Electrical signalling is the rapid transmission of information via changes in membrane voltage across excitable cells, primarily neurons. It operates through the coordinated opening and closing of voltage-gated ion channels, generating action potentials that propagate along axons at speeds up to 120 m/s. This system enables millisecond-scale integration of sensory input, motor control, and cognitive processing across the nervous system.
Think of electrical signalling as a wave in a stadium: one person stands and sits, triggering the next person to do the same, creating a propagating wave without any single person moving far. The neuron's membrane is like a row of stadium seats, each section equipped with spring-loaded gates (ion channels). At rest, most gates are locked with sodium outside and potassium inside—this is your ticket security system maintaining order. When a signal arrives, the first gate springs open, letting sodium flood in like fans rushing through a gate. This triggers the next gate, and the next, creating a self-propagating wave that races down the axon. But here's the clever part: immediately after each gate opens, it locks itself for a brief refractory period (like a turnstile that must reset), ensuring the wave only moves forward, never backward. In myelinated fibers, the wave doesn't open every single gate—instead it jumps between gaps in the insulation like a stone skipping across water, moving 50-100 times faster than if it had to touch every point.
Electrical signalling operates through a precise sequence of ion channel state changes:
Resting State:
- Na⁺/K⁺-ATPase pumps maintain ~-70mV membrane potential by pumping 3 Na⁺ out and 2 K⁺ in (consuming 1 ATP per cycle)
- Voltage-gated Na⁺ channels remain closed (activation gates shut, inactivation gates open)
- Voltage-gated K⁺ channels remain closed
- Leak channels permit slight K⁺ efflux, maintaining negative interior
Action Potential Cascade:
- Depolarization threshold (-55mV): Voltage-gated Na⁺ channels open → Na⁺ influx → rapid depolarization to +40mV
- Peak: Na⁺ channels inactivate (ball-and-chain inactivation gate closes) → Na⁺ entry stops
- Repolarization: Voltage-gated K⁺ channels open → K⁺ efflux → return toward -70mV
- Hyperpolarization: K⁺ channels slow to close → brief undershoot to -80mV
- Refractory periods:
- Absolute (1-2ms): Na⁺ channels inactivated, no stimulus can trigger another action potential
- Relative (2-4ms): Na⁺ channels recovering, only supramaximal stimulus effective
Propagation Mechanisms:
Unmyelinated fibers:
- Continuous conduction: local current spreads to adjacent membrane → sequential depolarization
- Velocity = 0.5-2 m/s (diameter-dependent)
Myelinated fibers:
- Saltatory conduction: action potentials regenerate only at Nodes of Ranvier (1-2 μm gaps every 0.2-2 mm)
- Myelin (oligodendrocytes in CNS, Schwann cells in PNS) provides high-resistance, low-capacitance insulation
- Velocity = 3-120 m/s (diameter-dependent, proportional to fiber diameter in µm)
- Na⁺ channel clustering at nodes (1200-2000 channels/μm²) ensures reliable regeneration
graph TD
A[Resting Potential -70mV] -->|Stimulus reaches threshold -55mV| B["Na+ channels open"]
B --> C["Rapid Na+ influx"]
C --> D["Depolarization to +40mV"]
D --> E["Na+ channels inactivate"]
E --> F["Voltage-gated K+ channels open"]
F --> G["K+ efflux"]
G --> H[Repolarization toward -70mV]
H --> I[Hyperpolarization -80mV]
I --> J["Na+/K+ ATPase restores gradients"]
J --> A
D -->|Depolarizes adjacent membrane| K[Propagation to next segment]
K -->|Unmyelinated| L[Continuous conduction 0.5-2 m/s]
K -->|Myelinated| M[Saltatory conduction 3-120 m/s]
M --> N[Nodes of Ranvier only]
Synaptic Transmission:
- Action potential reaches presynaptic terminal → voltage-gated Ca²⁺ channels open
- Calcium influx (10⁻⁷ to 10⁻⁴ M rise) triggers SNARE protein complex formation
- Vesicle fusion releases Neurotransmitters into synaptic cleft (0.2ms response time)
- Electrical → chemical → electrical signal conversion
Energy Demands:
- Active human brain: ~1 billion ATP molecules/second
- Na⁺/K⁺-ATPase accounts for 20-40% of resting brain ATP consumption
- Single action potential: ~10⁸ Na⁺ ions enter per 1cm of unmyelinated axon
- Myelination reduces energy cost 5000-fold per unit length
Electrical signalling dysfunction underlies a spectrum of neurological and pain conditions in cPNI practice:
Neuropathic Pain Conditions:
- Small fiber neuropathy: damaged C and A-delta fibres show altered electrical properties, generating spontaneous action potentials at ectopic sites (particularly sensitive to inflammatory cytokines like TNF-α and IL-1β which directly modulate voltage-gated sodium channels)
- Peripheral neuropathy: demyelination slows conduction velocity (measurable via nerve conduction studies: <40 m/s in large fibers indicates pathology), creating temporal dispersion that manifests as burning, tingling, or stabbing sensations
- Ion channel channelopathies: genetic variants in SCN9A (Nav1.7) cause either pain insensitivity (loss-of-function) or erythromelalgia (gain-of-function with hyperexcitability)
Inflammatory Modulation:
Metabolic Impact on Signalling:
- Hypoxia and mitochondrial dysfunction impair ATP production → Na⁺/K⁺-ATPase pump failure → loss of resting potential → spontaneous depolarization (explains fatigue-related cognitive symptoms)
- Hyperglycaemia and AGEs glycosylate ion channel proteins, altering their kinetics (mechanism underlying diabetic neuropathy progression)
cPNI Metamodel Connections:
- Selfish Brain: prioritizes glucose and oxygen delivery to maintain electrical signalling capacity, explaining why cognitive decline emerges when metabolic flexibility is lost
- Mismatch Paradigm: modern sedentary lifestyle reduces neurotrophic support (BDNF, NGF) for myelin maintenance, accelerating age-related slowing of conduction velocity
- 5+2 Metamodel: chronic stress elevates cortisol, which reduces hippocampal neurogenesis and impairs action potential firing patterns critical for memory consolidation
Clinical Thresholds:
- Normal nerve conduction velocity: median nerve >49 m/s, ulnar nerve >49 m/s, sural nerve >40 m/s
- Pathological slowing: <70% of lower limit indicates demyelination
- Compound muscle action potential amplitude: <80% of normal suggests axonal loss
- F-wave latency (tests proximal conduction): >31ms in upper limb or >56ms in lower limb indicates proximal dysfunction
Intervention Implications:
- Conduction velocity range: Unmyelinated C-fibers (0.5-2 m/s) vs. large myelinated A-alpha fibers (80-120 m/s)—a 60-240-fold difference in transmission speed
- Action potential duration: 1-2 milliseconds from initiation to full repolarization in most neurons
- Absolute refractory period: ~1ms, limits maximum firing frequency to approximately 1000 Hz (though sustained rates rarely exceed 200-300 Hz)
- Threshold voltage: typically -55mV (15mV depolarization from -70mV resting potential required to trigger action potential)
- All-or-nothing principle: once threshold is reached, action potential amplitude is constant (~110mV from peak to trough) regardless of stimulus strength
- Myelination increases speed: saltatory conduction is 50-100× faster than continuous conduction for same diameter fiber
- Energy cost: brain uses 20% of body's total oxygen despite being 2% of body mass, largely to maintain ion gradients for electrical signalling
- Node of Ranvier spacing: 0.2-2mm intervals depending on fiber diameter and location (shorter in CNS, longer in PNS)
- Temperature dependence: conduction velocity decreases ~2 m/s per 1°C drop (clinical relevance in hypothermia, cold exposure)
- Demyelination consequences: in multiple sclerosis, 30-50% reduction in conduction velocity creates temporal summation failures at synapses
- Action potential — The discrete electrical event that propagates along axons as the fundamental unit of electrical signalling
- Neurotransmitters — Chemical messengers released when action potentials trigger calcium influx at synaptic terminals
- Myelin — Lipid-rich insulation produced by oligodendrocytes and Schwann cells that enables rapid saltatory conduction
- Ion channels — Voltage-gated proteins that selectively permit Na⁺, K⁺, or Ca²⁺ flux to generate and propagate electrical signals
- Neuroinflammation — Cytokines like TNF-α and IL-1β alter voltage-gated channel kinetics, disrupting normal electrical signalling
- ATP — Energy currency consumed by Na⁺/K⁺-ATPase pumps to maintain the ion gradients essential for electrical signalling
- Sodium channels — Nav1.1-1.9 isoforms responsible for rapid depolarization phase of action potentials
- Calcium — Triggers neurotransmitter release when action potentials open voltage-gated Ca²⁺ channels at presynaptic terminals
- Small fiber neuropathy — Pathological condition where C and A-delta fiber electrical properties become abnormal, causing burning pain
- Peripheral neuropathy — Demyelination or axonal damage slows conduction velocity and disrupts normal electrical signalling patterns
- Central sensitization — Enhanced excitability of spinal neurons alters electrical signalling thresholds in pain pathways
- BDNF — Neurotrophic factor supporting myelin maintenance and electrical signalling capacity in neurons
- Mitochondria — Produce ATP required for Na⁺/K⁺-ATPase function; dysfunction impairs electrical signalling
- Chronic inflammation — Elevates cytokines that phosphorylate ion channels, lowering activation thresholds and creating hyperexcitability
- Multiple Sclerosis — Autoimmune demyelination disrupts saltatory conduction, causing conduction blocks and slowed transmission
- Inflammatory cytokines — IL-6, TNF-α, and IL-1β directly modulate voltage-gated channel gating kinetics
- Oxidative Stress — Reactive oxygen species damage ion channel proteins, altering their electrical properties
- Vagus nerve — Major parasympathetic nerve using electrical signalling to regulate inflammation via the cholinergic anti-inflammatory pathway
- Hypothalamus — Integrates electrical signals from multiple brain regions to coordinate neuroendocrine responses
- Cognitive decline — Associated with reduced conduction velocity and synaptic transmission efficiency in aging
- Synaptic plasticity — Long-term changes in electrical signalling strength underlie learning and memory formation
- Epilepsy — Pathological synchronous electrical signalling in neuronal networks creates seizure activity
- Acetylcholine — Neurotransmitter released by electrical signalling at neuromuscular junctions and autonomic synapses
- Dopamine — Neurotransmitter whose release is triggered by electrical signalling in reward and motor pathways
- Hypoxia — Reduces ATP availability, impairing Na⁺/K⁺-ATPase function and degrading electrical signalling capacity