INVITED REVIEW ABSTRACT: This review provides a comprehensive overview of the clini- cal uses of neuromuscular electrical stimulation (NMES) for functional and therapeutic applications in subjects with spinal cord injury or stroke. Func- tional applications refer to the use of NMES to activate paralyzed muscles in precise sequence and magnitude to directly accomplish functional tasks. In therapeutic applications, NMES may lead to a specific effect that enhances function, but does not directly provide function. The specific neuroprosthetic or “functional” applications reviewed in this article include upper- and lower- limb motor movement for self-care tasks and mobility, respectively, bladder function, and respiratory control. Specific therapeutic applications include motor relearning, reduction of hemiplegic shoulder pain, muscle strength- ening, prevention of muscle atrophy, prophylaxis of deep venous thrombo- sis, improvement of tissue oxygenation and peripheral hemodynamic func- tioning, and cardiopulmonary conditioning. Perspectives on future developments and clinical applications of NMES are presented. Muscle Nerve 35: 562–590, 2007 NEUROMUSCULAR ELECTRICAL STIMULATION IN NEUROREHABILITATION LYNNE R. SHEFFLER, MD, and JOHN CHAE, MD Cleveland Functional Electrical Stimulation Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, Ohio 44109, USA Accepted 4 January 2007 This article provides a comprehensive review of the performance of activities of daily living, and control clinical uses of neuromuscular electrical stimulation of respiration and bladder function. A neuropros- (NMES) in neurological rehabilitation. NMES refers thesis is a device or system that provides FES. Accord- to the electrical stimulation of an intact lower motor ingly, a neuroprosthetic effect is the enhancement of neuron (LMN) to activate paralyzed or paretic mus- functional activity that results when a neuroprosthe- cles. Clinical applications of NMES provide either a sis is utilized. NMES is also used for therapeutic functional or therapeutic benefit. Moe and Post207 purposes. NMES may lead to a specific effect that introduced the term functional electrical stimula- enhances function but does not directly provide tion (FES) to describe the use of NMES to activate function. One therapeutic effect is motor relearn- paralyzed muscles in precise sequence and magni- ing, which is defined as “the recovery of previously tude so as to directly accomplish functional tasks. In learned motor skills that have been lost following present-day applications, functional tasks may in- localized damage to the central nervous system.”180 clude standing or ambulatory activities, upper-limb Evolving basic science and clinical studies on central motor neuroplasticity now support the role of active repetitive-movement training of a paralyzed limb. If Available for Category 1 CME credit through the AANEM at www.aanem.org. active repetitive-movement training facilitates motor relearning, then NMES-mediated repetitive-move- Abbreviations: ANN, artificial neural network; DVT, deep venous thrombo- sis; ECU, external control unit; EMG, electromyography; FES, functional elec- ment training may also facilitate motor relearning. trical stimulation; Fint, fatigue-intermediate; FR, fatigue-resistant; LMN, lower Other examples of therapeutic applications include motor neuron; LSU-RGO, Louisiana State University Reciprocating Gait Or- thosis; LTP, long-term potentiation; MHC, myosin heavy chain; MRI, magnetic treatment of hemiplegic shoulder pain, cardiovascu- resonance imaging; NMES, neuromuscular electrical stimulation; PG/PS, pat- lar conditioning, treatment of spasticity, and preven- tern generator / pattern shaper; PID, proportional integral derivative; RF, ra- diofrequency; ROM, range of motion; SCI, spinal cord injury; TENS, transcu- tion of muscle atrophy, disuse osteoporosis, and taneous electrical nerve stimulation; UMN, upper motor neuron deep venous thrombosis (DVT). Key words: bladder function; functional electrical stimulation; motor relearn- ing; neuromuscular electrical stimulation; neuroprosthesis; rehabilitation; re- This review focuses on the clinical uses of NMES spiratory control; spinal cord injury; stroke for functional and therapeutic applications in pa- Correspondence to: L.R. Sheffler; e-mail: lsheffl[email protected] tients with spinal cord injury or stroke. In order to © 2007 Wiley Periodicals, Inc. Published online 13 February 2007 in Wiley InterScience (www.interscience. provide a foundation for the various clinical appli- wiley.com). DOI 10.1002/mus.20758 cations, the neurophysiology of NMES and compo- 562 Neuromuscular Electrical Stimulation MUSCLE & NERVE May 2007 nents of NMES systems are briefly reviewed. The fiber diameter. The Henneman size principle of vol- specific neuroprosthetic or “functional” applications untary motor unit recruitment described this pro- include upper- and lower-limb motor movement for gressive size-dependent recruitment of motor self-care tasks and mobility, respectively, bladder units.128 Arbuthnott et al.9 examined in detail this function, and respiratory control. Specific therapeu- relationship between fiber diameter and conduction tic applications include poststroke motor relearning velocity in peripheral nerve. The nerve fiber recruit- as well as the examples mentioned earlier. Lastly, ment pattern mediated by NMES follows the princi- perspectives on future developments and clinical ap- ple of “reverse recruitment order” wherein the nerve plications of NMES are presented. stimulus threshold is inversely proportional to the diameter of the neuron. Thus, large-diameter nerve NEUROPHYSIOLOGY OF NMES fibers, which innervate larger motor units, are re- cruited preferentially. Recent work by Lertmanorat NMES is initiated with the excitation of peripheral and Durand183 proposes the clinical applicability of a nervous tissue. The mathematical characterization of reshaping of the extracellular voltage that may allow neuronal action potential generation is largely predi- the reversal of the “reverse recruitment order” elic- cated on the seminal work of scientists and neurophysi- ited by NMES. ologists including Galvani,106 Lapicque175 and NMES is dependent on an intact (alpha) LMN. Hodgkin and Huxley.130 More recently, McNeal200 Several studies document the therapeutic benefit of mathematically defined the time course of events fol- electrical stimulation on muscle-fiber regeneration lowing stimulus application to the propagation of the in LMN denervation50,149,280; however, the clinical action potential in a normal healthy myelinated nerve. application of NMES is presently limited to neuro- The term “stimulus threshold” defines the lowest level logic injuries involving the upper motor neuron of electrical charge that generates an action potential. (UMN) such as spinal cord injury (SCI), stroke, The “all or none” phenomenon of the action potential brain injury, multiple sclerosis, and cerebral palsy. produced by natural physiologic means is identical to NMES is delivered as a waveform of electrical cur- the action potential induced by NMES. rent characterized by stimulus frequency, amplitude, Conduction of impulses in a nerve is influenced and pulse width. The amplitude and pulse width considerably by the nerve’s cable properties. determine the number of muscle fibers that are Hodgkin and Rushton in 1946131 used extracellular activated.209 Temporal summation is determined by electrodes to measure applied current along lobster the rate at which stimulus pulses are applied to axons to describe the spread of current along nerve muscle. The strength of the resultant muscle con- fibers of uniform diameter composed of a central traction is modulated by adjustment of the stimulus conductor and insulating sheath. Nerve fiber recruit- parameters. The minimum stimulus frequency that ment and resultant force characteristics of muscle generates a fused muscle response is ϳ12.5 Hz. contraction are modulated by both stimulus pulse Higher stimulus frequencies generate higher forces width277 and stimulus frequency.3 Other variables but result in muscle fiber fatigue and rapid decre- include distance from the stimulating electrode and ment in contractile force. An optimal NMES system membrane capacitance. The threshold for eliciting a utilizes the minimal stimulus frequency that pro- nerve fiber action potential is 100 to 1,000 times less duces a fused response.26,173,200 Ideal stimulation fre- than the threshold for muscle fiber stimulation.209 quencies range from 12–16 Hz for upper-limb appli- Thus, clinical NMES systems stimulate either the cations and 18–25 Hz for lower-limb applications nerve directly or the motor point of the nerve prox- (frequency range for NMES systems is 10–50 Hz). imal to the neuromuscular junction. Greater muscle force generation is accomplished by The nerve fiber recruitment properties elicited either increasing the pulse duration (typically 200 by NMES differ from those elicited by normal phys- ␮s) or stimulus amplitude to activate neurons at a iologic means. An action potential produced by nor- greater distance from the activating electrode. Pa- mal physiologic mechanisms initially recruits the rameters for safe stimulation for implanted NMES smallest-diameter neurons prior to recruitment of systems have been established experimentally.209 larger-diameter fibers, such as alpha motor neu- The clinical application of NMES systems is com- rons.127 Rushton248 was one of the first researchers to plicated by the fact that