Physiological Principles Underlying Electrodiagnosis and Neurophysiologic Testing

Overview and Description

Electrodiagnosis (EDX) isintegral to physical medicine and rehabilitation practice. A referral for electrodiagnostic studies is indicated when the clinician is uncertain about the etiology of neuromuscular symptoms, diagnosing and/or confirming a clinical picture, or seeking prognostic information. As an extension of the history and physical examination, electrodiagnostic studies are used to clarify the clinical picture of various neuromuscular pathologies. An electrodiagnostician needs to understand the basic physiological principles of nerve conduction studies (NCS) and needle electromyography (EMG). This article reviews and outlines these principles.

Relevance to Clinical Practice

Resting potential

The cell membranes of both nerves and muscles regulate the interchange of substances between the exterior and interior. It allows certain ions to pass freely while restricting the diffusion of others, resulting in an electrochemical gradient across the membrane. The imbalance of intracellular and extracellular charge is referred to as the resting potential. Nerve and muscle cells must maintain a steady resting potential to appropriately respond to stimuli.

Intracellular fluid has a higher potassium concentration but lower sodium and chloride concentrations relative to extracellular fluid. A sodium-potassium ATPase uses energy to move both Na⁺ and K⁺ against their concentration gradients (transporting 3 Na⁺ ions out for every 2 K⁺ ions into the cell), resulting in a large concentration of Na⁺ ions in the extracellular fluid and a large concentration of K⁺ ions in the intracellular fluid. Additionally, the membrane is selectively more permeable to K⁺, allowing K⁺ to freely leak down its concentration gradient into the extracellular space, leading to further accumulation of positively charged ions extracellularly. These factors contribute to a polarized cell membrane, where the inside of the cell is negatively charged relative to the outside.⁸

During electrochemical equilibrium, the net movement of ions across the membrane is zero. The calculated resting potential is derived by using the Nernst equation. With K⁺, for example,

where R is the gas constant, T is the temperature in Kelvin (K), z is the ion charge, F is Faraday’s constant (~96,500 coulombs/mol), [K⁺]e is the extracellular concentration of the ion, and [K⁺]i is the intracellular concentration of the ion. The equation results in -97 mV potential for K⁺. In comparison, the Nernst potential is ⁺60 mV for sodium alone.

To determine the membrane resting potential for any cell, the collective Nernst equations of K⁺, Na⁺ and Cl^– must be combined using the Goldman–Hodgkin–Katz equation (also called the Goldman Equation)

where Vm is the membrane potential, R is the gas constant, T is the temperature in K, F is Faraday’s constant, Pion is the membrane permeability of K⁺, Na⁺, and Cl^– ions, and [ion]i are the respective extracellular and intracellular concentrations of the ion. K⁺ is mainly responsible for the resting potential because the Na⁺ concentration is lower intracellularly, and anions have poor membrane permeability. The combination of resting potentials of the three ions (K⁺, Na⁺, Cl^–) yields a resting potential of approximately -75 mV in nerves and -80 mV in muscle.

To summarize

A resting potential is continuously maintained across the membrane of neurons and myocytes by establishing an electrochemical gradient. The gradient is established by the separation of electrical charges via selective K⁺ channels and sodium-potassium ATPase pumps, resulting in a net negative intracellular charge relative to the extracellular.⁸

Membrane excitability

A rapid increase in membrane potential followed by a return to its resting potential is called an action potential (AP). If a neuron or myocyte is electrically stimulated, the transmembrane potential changes, moving closer to neutral. Every time the current exceeds 10-30 mV above the resting potential, known as the threshold potential, it creates an action potential that then propagates depolarization along the entire cellular membrane.

For depolarization to occur, the membrane voltage must rise sufficiently to increase the membrane permeability to Na⁺ ions in the extracellular fluid. Voltage-gated Na⁺ channels are molecular pores that open and close in response to changes in membrane potential. When the threshold potential is reached, voltage sensors in the Na⁺ channels respond by opening the channels, allowing Na⁺ to pass intracellularly. Once the membrane is sufficiently depolarized, voltage-gated K⁺ channels will open. This increases membrane permeability to K⁺ and stimulates K⁺ efflux from the cell, counteracting the intracellular positive charge by Na+ influx. Additionally, when a greater positive charge accumulates within the cell, a second Na⁺ gate, called the inactivation gate, closes the Na⁺ channels. The membrane becomes temporarily unexcitable, which is referred to as the refractory period.⁸

Temperature also plays a role in Na+ channel kinetics. Cold temperature, for example, causes a slowing of Na+ channel inactivation gate closure, leading to extended depolarization. In contrast, high temperatures promote faster gate closure. These mechanisms play a role in certain conditions such as paramyotonia congenita.¹⁴

The AP is an all-or-none response that propagates within 1-2 ms and is moving away from the stimulation site. The conduction velocity (CV) of this propagated signal depends on several factors, including the diameter, insulation, and temperature of the axon. Larger axons conduct the action potential more rapidly than smaller-diameter fibers.^14,19

Some nerve fibers are encased in an insulating material called myelin. Myelin is laid down in concentric spirals and supported by Schwann cells in the peripheral nervous system. This creates a strong insulator, which decreases ion flow in this area by approximately 5000-fold. Segments of nerve covered by myelin are known as internodes. Between the internodes, the axons are exposed. These unmyelinated portions are known as the nodes of Ranvier and are about 1-2 micrometers in length. Depolarization occurs only at the nodes of Ranvier, and the action potential is propagated by way of saltatory conduction, where ‘saltatory’ is Latin for ‘leaping’ or ‘bounding’. After depolarizing one node, the AP jumps to the next and continues.

The CV of the action potential is slower in unmyelinated fibers, since the entire nerve fiber must be depolarized to propagate the signal. CV for unmyelinated axons ranges from 0.2-1.5 m/s. In contrast, myelinated human nerve fibers conduct at 35-75 m/s, which is approximately 50 times faster. In addition, there is overall less ion loss in myelinated fibers, resulting in less energy required to re-establish the resting potential.

Muscle contraction

A motor unit consists of an alpha motor neuron and all the muscle fibers its axon innervates. Activation of this motor unit will produce a motor unit action potential (MUAP). In the peripheral nervous system, alpha motor neuronsomas reside in the anterior horn of the spinal cord, and the axon extends into the periphery, gradually dividing into many branches before ending at the neuromuscular junction (NMJ). The NMJ is essentially an electrochemical link between the nerve terminal ends and the muscle. As the nerve AP reaches the presynaptic side of the NMJ, voltage-gated channels are activated, allowing influx of calcium ions (Ca2⁺). Ca2⁺ influx causes presynaptic vesicles called quanta to fuse with the cell membrane, releasing acetylcholine (ACh) into the synaptic cleft. Some quanta also fuse with the membrane spontaneously, resulting in miniature end-plate potentials (MEPPs). The MEPPs are too small to trigger a normal AP.

The post-synaptic membrane contains several folds lined with ACh receptors. As ACh diffuses across the synaptic cleft, it binds to post-synaptic ACh receptors, triggering the influx of Na⁺ to depolarize the muscle fiber membrane. When a muscle membrane depolarizes at the end plate, the signal propagates along the entire membrane and down the transverse tubular (T-tubule) system, then deeper into the muscle fibers. Membrane depolarization is then detected by voltage-gated dihydropyridine receptors, which in turn activate Ryanodine receptors (RyR). The activated RyR causes the sarcoplasmic reticulum to release Ca2⁺ into the muscle cells.

Muscle fibers contain bundles of myofibrils, which are composed of many filaments. Two of these filaments, actin and myosin, overlap and form a sarcomere, or the basic contractile unit of the muscle. Actin is a thin filament that interdigitates with myosin, a thicker filament. In the resting state, the binding sites on actin are covered by tropomyosin.¹⁹

When Ca2⁺ is released from the sarcoplasmic reticulum, it then binds to troponin, causing tropomyosin to change configuration and expose the binding sites for myosin. The myosin heads use ATP to cause muscle shortening and generate force. When a muscle contracts, the sarcomere shortens because the thin filaments move together. In a relaxed state, the thin filaments move apart. Skeletal muscle contains many thousands of muscle fibers that act in synchrony to produce the force for muscle contraction.

How are these potentials recorded?

Electrodiagnosis utilizes tools to record intracellular changes in the extracellular space. Surface electrodes record potentials transmitted to the skin during NCSs, whereas needle electrodes record EMG potentials as the intracellular potentials are transmitted through tissue to the electrodes. When potentials are recorded near their source generation, they are called near-field potentials. These potentials produce a triphasic response, or waveform, as the advancing AP approaches, passes under, and then away from the recording electrode. The electrical correlate is an initial positive, then a negative, and then a trailing positive phase. If a volume conducted near-field potential is directly under the recording electrode, an initial negative phase is seen.¹² The potential is biphasic and seen at the end plate. Examples of near-field potentials are compound motor action potential (CMAP), nerve action potential (NAP), sensory nerve action potential (SNAP), and motor unit action potentials (MUAPs).

Far-field potentials

Far-field potentials are routinely used in somatosensory evoked potential (SSEP) recordings. Two recording electrodes are used – one closer and one farther from the source, both of which see the source at the same time.² Far-field potentials have the potential to superimpose on near-field activity during NCSs.¹³ SSEPs can be used in surgical cases to detect electrophysiological changes in nerve conduction that may predict nerve injury.^6,15

Cutting Edge/Unique Concepts/Emerging Issues

• Over the past two decades, significant improvements in computer software have allowed better signal averaging. Automatic calculations of different parameters of NCSs by the computer are now possible. Some machines provide software to assist diagnosticians in generating reports and can interface with electronic medical records. More recently, there has been investigation into the roles of artificial intelligence and machine learning in enhancing the interpretation and reporting of EDX studies. This includes the potential to identify subtle abnormalities, which were previously technically challenging.⁹
• Electrodiagnosticians are increasingly using ultrasound while performing NCSs and needle EMG. A prior study shows that CMAPs for specific nerves improved when using ultrasound guidance for electrode placement instead of landmark guidance.²¹ Ultrasound (US) can detect and isolate pathologies that may not be recognized without direct visualization of the muscle or nerve.⁷ Prior studies demonstrate a correlation between the pathologic appearance of peripheral nerves on ultrasonography and EMG-NCSs.^5,20 A recent pilot study shows that US may also be useful in motor unit scanning EMG.¹⁶ In addition, using peripheral nerve stimulation in conjunction with US-guided EMG improved sensitivity and earlier detection of motor unit potentials after traumatic nerve lesions.¹⁷
• Magnetic resonance imaging (MRI) is another imaging modality that correlates well with electrodiagnostic findings, as noted by a growing body of evidence. Notably, these diagnostic tools can provide complementary information in certain pathologies.^4,10
• Many neuromuscular complications have resulted from the global COVID-19 pandemic. More recently, literature suggests that COVID-19 could lead to a demyelinating motor neuropathy and myopathy.² Silent Neuropathy of Long Covid: Small Fiber Neuropathy (SFN): While standard NCS/EMG remains normal in up to 100% of Long COVID cases, a new Multimodal EDX Protocol (including Sympathetic Skin Response, Cutaneous Silent Period, and Sudoscan) has shown that approximately 33–50% of these patients actually have measurable SFN^1,10.
• Recent clinical frameworks have expanded the utility of electrodiagnosis from purely diagnostic to a critical perioperative tool for nerve transfer surgery, particularly in cervical spinal cord injury (SCI). Clinicians now use CMAP amplitude and recruitment patterns to identify robust donor nerves (typically with 5/5 strength and normal electrical parameters) to bypass damaged segments. Furthermore, serial needle EMG is increasingly used postoperatively to identify ‘nascent’ motor units—small, polyphasic potentials that provide the first physiological evidence of successful reinnervation as early as 3–6 months following the transfer.³
• Advances in genetics, including next-generation sequencing and whole-genome sequencing, have promoted understanding and classifications of several genetic conditions. For example, Hereditary Polyneuropathies are now understood as a group of polyneuropathies with an increasing number of gene associations. EDX has been integrated into playing a key role in further subclassifications based on varying electrophysiologic features.¹⁸

Gaps in Knowledge/Evidence Base

• Despite recent advances in genetics, it is not completely understood how nerve conduction abnormalities are related to many genetic conditions.
• The effects of medication on remyelination are still poorly understood.
• Due to limitations in sensitivity of signal processing as well as the size of the thinnest nerves, electromyography remains unable to detect pathologies in small fiber polyneuropathies
• Despite emerging evidence, more research is needed to understand the effects of COVID-19 on the peripheral nervous system.

References

1. Abrams RMC, Simpson DM, Navis A, Jette N, Zhou L, Shin SC. Small fiber neuropathy associated with SARS-CoV-2 infection. Muscle Nerve. Apr 2022;65(4):440-443. doi:10.1002/mus.27458
2. Al-Mazidi S, Al-Dakhil L. Electrophysiological assessment in patients with COVID-19-related peripheral neuropathies and myopathies: a systematic review. J Neurophysiol. 2023 Jan 1;129(1):191-198. doi: 10.1152/jn.00386.2022.
3. Berger M, Adewuyi A,  Fox I,  Franz C, Clinical electrodiagnostic evaluation for nerve transfer surgery in spinal cord injury: a new indication and clinical pearls J Neurophysiology 2022 Aug 31;128(4):847–853. doi: 10.1152/jn.00289.2022
4. Deroide N, Bousson V, Mambre L, Vicaut E, Laredo JD, Kubis N. Muscle MRI STIR signal intensity and atrophy are correlated to focal lower limb neuropathy severity. Eur Radiol. Mar 2015;25(3):644-51. doi:10.1007/s00330-014-3436-y
5. Domkundwar S, Autkar G, Khadilkar SV, Virarkar M. Ultrasound and EMG-NCV study (electromyography and nerve conduction velocity) correlation in diagnosis of nerve pathologies. J Ultrasound. Jun 2017;20(2):111-122. doi:10.1007/s40477-016-0232-3
6. Epstein NE, Danto J, Nardi D. Evaluation of intraoperative somatosensory-evoked potential monitoring during 100 cervical operations. Spine (Phila Pa 1976). May 1993;18(6):737-47. doi:10.1097/00007632-199305000-00011
7. Gentile L, Coraci D, Pazzaglia C, et al. Ultrasound guidance increases diagnostic yield of needle EMG in plegic muscle. Clin Neurophysiol. Feb 2020;131(2):446-450. doi:10.1016/j.clinph.2019.10.012
8. Grider MH, Jessu R, Kabir R. Physiology, Action Potential. [Updated 2023 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538143/
9. Gorenshtein A, Sorka M, Khateb M, Aran D, Shelly S. Agent-guided AI-powered interpretation and reporting of nerve conduction studies and EMG (INSPIRE). Clin Neurophysiol. 2025 Sep;177:2110792. doi: 10.1016/j.clinph.2025.2110792.
10. Kamath S, Venkatanarasimha N, Walsh MA, Hughes PM. MRI appearance of muscle denervation. Skeletal Radiol. May 2008;37(5):397-404. doi:10.1007/s00256-007-0409-0
11.  Khoo A, Manuel K, Ng T, Crotty M, Non-invasive electrodiagnostic testing for small fiber neuropathy in long COVID-19 BMJ Neurol Open. 2026 Jan 29;8(1):e001399. doi: 10.1136/bmjno-2025-001399
12. Kimura J. Principles and pitfalls of nerve conduction studies. Annals of neurology. 1984;4:415-429. doi:10.1002/ana.410160402
13. Kimura J. Volume conduction, waveform analysis, and near- and far-field potentials. Handb Clin Neurol. 2019;160:23-37. doi:10.1016/B978-0-444-64032-1.00002-3
14. Kriegeskorte S, Bott R, Hampl M, Korngreen A, Hausmann R, Lampert A. Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents. J Gen Physiol. 2023 Sep 4;155(9):e202213312. doi: 10.1085/jgp.202213312
15. Lueders H, Gurd A, Hahn J, Andrish J, Weiker G, Klem G. A new technique for intraoperative monitoring of spinal cord function: multichannel recording of spinal cord and subcortical evoked potentials. Spine (Phila Pa 1976). 1982;7(2):110-5. doi:10.1097/00007632-198203000-00004
16. Maitland S, Hall J, McNeill A, Stenberg B, Schofield I, Whittaker R. Ultrasound-guided motor unit scanning electromyography. Muscle Nerve. Dec 2022;66(6):730-735. doi:10.1002/mus.27720
17. Padua L, Fusco A, Erra C, et al. Ultrasound-guided-electromyography in plegic muscle: Usefulness of nerve stimulation. Muscle Nerve. Mar 2023;67(3):204-207. doi:10.1002/mus.27727
18. Paketci C, Karakaya M, Edem P, Bayram E, Keller N, Daimaguler HS et al (2020) Clinical, electrophysiological and genetic characteristics of childhood hereditary polyneuropathies. Rev Neurol (Paris) 176:846–855
19. Sherman DL, Brophy PJ. Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci. Sep 2005;6(9):683-90. doi:10.1038/nrn1743
20. Toia F, Gagliardo A, D’Arpa S, Gagliardo C, Gagliardo G, Cordova A. Preoperative evaluation of peripheral nerve injuries: What is the place for ultrasound? J Neurosurg. Sep 2016;125(3):603-14. doi:10.3171/2015.6.JNS151001
21. Wei KC, Chiu YH, Wu CH, Liang HW, Wang TG. Ultrasound guidance may have advantages over landmark-based guidance for some nerve conduction studies. Muscle Nerve. Apr 2021;63(4):472-476. doi:10.1002/mus.27165

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Kandel ER, Schwartz JH, Jessell TM. Principles of Neuroscience. 4th ed. New York, NY: McGraw-Hill; 2000. Kimura J. Electrodiagnosis in Disease of Nerve and Muscle: Principles and Practice. 3rd ed. New York, NY: Oxford University Press; 2001. 6. Patton HD, Sundsten JW, Crill WE, Swenson PD. Introduction to Basic Neurology. Philadelphia, PA: WB Saunders; 1976.

Original Version of the Topic

Subhadra L. Nori, MD. Physiological principles underlying electrodiagnosis and neurophysiologic testing. 9/20/2014.

Previous Revision(s) of the Topic

Jason Kiene, MD, Benjamin Westerhaus, MD, David Sherwood, DO. Physiological principles underlying electrodiagnosis and neurophysiologic testing. 4/19/2020

Jason Kiene, MD, Andrew Hiett, MD. Physiological Principles Underlying Electrodiagnosis and Neurophysiologic Testing. 4/20/2023

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Pramod Kumar, MD
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Nicholas J White, MD
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