Nerve Physiology — Action Potential and Conduction

Resting Membrane Potential

• The neuronal membrane potential at rest is approximately -70 mV, maintained by the Na+/K+-ATPase (sodium-potassium pump)
• The pump moves 3 Na+ out and 2 K+ in, consuming ATP and creating an inward-directed Na+ electrochemical gradient and outward-directed K+ gradient
• At rest, the membrane is ~25× more permeable to K+ than Na+ due to leak channels, resulting in net K+ efflux that hyperpolarizes the membrane
• The Nernst equation calculates the equilibrium potential for a given ion; the Goldman-Hodgkin-Katz equation accounts for multiple permeant ions to predict actual resting potential

Depolarization Phase

• Stimulus threshold (typically -55 mV) triggers opening of voltage-gated Na+ channels in the axon initial segment
• Inward Na+ current dominates, driven by both electrical gradient (inside negative) and chemical gradient (high extracellular Na+)
• Depolarization is regenerative: as membrane potential approaches +30 mV, Na+ channel inactivation gates close, preventing further Na+ influx
• The all-or-none principle dictates that once threshold is reached, a full-amplitude action potential is generated; subthreshold stimuli produce only local currents that decay exponentially

Repolarization Phase

• As Na+ channels inactivate, voltage-gated K+ channels open with a slight delay (~1 millisecond)
• The outward K+ current (driven by the large positive electrochemical gradient) causes repolarization back toward the K+ equilibrium potential
• Delayed rectifier K+ channels carry the bulk of repolarization current; some K+ channels remain open slightly too long, causing hyperpolarization (afterhyperpolarization) to approximately -90 mV
• This hyperpolarized state temporarily increases the threshold for the next action potential, creating the relative refractory period

Conduction Along Unmyelinated Axons

• In unmyelinated axons, action potentials propagate via local circuit currents between adjacent membrane segments
• Inward current (depolarizing) through open Na+ channels at the active region spreads longitudinally along the axon interior and radially outward across the membrane at adjacent sites
• Neighboring regions are depolarized and may reach threshold, triggering their own action potentials
• This continuous conduction travels at relatively slow speeds (~0.5–2 m/s) because each segment must regenerate the full action potential

Saltatory Conduction in Myelinated Axons

• Myelin, formed by oligodendrocytes (CNS) or Schwann cells (PNS), is a multilayered insulating sheath that wraps axons
• Nodes of Ranvier are unmyelinated gaps (~1 μm) between myelin sheaths spaced ~1 mm apart where voltage-gated Na+ channels cluster at high density (~2000/μm²)
• Saltatory conduction ("jumping conduction") occurs when action potentials "skip" over myelinated internodes because myelin prevents ion flux across the insulated segments
• Inward current at one node depolarizes the membrane at the next node directly; the high channel density ensures reliable depolarization to threshold
• This mechanism increases conduction velocity to 50–120 m/s (100-fold faster than unmyelinated fibers) while maintaining low metabolic cost

Ion Channel Structure and Function

• Voltage-gated Na+ channels are large transmembrane proteins with four homologous domains (I–IV), each containing six transmembrane segments (S1–S6)
• The S4 segment in each domain serves as the voltage sensor with positively charged amino acids; depolarization causes outward movement, opening the channel
• The inactivation gate is a cytoplasmic linker between domains III and IV; depolarization triggers inactivation by blocking the pore from the inside, stopping Na+ influx
• Voltage-gated K+ channels share similar architecture but lack rapid inactivation, allowing sustained K+ efflux during repolarization

Absolute and Relative Refractory Periods

• The absolute refractory period (overlapping with repolarization) is when Na+ channels are inactivated and a new action potential cannot be generated regardless of stimulus strength
• The relative refractory period (during hyperpolarization) is when a suprathreshold stimulus can trigger an action potential because some Na+ channels have recovered from inactivation
• These periods reflect the kinetics of Na+ channel inactivation and recovery, controlling the maximum action potential frequency (tetanic stimulation can achieve ~200–300 Hz in some neurons)

Channelopathies (Genetic Ion Channel Mutations)

• Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE): mutations in CHRNA4 gene (nicotinic acetylcholine receptor), causing gain-of-function and hyperexcitability
• Generalized epilepsy with febrile seizures plus (GEFS+): loss-of-function mutations in SCN1A (Na+ channel α subunit) or GABRA1 (GABA receptor)
• Paramyotonia congenita: gain-of-function mutations in SCN4A (skeletal muscle Na+ channel), causing abnormal muscle excitability and periodic paralysis
• Long QT syndrome: mutations in cardiac K+ or Na+ channels (KCNQ1, KCNH2, SCN5A), predisposing to arrhythmias and sudden cardiac death
• Episodic ataxia type 1 (EA1): mutations in KCNA1 (voltage-gated K+ channel), causing paroxysmal cerebellar symptoms

Demyelinating Diseases

• Multiple sclerosis (MS): autoimmune destruction of myelin by T cells and B cells, reducing saltatory conduction and causing variable conduction block
• Guillain-Barré syndrome (GBS): autoimmune attack on myelin of peripheral nerves (especially AIDP—acute inflammatory demyelinating polyneuropathy), causing conduction slowing and block
• Chronic inflammatory demyelinating polyneuropathy (CIDP): slowly progressive demyelination causing progressive sensorimotor weakness
• Charcot-Marie-Tooth disease type 1 (CMT1): inherited demyelinating neuropathy due to PMP22 duplication or other myelin protein mutations

Toxins and Medications

• Tetrodotoxin (TTX) and saxitoxin: block voltage-gated Na+ channels by occluding the pore from the extracellular side; mechanism of shellfish poisoning
• Local anesthetics (lidocaine, procaine): block Na+ channels in a use-dependent manner, stabilizing the inactivated state
• Antiarrhythmics (Class I agents): Na+ channel blockers used to suppress ectopic activity but may paradoxically promote arrhythmias
• Anticonvulsants (phenytoin, carbamazepine): enhance Na+ channel inactivation, reducing repetitive firing

Ischemia and Hypoxia

• Cerebral ischemia: reduces ATP availability, impairing Na+/K+-ATPase function; Na+ accumulates intracellularly, depolarizing the membrane and triggering excitotoxic glutamate release
• Hypoxia: impairs oxidative phosphorylation, reducing ATP production and allowing progressive membrane depolarization

Metabolic Derangements

• Hypokalemia (K+ <3.0 mEq/L): lowers extracellular K+ concentration, increasing the K+ equilibrium potential and hyperpolarizing the resting membrane potential, making neurons less excitable (paradoxical weakness despite hyperexcitability risk with severe hypokalemia)
• Hyperkalemia (K+ >6.5 mEq/L): raises extracellular K+, depolarizing the resting potential and initially increasing excitability; with severe hyperkalemia, Na+ channels inactivate, causing conduction block and paralysis
• Hypocalcemia: reduces the voltage at which Na+ channels inactivate, increasing neuronal excitability (tetany, seizures)
• Hyponatremia: reduces the Na+ equilibrium potential, limiting the driving force for Na+ influx and reducing action potential amplitude and conduction velocity

Seizures (Hyperexcitability)

• Generalized tonic-clonic seizure: loss of consciousness with rigid muscular contraction (tonic phase) followed by rhythmic jerking (clonic phase), reflecting excessive synchronized action potentials across cortex
• Focal seizures: abnormal behavior, sensory phenomena, or motor activity confined to one body region, arising from localized hyperexcitable cortical focus
• Status epilepticus: prolonged or repetitive seizures lasting >5 minutes; life-threatening due to metabolic exhaustion and risk of aspiration or hypoxia

Myelin-Related Conduction Abnormalities

• Weakness and numbness (demyelinating polyneuropathy): variable conduction slowing and block in peripheral nerves cause distal-predominant weakness and sensory loss that progresses proximally
• Optic neuritis (MS): demyelination of optic nerve causes painful vision loss, relative afferent pupil defect (RAPD), and abnormal visual evoked potentials
• Ataxia and vertigo (cerebellar involvement in MS): demyelination of cerebellar tracts causes incoordination and imbalance
• Respiratory failure (GBS): demyelination of phrenic nerves and motor roots to respiratory muscles can necessitate mechanical ventilation

Channelopathy-Related Presentations

• Episodic paralysis (periodic paralysis syndromes): attacks of flaccid paralysis lasting hours, triggered by potassium shifts or carbohydrate intake
• Myotonia: persistent muscle contraction after voluntary effort or percussion, reflecting repetitive action potentials in muscle fibers (characteristic of paramyotonia congenita and myotonic dystrophy)
• Nystagmus and ataxia (episodic ataxia type 1): intermittent cerebellar dysfunction with brief attacks of incoordination
• Nocturnal seizures (ADNFLE): brief focal motor seizures, often with preserved awareness, occurring primarily during sleep

Metabolic/Ischemic Disturbances

• Muscle cramps and weakness (hypokalemia): reflect altered resting potential and impaired muscle excitability
• Cardiac arrhythmias (hyperkalemia): peaked T waves, prolonged PR interval, widened QRS due to altered conduction velocity in ventricular myocardium
• Tetany (hypocalcemia): involuntary muscle contractions triggered by spontaneous action potentials in motor nerves due to reduced inactivation threshold for Na+ channels
• Confusion and obtundation (severe hyponatremia): cerebral edema and altered neuronal function from impaired osmotic gradient

Electrodiagnostic Studies

• Electromyography (EMG): needle electrode records action potentials from individual muscle fibers; reduced motor unit recruitment in weakness, fibrillations in denervation, myopathic potentials (small, short duration) in primary muscle disease
• Nerve Conduction Studies (NCS):
• Motor NCS: measures compound muscle action potential (CMAP) amplitude and conduction velocity (CV) along peripheral nerves; reduced CV (<50% lower limit of normal) indicates demyelination; reduced CMAP amplitude indicates axonal loss
• Sensory NCS: assesses sensory nerve conduction; absent sensory responses with preserved motor responses indicates sensory neuronopathy
• F-wave: measures conduction in proximal nerve and nerve root by stimulating motor nerve and recording response from muscle; prolonged F latency indicates demyelination
• H-reflex: assesses S1 root and Ia fiber function; commonly abnormal in GBS and spinal cord disorders
• Temporal Dispersion and Conduction Block: in demyelinating neuropathies, stimulating nerve at proximal vs. distal sites shows progressive decrease in CMAP amplitude (>50% decrease = conduction block) and prolongation of latency due to slowed conduction through demyelinated segments

Electrophysiology Recordings (Research/Specialized)

• Patch-clamp electrophysiology: measures currents through single ion channels, revealing properties of Na+, K+, and Ca2+ channels; abnormalities in channelopathies
• Voltage clamp and current clamp: whole-cell recordings measure macroscopic currents and membrane potential changes, revealing defects in channel kinetics

MRI Brain and Spinal Cord

• MS: T2/FLAIR hyperintensities in periventricular white matter, juxtacortical regions, and infratentorial areas; T1 gadolinium enhancement indicates active demyelination with blood-brain barrier disruption
• GBS: typically normal brain MRI but may show nerve root enhancement on spinal imaging
• Ischemic stroke: diffusion-weighted imaging (DWI) shows acute ischemic changes (hyperintense) before conventional T2 changes; indicates acute conduction block from hypoxia

Laboratory Studies

• Serum electrolytes: K+, Na+, Ca2+, Mg2+ abnormalities directly affect resting potential and action potential propagation
• Cerebrospinal fluid (CSF): elevated protein (>100 mg/dL) in GBS with normal or mildly elevated cell count ("albumin-cytologic dissociation"); oligoclonal bands in MS
• Genetic testing: sequencing of SCN1A, KCNQ1, KCNH2, CHRNA4 in channelopathy syndromes
• Serum antibodies: anti-ganglioside antibodies (anti-GM1 in AMAN variant of GBS); aquaporin-4 or MOG antibodies in demyelinating disorders

Clinical Criteria and Diagnostic Algorithms

• AIDP (demyelinating variant of GBS): progressive weakness over days/weeks, demyelination on NCS (slowed CV, prolonged latencies, conduction block), elevated CSF protein with few cells
• Multiple sclerosis (McDonald Criteria 2017): requires dissemination in space (MRI lesions in ≥2 CNS regions) and dissemination in time (simultaneous presence of gadolinium-enhancing and non-enhancing lesions, or 2+ clinical relapses)
• Channelopathy diagnosis: clinical presentation of episodic symptoms (seizures, paralysis, ataxia), normal baseline neuroimaging, genetic confirmation, or abnormal single-channel electrophysiology

Antiepileptic Drugs (Hyperexcitability)

• Sodium channel blockers: Phenytoin (Dilantin) and carbamazepine stabilize the inactivated state of Na+ channels, reducing repetitive firing; phenytoin loading (15–20 mg/kg IV) rapidly achieves therapeutic levels for acute seizure control; maintenance dosing adjusted for therapeutic drug levels (10–20 μg/mL); carbamazepine preferred for focal seizures with better tolerability
• Valproic acid: enhances **

Disease-related — emergencies first

• Status epilepticus (emergency): sustained synchronous firing outstrips ATP supply, causing lactic acidosis, hyperthermia, rhabdomyolysis, and eventually GABA-A receptor internalization that makes seizures benzodiazepine-refractory. The American Epilepsy Society treatment guideline defines the operational threshold at ≥5 minutes of continuous convulsion and makes an IV/IM benzodiazepine the first-line agent; the signal of impending disaster is ongoing electrographic seizure after motor activity stops.
• Neuromuscular respiratory failure in GBS (emergency): demyelination of phrenic and intercostal motor axons produces conduction block before any hypoxemia appears. Pulse oximetry is a late and falsely reassuring sign — serial bedside spirometry (forced vital capacity, negative inspiratory force), single-breath counting, and staccato speech signal the need for elective intubation.
• GBS dysautonomia (emergency): aberrant conduction in autonomic fibers causes labile hypertension, bradyarrhythmias, and asystole; continuous telemetry is standard.
• Hyperkalemic conduction block (emergency): sustained depolarization holds voltage-gated Na+ channels in the inactivated state, producing flaccid paralysis and a widening QRS that degenerates into a sine wave; IV calcium to restore the threshold gradient precedes any potassium-lowering therapy.
• Hypocalcemic tetany with laryngospasm (emergency): loss of divalent charge screening lowers the threshold for Na+ channel opening; Chvostek and Trousseau signs precede stridor.
• Secondary axonal degeneration: chronic demyelination exposes axons to metabolic stress; on nerve conduction studies the tell-tale shift is falling CMAP amplitude superimposed on slowed velocity, and deficits become fixed.
• Ephaptic transmission between demyelinated axons underlies Lhermitte sign and MS-associated trigeminal neuralgia; Uhthoff phenomenon (heat-induced conduction block) is a pseudo-relapse, not new inflammation.

Treatment-related

• IV phenytoin: the propylene glycol/ethanol vehicle causes hypotension and bradyarrhythmia when infused faster than 50 mg/min, so blood pressure and ECG monitoring are required; extravasation causes tissue necrosis and purple glove syndrome. Chronic use causes gingival hyperplasia and cerebellar atrophy with ataxia and nystagmus.
• Fosphenytoin: a water-soluble phosphate ester prodrug formulated without propylene glycol, which is why it may be infused considerably faster (labeled up to 150 mg phenytoin-equivalents/min) with less hypotension and less local tissue injury; its characteristic nuisance effect is transient perineal/facial paresthesias and pruritus. Purple glove syndrome is a phenytoin, not fosphenytoin, phenomenon.
• Carbamazepine: SIADH-mediated hyponatremia (which itself lowers Na+ driving force), agranulocytosis/aplastic anemia, and Stevens-Johnson syndrome — FDA labeling directs HLA-B*1502 screening in patients of Asian ancestry before initiation.
• Valproate: hyperammonemic encephalopathy, hepatotoxicity, and neural tube defects; ACOG and AAN advise against use in people who may become pregnant when alternatives exist.
• IVIG: thrombosis, aseptic meningitis, renal dysfunction, and anaphylaxis in IgA deficiency. Plasma exchange: citrate-induced hypocalcemia and catheter complications.
• Local anesthetic systemic toxicity (emergency): perioral numbness and tinnitus precede seizures and, with bupivacaine, refractory cardiac arrest; ASRA recommends 20% lipid emulsion rescue.

• Demyelination slows, axonal loss shrinks: the single most tested nerve conduction study distinction is reduced conduction velocity with prolonged distal latency and conduction block (demyelinating, e.g., AIDP, CIDP, CMT1) versus reduced amplitude with preserved velocity (axonal). Within the axonal group, subclassify by the sensory response: reduced CMAP with spared SNAPs is the pure motor axonal pattern of AMAN, whereas reduced CMAP and SNAP occurs in AMSAN and in diabetic and toxic length-dependent axonal neuropathies.
• The refractory period is a Na+ channel property, not a pump property: absolute refractoriness reflects closed inactivation gates that require repolarization to reset. It enforces unidirectional propagation and caps firing frequency. The common distractor is attributing it to the Na+/K+-ATPase — only a minute fraction of the ion gradient is spent per action potential, so an axon poisoned with ouabain fires for many impulses before failing.
• All-or-none means frequency codes intensity: a stronger stimulus produces more action potentials per second, never a taller one. Amplitude scales with the Na+ equilibrium potential, which is why hyponatremia blunts the upstroke.
• Hypocalcemia causes tetany: extracellular Ca2+ screens membrane surface charge, so low Ca2+ lowers the effective threshold and neurons fire spontaneously. Do not reason from intracellular Ca2+ signaling — that is the classic trap.
• Hyperkalemia first excites, then paralyzes: modest elevation depolarizes toward threshold; severe elevation depolarizes past it and inactivates Na+ channels. Best next step in suspected hyperkalemia is an ECG, and if conduction is abnormal, IV calcium for membrane stabilization before insulin/glucose or a binder.
• Local anesthetics are use-dependent and pH-dependent: they enter as the neutral base and block the open/inactivated pore from inside as the cation, so rapidly firing small fibers (pain, autonomic) are blocked first — and infected acidic tissue traps the drug extracellularly, explaining anesthetic failure in an abscess.
• One oligodendrocyte myelinates many axons; one Schwann cell makes one internode — the anatomic basis for why CNS remyelination is poor and why MS and GBS behave so differently.
• Albuminocytologic dissociation is the GBS buzzword, and the best next step in a patient with ascending areflexic weakness is serial bedside vital capacity, not imaging; corticosteroids are not effective in GBS, whereas IVIG or plasma exchange are.