Nervous System

The Na⁺/K⁺-ATPase (3 Na⁺ out, 2 K⁺ in) builds the concentration gradients. K⁺ leak channels make the resting membrane mostly permeable to K⁺, so the resting potential (≈ −70 mV) lies close to E_K (≈ −90 mV).

Graded potentials (receptor and postsynaptic potentials) decay with distance and can be summed. When they bring the axon initial segment to threshold (≈ −55 mV), voltage-gated Na⁺ channels open by positive feedback and fire an all-or-none action potential. Na⁺ channel inactivation and delayed K⁺ channel opening then repolarise the membrane, followed by a brief after-hyperpolarisation.

The refractory periods make conduction one-way and cap firing frequency. Stimulus intensity is therefore coded by firing frequency and by recruitment, not by action-potential size. Conduction velocity rises with axon diameter and with myelination (saltatory conduction).

An action potential invading the terminal opens voltage-gated Ca²⁺ channels. Ca²⁺ binds synaptotagmin, and SNARE proteins fuse vesicles with the membrane at the active zone. The synaptic delay is ≈0.5 ms.

Transmitter acts on ionotropic receptors, which are fast (ms) ligand-gated channels, or on metabotropic receptors, which are slower G-protein-coupled cascades.
• An EPSP is a depolarisation, e.g. Na⁺ entry through AMPA receptors.
• An IPSP is a hyperpolarisation or shunting, e.g. Cl⁻ entry through GABA-A or glycine receptors.

Each neuron sums thousands of inputs spatially and temporally at the initial segment. Signalling ends by reuptake, enzymatic degradation (acetylcholinesterase, MAO and COMT) or diffusion. Activity-dependent changes in synaptic strength (LTP/LTD, NMDA-receptor dependent) underlie learning.

Conscious somatic sensation reaches the cortex through a three-neuron chain:
• First-order neuron: a pseudounipolar cell in the dorsal root or trigeminal ganglion.
• Second-order neuron: in the dorsal horn or a brainstem nucleus. It decussates and projects to the thalamus.
• Third-order neuron: in the thalamus (VPL for the body, VPM for the face), projecting through the posterior limb of the internal capsule to the postcentral gyrus.

The DCML (fine touch, vibration, proprioception) crosses in the medulla, while the anterolateral/spinothalamic system (pain, temperature, crude touch) crosses in the cord. That is why a hemicord lesion produces dissociated sensory loss (Brown-Séquard).

Every relay preserves somatotopy, which is drawn as the sensory homunculus. Unconscious proprioception travels to the ipsilateral cerebellum in the spinocerebellar tracts.

The upper motor neurons of the motor cortex (corticospinal and corticobulbar tracts) and of the brainstem (rubro-, reticulo-, vestibulo- and tectospinal tracts) act on lower motor neurons in the ventral horn and the cranial motor nuclei. The lower motor neurons are the "final common pathway" to muscle.

Two side loops refine movement without projecting to the spinal cord directly:
• The basal nuclei (cortex → striatum → GPi/SNr → thalamus → cortex) select and scale actions through the direct (go) and indirect (no-go) pathways. Dopamine biases them towards movement.
• The cerebellum compares intended with actual movement and corrects timing, force and coordination.

Spinal reflex circuits (stretch, reciprocal inhibition, withdrawal, crossed extension) provide the substrate on which descending commands act.

The hypothalamus, the nucleus of the solitary tract and the ventrolateral medulla, the periaqueductal grey, the amygdala and the insula form a central autonomic network.

Visceral afferents (baroreceptors, chemoreceptors, stretch receptors) mostly travel with the vagus and glossopharyngeal nerves to the NTS. Outflow passes through two-neuron chains:
• Sympathetic: short preganglionic (ACh → nicotinic), long postganglionic (noradrenaline → α/β).
• Parasympathetic: long preganglionic, short postganglionic (ACh → muscarinic).

Most organs have dual, antagonistic innervation with continuous tone. The exceptions are sympathetic only: most blood vessels, sweat glands, arrector pili and the adrenal medulla. The baroreceptor reflex, for example, adjusts heart rate and vascular resistance within seconds of a change in posture.

Wakefulness depends on the ascending arousal system in the upper pons and midbrain. Its parallel streams are:
• cholinergic (pedunculopontine and laterodorsal tegmental nuclei);
• noradrenergic (locus coeruleus);
• serotonergic (raphe);
• dopaminergic;
• histaminergic (tuberomammillary nucleus);
• orexinergic (lateral hypothalamus).

These project to the thalamus and cortex. Coma results from a lesion of this system or from bilateral hemispheric dysfunction.

Sleep cycles every ≈90 minutes between NREM (stages N1–N3, slow-wave delta activity in N3) and REM (desynchronised EEG, atonia, dreaming). A sleep "switch" between the sleep-promoting ventrolateral preoptic nucleus and the arousal centres keeps the transitions sharp, and the suprachiasmatic nucleus entrains the cycle to daylight. Loss of orexin causes narcolepsy.

Declarative (explicit) memory covers facts and events and needs the medial temporal lobe (hippocampus, entorhinal cortex) for consolidation. Long-term storage is distributed in the neocortex.

Non-declarative (implicit) memory includes:
• skills and habits (basal nuclei, cerebellum);
• priming (neocortex);
• classical conditioning (cerebellum for motor responses, amygdala for fear).

Working memory is held by the dorsolateral prefrontal cortex. At the cellular level, long-term potentiation at hippocampal CA3→CA1 synapses needs coincident pre- and postsynaptic activity. That coincidence opens NMDA receptors (relieving the Mg²⁺ block) and admits Ca²⁺, which triggers insertion of AMPA receptors and later structural growth.

Bilateral medial temporal damage (patient H.M., herpes encephalitis, Alzheimer disease) causes anterograde amnesia while sparing skills learned before the damage.

The brain has almost no energy reserve. Consciousness is lost within ≈10 s of circulatory arrest, and irreversible neuronal injury begins after ≈4–5 min of anoxia.

Cerebral perfusion pressure = MAP − ICP. Autoregulation (myogenic and metabolic) keeps flow constant over a wide range of mean arterial pressure (classically ≈60–150 mmHg). Flow is highly sensitive to PaCO₂: hypercapnia dilates the vessels, and hyperventilation constricts them and lowers ICP briefly. Active regions receive more flow (neurovascular coupling), which is the basis of functional MRI.

The Monro–Kellie doctrine describes the fixed skull containing brain, blood and CSF. An expanding mass is buffered first by displacing CSF and venous blood. Once these are exhausted, ICP rises steeply, producing headache, vomiting, papilloedema and a CN VI palsy, and finally herniation with the Cushing response (hypertension, bradycardia, irregular breathing).

About 85% of strokes are ischaemic (large-artery thrombosis, cardioembolism such as atrial fibrillation, small-vessel lacunes) and ≈15% are haemorrhagic. The territory involved predicts the deficit:
• MCA: contralateral face and arm more than leg weakness and sensory loss, homonymous hemianopia, and gaze deviation towards the lesion. Aphasia follows a dominant-hemisphere lesion (Broca's with the superior division, Wernicke's with the inferior division); neglect follows a non-dominant lesion.
• ACA: contralateral leg more than arm weakness, urinary incontinence, abulia and a grasp reflex.
• PCA: contralateral homonymous hemianopia with macular sparing, alexia without agraphia (dominant side plus splenium), and thalamic sensory loss.
• Lacunar infarcts (lenticulostriate and pontine perforators): pure motor, pure sensory, ataxic hemiparesis, or dysarthria–clumsy hand.
• Vertebrobasilar strokes: vertigo, ataxia, diplopia, dysarthria, crossed brainstem syndromes (Wallenberg, Weber), or the locked-in syndrome.

Roughly 1.9 million neurons die each minute of a large-vessel occlusion ("time is brain"). Non-contrast CT excludes haemorrhage. IV thrombolysis is given within 4.5 h, and mechanical thrombectomy treats large-vessel occlusions in selected patients up to 24 h.

• Epidural (extradural) haematoma: arterial bleeding, classically from the middle meningeal artery after a fracture at the pterion. Blood strips the dura from the skull, giving a biconvex (lentiform) collection that does not cross sutures. A lucid interval followed by rapid deterioration and uncal herniation is classic but occurs in only a minority. It needs urgent evacuation.
• Subdural haematoma: venous bleeding from torn bridging veins crossing to the dural sinuses. It forms a crescent that crosses sutures but not the falx. It is common in the elderly (atrophy stretches the veins), people with alcohol use disorder, anticoagulated patients and abused infants. Chronic subdurals present over weeks with fluctuating confusion.
• Subarachnoid haemorrhage: non-traumatic SAH is ≈85% due to a ruptured saccular (berry) aneurysm of the circle of Willis, most often the anterior communicating artery. It causes a sudden thunderclap "worst-ever" headache, meningism and reduced consciousness. CT is sensitive early; after that, lumbar puncture shows xanthochromia. Complications are rebleeding, vasospasm (days 3–14, so nimodipine is given), hydrocephalus and hyponatraemia.
• Intracerebral haemorrhage: hypertensive bleeds favour the putamen, thalamus, pons and cerebellum. Amyloid angiopathy causes lobar bleeds in older people.

MS is a chronic immune-mediated demyelinating disease of the CNS: T and B cells target oligodendrocyte myelin, and the peripheral nerves are spared. It typically starts at 20–40 years, affects women 2–3 times more often, and is associated with EBV, low vitamin D, smoking, high latitude and HLA-DRB1*15:01.

Lesions are disseminated in time and space (McDonald criteria). Typical presentations:
• optic neuritis: painful monocular visual loss with a relative afferent pupillary defect;
• internuclear ophthalmoplegia from an MLF lesion;
• partial myelitis with Lhermitte sign;
• sensory symptoms;
• cerebellar signs.
Symptoms worsen with heat (Uhthoff phenomenon).

MRI shows periventricular (Dawson fingers), juxtacortical, infratentorial and spinal lesions. CSF shows oligoclonal IgG bands absent from serum. About 85% of patients start with a relapsing–remitting course. Relapses are treated with high-dose methylprednisolone, and disease-modifying therapies include interferon-β, natalizumab and anti-CD20 antibodies.

Parkinson disease is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra pars compacta, with α-synuclein Lewy bodies. Motor signs appear once ≈50–60% of nigral neurons and ≈70–80% of striatal dopamine are lost. Reduced dopamine weakens the direct (go) pathway and releases the indirect (no-go) pathway, so the thalamus is over-inhibited.

The cardinal signs (TRAP) are:
• Tremor: at rest, 4–6 Hz, "pill-rolling" and asymmetric;
• Rigidity: lead-pipe, or cogwheel when combined with tremor;
• Akinesia or bradykinesia, the essential feature;
• Postural instability, which appears late.
Other motor signs are hypomimia, micrographia, hypophonia and a shuffling, festinating gait. Non-motor features (anosmia, REM sleep behaviour disorder, constipation, depression) often precede the motor signs.

Treatment is levodopa with carbidopa, a peripheral DOPA-decarboxylase inhibitor that does not cross the BBB. Alternatives and adjuncts are dopamine agonists, MAO-B and COMT inhibitors, and deep brain stimulation of the subthalamic nucleus or GPi.

Alzheimer disease is the most common cause of dementia (≈60–70%). Extracellular β-amyloid plaques form from APP cleavage, and intracellular neurofibrillary tangles form from hyperphosphorylated tau. Atrophy starts in the entorhinal cortex and hippocampus, which explains early episodic memory loss, and spreads to the temporoparietal association cortex, causing language, visuospatial and executive deficits. Loss of cholinergic neurons in the nucleus basalis of Meynert reduces cortical ACh.

Risk factors are age, APOE ε4 and Down syndrome (APP gene on chromosome 21). APP, PSEN1 and PSEN2 mutations cause early-onset familial disease.

Treatment comprises cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine, an NMDA antagonist. Anti-amyloid monoclonal antibodies modestly slow early disease.

Guillain–Barré syndrome is an acute immune-mediated polyradiculoneuropathy of the PNS, usually demyelinating (AIDP). It typically follows an infection by 1–4 weeks, classically Campylobacter jejuni, which is linked to the axonal anti-GM1 variant through molecular mimicry. CMV and EBV are other triggers.

The weakness is ascending, symmetrical and flaccid, with areflexia and mild distal paraesthesia. It reaches its worst within 4 weeks and may involve the facial and bulbar muscles, the autonomic system (arrhythmias, labile blood pressure) and the respiratory muscles, so forced vital capacity is monitored serially. The Miller Fisher variant (ophthalmoplegia, ataxia, areflexia) carries anti-GQ1b antibodies.

CSF shows albuminocytologic dissociation (high protein, normal cell count), and nerve conduction studies confirm demyelination. Treatment is IVIG or plasma exchange; corticosteroids do not help. Most patients recover because Schwann cells remyelinate.

Meningitis is inflammation of the leptomeninges (pia and arachnoid) and the CSF. The usual bacterial causes vary with age:
• Neonates: group B Streptococcus, E. coli, Listeria.
• Children and adults: Streptococcus pneumoniae (the commonest in adults) and Neisseria meningitidis (non-blanching petechial or purpuric rash, outbreaks in young adults). Haemophilus influenzae type b is now rare thanks to vaccination.
• Older or immunosuppressed patients: Listeria is added to the list.

Features are fever, headache, neck stiffness, photophobia and altered mental state, with Kernig and Brudzinski signs. The full triad occurs in fewer than half of patients.

Typical CSF findings:
• bacterial: neutrophils, high protein, low glucose;
• viral: lymphocytes, normal glucose;
• tuberculous: lymphocytes, very high protein, low glucose.

Empirical antibiotics (ceftriaxone ± vancomycin, plus ampicillin for Listeria) and dexamethasone must not be delayed for imaging or LP. Sequelae include sensorineural hearing loss, hydrocephalus and seizures.

Hydrocephalus is excess CSF with ventricular enlargement and usually raised pressure.
• Non-communicating (obstructive): a block within the ventricular system. Causes include aqueductal stenosis, colloid cyst at the foramen of Monro, posterior-fossa tumours (medulloblastoma, ependymoma), Chiari II and Dandy–Walker malformation.
• Communicating: flow out of the ventricles is free but absorption at the arachnoid granulations fails, typically after meningitis or SAH. Rarely it results from overproduction by a choroid plexus papilloma.
• Normal-pressure hydrocephalus in older adults causes the triad of gait apraxia ("magnetic" gait), urinary incontinence and dementia ("wet, wobbly, wacky"). It improves after a large-volume LP tap test.
• Hydrocephalus ex vacuo is passive ventricular enlargement from atrophy and is not true hydrocephalus.

Infants present with an enlarging head, a bulging fontanelle and "sunset" eyes. Adults present with headache, vomiting, papilloedema and a CN VI palsy. Treatment is a ventriculoperitoneal shunt or endoscopic third ventriculostomy.

• Brown-Séquard (hemisection): below the lesion there is ipsilateral spastic weakness (corticospinal) and loss of vibration and proprioception (dorsal column). There is contralateral loss of pain and temperature starting 1–2 segments below (spinothalamic). Ipsilateral LMN signs and a band of anaesthesia occur at the level of the lesion.
• Central cord (syringomyelia, or hyperextension injury in a spondylotic neck): crossing spinothalamic fibres are interrupted, giving "cape-like" loss of pain and temperature, and the arms are weaker than the legs.
• Anterior cord (anterior spinal artery occlusion, e.g. after aortic surgery): bilateral paralysis and loss of pain and temperature with dorsal columns preserved.
• Posterior cord (B12 deficiency, which also involves the corticospinal tracts as subacute combined degeneration; tabes dorsalis): sensory ataxia with a positive Romberg sign.
• Complete transection: spinal shock (flaccid, areflexic) evolves over days to weeks into UMN signs.
• Cauda equina syndrome: saddle anaesthesia, urinary retention and LMN leg signs. It is a surgical emergency.

• Upper motor neuron (UMN) lesions affect the cortex, internal capsule, brainstem or corticospinal tract. They produce weakness in a pyramidal distribution (arm extensors and leg flexors weakest), spasticity (velocity-dependent, clasp-knife), hyperreflexia with clonus, an extensor plantar response (Babinski sign) and only mild disuse atrophy. Shortly after an acute lesion, tone and reflexes are reduced ("shock").
• Lower motor neuron (LMN) lesions affect the anterior horn cell, root or peripheral nerve. They produce weakness confined to the muscles supplied, hypotonia, hyporeflexia or areflexia, marked wasting and fasciculations, with a flexor or absent plantar response.

Amyotrophic lateral sclerosis characteristically combines UMN and LMN signs in the same region.

Horner syndrome results from interruption of the three-neuron oculosympathetic pathway:
• First-order neuron: hypothalamus → brainstem → ciliospinal centre (C8–T2).
• Second-order neuron: T1 → sympathetic trunk over the lung apex → superior cervical ganglion.
• Third-order neuron: along the internal carotid artery → V1 → dilator pupillae and superior tarsal muscle.

The signs are ipsilateral ptosis (partial, from the superior tarsal muscle), miosis with dilation lag, anhidrosis of the face (central and preganglionic lesions) and apparent enophthalmos.

Causes depend on the level:
• Central: lateral medullary syndrome, syringomyelia.
• Preganglionic: Pancoast tumour at the lung apex, cervical rib, Klumpke palsy, neck surgery.
• Postganglionic: internal carotid artery dissection (painful Horner), cavernous sinus lesions, cluster headache.

Bell palsy is an acute idiopathic lower motor neuron facial nerve palsy, probably viral (HSV-1 reactivation), with swelling of the nerve in the narrow facial canal. The whole ipsilateral half of the face, including the forehead, is weak: the patient cannot wrinkle the brow or close the eye (Bell phenomenon, upward rolling of the eye), and the corner of the mouth droops.

Depending on the level of the lesion there may be hyperacusis (nerve to stapedius), loss of taste over the anterior two-thirds of the tongue (chorda tympani) and reduced lacrimation (greater petrosal nerve).

In a UMN lesion such as a stroke the forehead is spared, because the part of the facial nucleus that supplies the upper face receives bilateral cortical input. Treatment is prednisolone within 72 h plus eye protection; about 70–85% of patients recover fully. Ramsay Hunt syndrome (VZV, with ear vesicles) has a worse prognosis.