built from one elementary event: one neuron firing at another across a synapse. You have about 86 billion neurons and roughly 100 trillion synapses, but the molecular logic of each individual contact is the same. When the AP arrives at the presynaptic terminal, voltage-gated Ca²⁺ channels open, calcium rushes in, synaptic vesicles fuse with the membrane, and neurotransmitter spills into the cleft. The transmitter diffuses across the cleft, binds receptors on the postsynaptic side, and either depolarises the next cell (EPSP, excitatory) or hyperpolarises it (IPSP, inhibitory). The output neuron sums hundreds or thousands of these signals every millisecond at its axon hillock; if the net depolarisation crosses threshold there, it fires its own AP. That is the entire computational basis of the brain — in/out, sum, decide, fire. Repeated 86 billion times in parallel.

A synapse is the specialised contact between two neurons (or between a neuron and an effector). Synapses are classified in three useful ways:

• Pre-synaptic membrane: bears active zones with voltage-gated Ca²⁺ channels; the terminal is packed with mitochondria (ATP supply) and synaptic vesicles (~40 nm) holding transmitter quanta.
• Synaptic cleft: 20–40 nm gap containing extracellular matrix & sometimes degrading enzymes (e.g. AChE).
• Post-synaptic membrane: dense with receptor proteins (ionotropic or metabotropic) coupled to ion channels.

1. Pre-synaptic AP arrives → depolarises terminal → voltage-gated Ca²⁺ channels open.
2. Ca²⁺ influx triggers SNARE-mediated fusion of vesicles → quantal release of transmitter by exocytosis.
3. Transmitter diffuses across the cleft → binds post-synaptic receptors.
4. Receptor opening allows ion flux → EPSP or IPSP.
5. Transmitter action ends by reuptake (e.g. NE, dopamine), enzymatic degradation (ACh by AChE), or diffusion.

• One-way conduction (Dale’s principle): transmitter is released only from the pre-synaptic side → signal flows pre → post.
• Synaptic delay (~0.5 ms): the time for Ca²⁺ entry → vesicle fusion → transmitter binding. Counting synapses in a pathway estimates delay.
• Summation: temporal (one input fires rapidly) and spatial (many inputs fire together).
• After-discharge: output continues after stimulus stops, because of reverberating circuits.
• Synaptic fatigue: sustained high-frequency input depletes transmitter → response wanes (basis of post-tetanic depression; protective against seizures).
• Sensitivity to environment: hypoxia, acidosis, alkalosis, drugs (anaesthetics, caffeine, strychnine) strongly modulate transmission; synapses are far more vulnerable than axons.

A reflex is a stereotyped involuntary response to a stimulus, mediated by a 5-element reflex arc:

1. Receptor → (2) afferent (sensory) neuron → (3) centre (cord or brainstem) → (4) efferent (motor) neuron → (5) effector (muscle / gland).

Reflexes may be monosynaptic (one synapse in the centre — stretch reflex) or polysynaptic (multiple interneurons — flexor / withdrawal reflex).

The spindle is reset by γ-motor neurons that contract intrafusal fibres — keeping the spindle sensitive at any muscle length (α–γ coactivation).

Reciprocal inhibition: when an agonist is reflexly excited, the antagonist is simultaneously inhibited (Ia inhibitory interneuron), so movement is smooth.

Complete spinal cord transection produces three sequential phases:

1. Spinal shock (days–weeks): flaccid paralysis, areflexia, atonic bladder, loss of sensation below the level — due to abrupt loss of descending facilitation.
2. Recovery phase (weeks): reflexes return progressively (anal → tendon → flexor → crossed-extensor).
3. Chronic phase: hyper-reflexia, spasticity, positive Babinski, mass reflexes — pure UMN syndrome.

Touch a kettle, hear a violin, see the page in front of you — every sensation begins at a receptor that converts a physical stimulus into a nerve impulse. This step is called transduction, and the rest of the sensory system is just relay and decoding. Each receptor has an adequate stimulus — the type of energy it’s tuned to (light for photoreceptors, pressure for mechanoreceptors, chemical for nociceptors, etc.) — and a receptive field — the patch of body or world it samples. Two strong stimuli on adjacent fingertips feel separate because they activate different receptive fields; that’s the basis of two-point discrimination, the densest on the fingertip and lips (small receptive fields), the loosest on the back (large fields).

A sensory receptor converts a physical/chemical stimulus into a neural signal (transduction). Each receptor responds best to its adequate stimulus; an inadequate stimulus needs a much larger energy to fire.

Stimulus → receptor potential (graded) → if it reaches threshold in the first node of Ranvier → action potentials whose frequency encodes stimulus intensity.

Adaptation lets us ignore continuous unimportant stimuli (clothing on skin) but still detect new or changing inputs.

Pain is unique among sensations — it’s the one we’d most like to switch off, yet without it, life is dangerous (think leprosy, where lost pain leads to unnoticed injuries that destroy hands and feet). Pain receptors are nociceptors, bare nerve endings activated by tissue damage. They come in two functional flavours: fast Aδ fibres (thinly myelinated, sharp first pain) and slow C fibres (unmyelinated, dull burning second pain). They synapse in the dorsal horn and ascend in the contralateral spinothalamic tract to thalamus and cortex. The brain doesn’t just receive pain — it modifies it. Descending fibres from periaqueductal grey can release endogenous opioids (enkephalins) in the dorsal horn, blunting pain transmission. This is why distraction reduces pain, why stress can mask serious injury, and why opioids work where they do.

Receptors are polymodal free nerve endings activated by TRPV1 (heat / capsaicin / acid >43°C) and TRPM8 (cold / menthol). Tissue damage releases K⁺, H⁺, prostaglandins, bradykinin, histamine, serotonin — these sensitise nociceptors (hyperalgesia).

• Gate control theory (Melzack & Wall): non-painful Aβ input excites inhibitory interneurons in the dorsal horn → "closes the gate" on C-fibre pain transmission. Rubbing or TENS works by this mechanism.
• Endogenous analgesia: the periaqueductal grey & raphe magnus send serotonergic & enkephalinergic fibres that inhibit dorsal-horn pain neurons. Opioids work here.
• Referred pain: visceral pain is felt in a somatic dermatome that shares the spinal segment (cardiac → left arm/jaw via T1–T4; diaphragm → shoulder C3–C5).

The primary motor cortex (M1) is a strip running across the back of the frontal lobe, just in front of the central sulcus. Its layout is famously somatotopic — the body is mapped onto it like a distorted little man, the motor homunculus. Body parts that need fine motor control get massive cortical real estate: hands, lips, tongue, face. Body parts moved as a whole (trunk, thigh) get tiny representations. Stimulate a spot on M1 (Penfield’s open-brain experiments showed this in conscious patients) and the corresponding muscle group twitches. A stroke that knocks out the “hand area” leaves the patient with weak hand but spared face; a stroke that knocks out the “face area” does the opposite. Knowing the map predicts the deficit.

The primary motor cortex (M1, precentral gyrus, Brodmann 4) contains a somatotopic map — the motor homunculus. Body parts requiring fine control (hand, face, lips, tongue) occupy disproportionately large areas. Lateral parts of M1 control the face/hand; medial parts (paracentral lobule) control the leg.

• Premotor cortex (BA 6): plans externally-cued movement & postural set.
• Supplementary motor area (SMA, medial BA 6): plans internally-generated, sequential movement.
• Broca area (BA 44/45, dominant hemisphere): motor planning of speech.

The corticospinal tract carries voluntary motor commands directly from cortex to spinal motor neurons.

1. Cell bodies in motor cortex (giant Betz cells in layer V of M1) → axons descend through the posterior limb of the internal capsule → cerebral peduncle → pons → medulla.
2. In the lower medulla ~85% decussate in the medullary pyramids → form the lateral corticospinal tract (controls contralateral distal limb muscles).
3. ~15% remain ipsilateral as the anterior corticospinal tract → cross at the cord segment of synapse (controls axial / proximal muscles bilaterally).
4. Synapses on α-motor neurons in the ventral horn — directly or via interneurons.

The corticobulbar tract targets cranial-nerve motor nuclei. Most are bilaterally innervated; CN VII lower face & CN XII are contralateral only → UMN facial palsy spares forehead, LMN (Bell’s) affects whole half-face.

The cerebellum is the brain’s coach — it doesn’t initiate movement, it makes movements smooth. Every time the motor cortex sends a command down to muscle, a copy goes to the cerebellum (corollary discharge). The cerebellum simultaneously gets the sensory feedback — what the muscles actually did. It compares intended with actual and corrects the next command in real time, all without conscious awareness. Lose the cerebellum and movements still happen, but they overshoot, undershoot, wobble, and lack timing — ataxia. Importantly cerebellar signs are ipsilateral (right cerebellum → right-sided ataxia) because cerebellar output crosses to the contralateral cortex, which then crosses back via the corticospinal tract — two crosses cancel out. It also stores procedural motor memory: how to ride a bike, throw a ball, type without looking.

The cerebellum does not initiate movement; it compares the intended movement (cortex) with the actual movement (proprioception) and corrects timing, smoothness & force in real time.

Inputs arrive via mossy fibres (from pons, cord, vestibular nuclei) → granule cells → parallel fibres to Purkinje cells, and climbing fibres (from inferior olive) directly onto Purkinje cells. Purkinje cells are the sole output of the cerebellar cortex — and they are inhibitory (GABA), projecting to the deep cerebellar nuclei (dentate, interposed, fastigial). Outputs leave via the superior cerebellar peduncle → thalamus → motor cortex.

The basal ganglia comprise the caudate, putamen, globus pallidus (internal & external), substantia nigra (pars compacta = dopamine; pars reticulata) and subthalamic nucleus. Striatum = caudate + putamen. They modulate movement via two opposing pathways:

Net: dopamine from substantia nigra facilitates movement by both excitation of direct and inhibition of indirect pathways. Loss of dopamine → hypokinesia.

All autonomic ganglia & the NMJ use ACh on nicotinic receptors. The adrenal medulla is a modified sympathetic ganglion — pre-ganglionic ACh makes it release adrenaline/noradrenaline into the blood.

• Non-REM (NREM): N1 (theta) → N2 (sleep spindles, K-complexes) → N3 (slow-wave delta). Dominates first third of night; growth hormone peaks here.
• REM: low-voltage fast EEG (similar to waking), rapid eye movements, skeletal muscle atonia, vivid dreams, irregular HR/BP. Dominates last third; ~25% of sleep, every ~90 min.
• Wakefulness is maintained by the ascending reticular activating system (ARAS) using ACh, NE, 5-HT, histamine, orexin. Loss of orexin neurons → narcolepsy.