Chapter B: Basic Concepts in Electrical Stimulation

Topic 1: Resting Membrane Potential

Definition

Why the Cell Interior Is Negative

• K⁺ diffusion alone → -94 mV
• Na⁺ diffusion (slight) → reduces negative value
• Goldman equation result (both ions) → ~ -86 mV
• Electrogenic Na⁺-K⁺ pump → adds ~ -4 mV more
• Final RMP ≈ -70 mV (neuron), -80 to -90 mV (skeletal muscle)

Topic 2: Action Potential

Definition

Phases of an Action Potential

• Within <1 ms, the inactivation gate of Na⁺ channels closes - stopping Na⁺ entry
• Voltage-gated K⁺ channels open (more slowly) - K⁺ rushes OUT
• The rapid efflux of K⁺ restores the negative membrane potential

Voltage-Gated Ion Channels

• Activation gate (outside): opens rapidly when membrane reaches threshold
• Inactivation gate (inside): closes more slowly (a few ten-thousandths of a second after the activation gate opens), terminating Na⁺ influx

Na⁺ and K⁺ Conductance Changes

• At the onset of the AP, Na⁺ conductance rises more than 1,000-fold relative to K⁺ conductance - driving depolarization
• As Na⁺ channels inactivate, K⁺ conductance rises ~30-fold - driving repolarization
• The entire AP lasts approximately 1-2 milliseconds in a neuron; 1-5 ms in skeletal muscle

Key Features of Action Potentials

• All-or-none law: An AP either fires fully or not at all - there is no partial AP
• Refractory period: After an AP, the membrane cannot be re-excited (absolute refractory period) or needs a stronger-than-normal stimulus (relative refractory period), because the inactivation gate of Na⁺ channels will not reopen until the membrane repolarizes
• Threshold: Typically ~15-30 mV above the resting potential (approximately -55 mV in neurons)

Topic 3: Propagation of the Action Potential

Definition

Mechanism of Propagation

1. The depolarized spot becomes positive inside while adjacent resting areas remain negative inside
2. This creates a local current flow - positive ions flow intracellularly from the active (depolarized) region toward the adjacent resting region, and extracellularly in the reverse direction
3. These local currents depolarize the adjacent membrane to threshold
4. Voltage-gated Na⁺ channels in the adjacent region open, generating a new AP there
5. This new AP then depolarizes the next adjacent region, and so on
6. The wave of depolarization continues along the entire fiber until it reaches the end

Conduction in Myelinated vs Unmyelinated Fibers

• Current flows continuously along the entire membrane
• The AP moves slowly (0.5-2 m/sec)
• More energy is consumed

• Myelin sheath insulates the axon, except at Nodes of Ranvier (gaps every 1-3 mm)
• Ion channels are concentrated at the Nodes of Ranvier
• The AP "jumps" from one node to the next (saltatory = "jumping" from Latin)
• This greatly increases conduction velocity (up to 70-120 m/sec in large myelinated fibers) and saves metabolic energy
• In skeletal muscle, conduction velocity is 3-5 m/sec (about 1/13 that of large myelinated nerve fibers)

Energy Restoration After Propagation

Clinical Relevance

• Demyelinating diseases (e.g., Multiple Sclerosis, Guillain-Barre syndrome) destroy the myelin sheath - this slows or blocks AP propagation, causing weakness, sensory loss, and paralysis
• Local anesthetics (e.g., lidocaine) block voltage-gated Na⁺ channels in nerve fibers, preventing AP generation and propagation

Topic 4: Motor Unit

Definition

• A single alpha motor neuron (located in the spinal cord ventral horn or brainstem)
• All the muscle fibers it innervates

Structure of a Motor Unit

• The motor neuron's cell body is in the anterior horn of the spinal cord
• Its axon exits through the ventral root and travels in a peripheral nerve to the muscle
• When the axon reaches the muscle, it branches and innervates multiple muscle fibers scattered throughout the muscle
• A typical muscle is controlled by a few hundred motor neurons clustered in a motor nucleus in the spinal cord
• The number of muscle fibers per motor unit varies:
  • Small, precise muscles (e.g., extraocular muscles, hand muscles): 3-10 fibers per motor unit - allows fine motor control
  • Large, powerful muscles (e.g., quadriceps, gastrocnemius): hundreds to thousands of fibers per motor unit - for power generation

How a Motor Unit Fires

1. Synaptic input from descending motor pathways depolarizes the motor neuron above threshold
2. The motor neuron generates an AP that propagates along its axon to all neuromuscular junctions
3. The AP releases acetylcholine (ACh) at the neuromuscular junction (NMJ)
4. ACh binds to nicotinic receptors on the sarcolemma of each muscle fiber
5. This triggers an AP in each muscle fiber, which propagates via the T-tubule system and leads to Ca²⁺ release from the sarcoplasmic reticulum and muscle contraction

Types of Motor Units

• Slow motor units have long twitch contraction times and are used for sustained, postural activities
• Fast fatigable units have short contraction times and large forces - used for brief, explosive movements

Recruitment and Force Grading

1. Recruitment (Spatial summation): Activating more motor units to increase force. Small (slow) motor units are recruited first, then progressively larger (faster) ones - this is Henneman's Size Principle (1965). Small motor neurons have lower thresholds and are recruited before large ones.
2. Rate coding (Temporal summation): Increasing the firing frequency of already-active motor units. A single AP produces a twitch. When APs fire rapidly enough that twitches overlap and summate, the result is a tetanic contraction - a smooth, sustained, stronger contraction.

Mechanical Responses

• Twitch: The mechanical response to a single AP
• Unfused tetanus: Low-frequency stimulation; individual twitches are visible as ripples but partially summate
• Fused tetanus (complete tetanus): High-frequency stimulation; twitches fully summate into a smooth, maximal contraction

Clinical Relevance of Motor Unit Concepts

• EMG (Electromyography) records motor unit action potentials (MUAPs) to diagnose neuromuscular diseases
• In lower motor neuron lesions (e.g., polio, ALS), motor neurons are lost - surviving neurons sprout to reinnervate orphaned muscle fibers, creating giant motor units
• Electrical stimulation therapy works by artificially activating motor units through applied electrical current - forms the basis of neuromuscular electrical stimulation (NMES) and functional electrical stimulation (FES)
• Physical training can alter motor unit properties (e.g., endurance training shifts fast fatigable units toward more fatigue-resistant profiles)

Summary Table

Chapter B: Basic Concepts in Electrical Stimulation

Topic 1: Resting Membrane Potential (RMP)

Definition

Three Factors That Establish the RMP

• Pumps 3 Na⁺ OUT and 2 K⁺ IN per cycle using ATP energy
• Because more positive ions are pumped out than in, it creates a net deficit of positive charge inside
• This directly contributes about -4 mV to the resting potential
• It also establishes the ion concentration gradients:

• K⁺ is ~35x more concentrated inside than outside
• K⁺ continuously leaks OUT down its concentration gradient through "leak" channels
• This outflow of positive ions makes the inside more negative
• K⁺ alone would give a Nernst potential of -94 mV

• Membrane has slight permeability to Na⁺ (100x less permeable than to K⁺)
• Na⁺ leaks IN slightly, partially offsetting K⁺ effect
• Na⁺ alone would give a Nernst potential of +61 mV
• Combined (Goldman equation): approximately -86 mV from diffusion + (-4 mV pump) = ~-90 mV

Summary of RMP Values

Topic 2: Action Potential

Definition

Phases of an Action Potential

• Membrane is "polarized" - inside negative, outside positive
• Voltage-gated Na⁺ channels are CLOSED (activation gate shut)
• K⁺ leak channels are open; Na⁺-K⁺ pump maintains gradients

• A stimulus raises the membrane potential toward threshold (-55 mV)
• At threshold: voltage-gated Na⁺ channels open explosively via positive feedback
• Na⁺ rushes IN → membrane potential shoots from -70 mV up to +35 to +40 mV (overshoot)
• Na⁺ conductance increases up to 5,000-fold
• This entire process takes a fraction of a millisecond

• Inactivation gate of Na⁺ channels closes → Na⁺ entry stops
• Voltage-gated K⁺ channels open (slowly) → K⁺ rushes OUT
• Membrane potential rapidly returns toward negative

• K⁺ channels stay open slightly too long
• Membrane briefly overshoots to ~-80 mV (more negative than resting)
• K⁺ channels eventually close → membrane returns to -70 mV

Voltage-Gated Ion Channels in Detail

• Resting (-70 mV): Activation gate CLOSED, inactivation gate OPEN → no Na⁺ flow
• Activated (-70 to +35 mV): Activation gate OPENS → Na⁺ floods in → depolarization
• Inactivated (+35 to -70 mV, delayed): Inactivation gate CLOSES → Na⁺ entry stops → repolarization begins. The inactivation gate will NOT reopen until the membrane repolarizes back to resting potential

• Resting (-70 mV): Gate CLOSED
• Slow activation (during repolarization): Gate opens SLOWLY → K⁺ flows out → restores negative potential

Ion Conductance Changes During AP

• During the early AP: Na⁺/K⁺ conductance ratio rises >1,000-fold → Na⁺ dominates → depolarization
• During repolarization: Na⁺ channels inactivate, K⁺ conductance rises ~30-fold → K⁺ dominates → repolarization
• Total AP duration: ~1-2 ms in neurons; 1-5 ms in skeletal muscle

Key Laws and Properties

Action Potential in Skeletal Muscle vs Neuron

Topic 3: Propagation of Action Potential

Definition

Mechanism of Propagation

• Inside the fiber: positive ions flow FROM the active region TOWARD the resting region
• Outside the fiber: current flows in the reverse direction
• These local currents form a complete circuit

Why Does the AP Travel in Only One Direction?

Propagation in Unmyelinated vs Myelinated Fibers

• Local currents flow continuously along the entire membrane surface
• Every section of membrane must be depolarized one by one
• Conduction velocity: 0.5 - 2 m/sec (slow)
• High metabolic energy cost (more Na⁺-K⁺ pump work needed)

• Myelin sheath (formed by Schwann cells) insulates the axon
• Ion channels are concentrated ONLY at Nodes of Ranvier (bare gaps every 1-3 mm)
• Local currents jump directly from one node to the next
• The AP "leaps" (Latin: saltare) from node to node
• Conduction velocity: up to 70-120 m/sec (large myelinated fibers)
• Much more energy-efficient - only the nodes need to be repolarized

Energy Restoration After Propagation

Clinical Applications

• Multiple Sclerosis / Guillain-Barré syndrome: Demyelination slows or blocks AP propagation → weakness, sensory loss, paralysis
• Local anesthetics (lidocaine, bupivacaine): Block voltage-gated Na⁺ channels → prevent AP generation and propagation → pain relief
• Electrical nerve stimulation (TENS, NMES): Applied current generates APs in nerve fibers, which then propagate naturally

Topic 4: Motor Unit

Definition

• One alpha (α) motor neuron (in the spinal cord ventral horn or brainstem)
• All the skeletal muscle fibers it innervates

Anatomy of a Motor Unit

Brain/Descending tracts
        ↓
Alpha Motor Neuron (anterior horn, spinal cord)
        ↓ (axon exits via ventral root → peripheral nerve)
        ↓
Axon branches at the muscle
        ↓
Neuromuscular Junctions (NMJ) on each muscle fiber
        ↓
All muscle fibers contract simultaneously

• A typical muscle is controlled by a few hundred motor neurons clustered in a motor nucleus
• Muscle fibers of one motor unit are scattered throughout the muscle (not clustered together)
• This ensures smooth, even force distribution across the entire muscle

Innervation Ratio (Fibers per Motor Unit)

How a Motor Unit Fires - Step by Step

1. Synaptic input from upper motor neurons depolarizes the alpha motor neuron above threshold
2. AP is generated in the motor neuron and propagates along its axon to all its terminals
3. At each neuromuscular junction (NMJ):
   • AP releases acetylcholine (ACh) from presynaptic terminal
   • ACh binds to nicotinic receptors on the muscle sarcolemma
   • End-plate potential (EPP) is generated → triggers a muscle AP
4. The muscle AP spreads along the sarcolemma AND down the T-tubules into the fiber's interior
5. T-tubule APs trigger Ca²⁺ release from the sarcoplasmic reticulum
6. Ca²⁺ binds troponin → allows actin-myosin cross-bridge cycling → muscle contraction

Types of Motor Units

• Type I units are recruited for prolonged activities: walking, maintaining posture
• Type II units are recruited for brief, powerful bursts: jumping, sprinting, lifting heavy weights

How the Nervous System Controls Muscle Force

• To increase force, more motor units are activated
• Follows Henneman's Size Principle (1965): Small (low-threshold) motor units are recruited FIRST, then progressively larger ones as more force is needed
• Small motor neurons have lower thresholds because their smaller surface area = higher input resistance = easier to depolarize
• Order: Type I → Type IIa → Type IIb

• Already-active motor units fire faster to increase force
• A single AP → single twitch contraction
• Repeated APs at increasing rates → twitches overlap and summate:
  • Low frequency → Unfused tetanus (rippled, incomplete summation)
  • High frequency → Fused tetanus = smooth, maximal sustained contraction

Mechanical Responses of a Motor Unit

Physical Training Effects on Motor Units

• Increases mitochondrial density and oxidative capacity of muscle fibers
• Can shift Type IIb toward more fatigue-resistant IIa phenotype
• Increases capillary density around motor units

• Increases muscle fiber cross-sectional area (hypertrophy)
• Improves neural drive (more efficient recruitment and rate coding)
• No change in number of motor neurons

Clinical Relevance of Motor Units

Master Summary