The history of neuromuscular electrical stimulation has been well documented by Donald R. McNeal (“2000 years of electrical stimulation” in Functional Electrical Stimulation edited by ) and F. Terry Hambrecht (“A brief history of neural prostheses for motor control of paralyzed extremities” in Neural Prostheses edited by ). Depending upon how far back in time one chooses to go, it is clear that the field has a checkered past. It is generally agreed that the experiments of Volta, Galvani, and Lyden, discussed in both books, demonstrated the early potential of activating neural tissue by electrical currents. However, over the following decades individuals who we now most likely would refer to as charlatans claimed miracle cures from the delivery of electricity to various parts of the human anatomy. Apparently, the lack of a regulatory body and reimbursement mechanism enabled these individuals to make incredibly spurious claims and find desperate patients who would accept these treatments and had the capability to pay for them. Quoting McNeal, “paralysis, hemiplegia, epilepsy, kidney stones, sciatica, and angina pectoralis are only a few of the conditions that were ‘successfully’ treated.” Clearly these conditions remain as unmet clinical needs. It is safe to say that the more recent applications now achieving true clinical impact are not a direct result of this early experimentation.

The modern-day approach to electrical stimulation of human tissue was born from the evolution of electronic technology, the development of implantable devices within the body, a growing understanding of modern physiology and anatomy, and successful collaborations between physicians and engineers. Working together, these individuals have identified realistic clinical problems and brought the knowledge and skills to translate a solution into early prototypic devices. The vision of early pioneers such as Paul Zoll, Walton Lillehei, Earl Baaken, and Wilson Greatbatch, developing the cardiac pacemaker, and Norman Shealey and Thomas Mortimer, inventing spinal cord stimulation, created the first modern neuroprostheses. Thanks to the grit and determination of persons in the biomedical engineering field and physicians studying pain, neurosurgery, urology and other clinical fields, these have led to a whole neurotechnology industry and the field of neuromodulation.

This author has had the fortunate experience over his career to have benefited from working directly with the fathers of the field of neuromuscular electrical stimulation, including James B. Reswick, Lojze Vodovnik, J. Thomas Mortimer, and Charles Long. Their leadership, combined with that of Terry Hambrecht, William Heetderks, Donald McNeal, and Alojz Kralj, established the field of neuromuscular electrical stimulation, and today’s practitioners owe a debt of gratitude to these pioneers for their vision and contributions.

In the late 1960s studies of finger extension with spinal cord injury (SCI) ( ), walking after SCI ( ), and control of foot drop in stroke survivors ( ) were the early clinical demonstrations of the functional potential of electrical stimulation for control of the neuromuscular system. All these “systems” were implemented with electrodes placed on the skin surface (“surface stimulation”), and all were small feasibility studies conducted in no more than a few subjects. At Case Western Reserve University (CWRU) in Cleveland, Vodovnik was a postdoctoral fellow with Reswick and Long was the head of the division of Physical Medicine and Rehabilitation. These three individuals were the leaders of the activity that initiated significant investigation into neuromuscular stimulation in Cleveland and spawned broader functional neuromuscular stimulation (FNS) investigation across the world.

The early clinical demonstrations created enthusiasm for the potential for relieving the clinical burden of neurological disorders. Significant investment was made at the United States federal level, in the National Institutes of Health (NIH) and the Social and Rehabilitation Service (SRS) in the Department of Education, to advance the basic science, engineering, and clinical applications of FNS. At the NIH National Institute of Neurological and Communicative Disorders and Stroke, Dr. Karl Frank launched a contract program that became the Neural Prosthesis Program (NPP), now housed in the National Institute of Neurological Disorders and Stroke with Hambrecht as the first director, soon to be joined by Heetderks. This was a critical stage for the development of FNS, as it cemented the vision that to realize the potential of this new approach to treating neurological disorders, scientists, engineers, and clinicians would have to be brought together in multidisciplinary teams to address new and complex issues and bring a new science to bear to understand the fundamental challenges. The NPP launched not only studies of neuromuscular control but also studies for hearing loss, urinary incontinence, and vision. It is noteworthy that the vision of Frank, Hambrecht, and Heetderks has had broad impacts for disorders of the nervous system and resulted in neuroprosthetic products for treating all these disorders.

At the SRS, the Rehabilitation Engineering Center (REC) program was launched and Reswick, then at Case Institute of Technology in Cleveland, was recruited to be the codirector at the Rancho Los Amigos REC in Downey, California. The focus of this center was functional electrical stimulation, and a coleader was Donald McNeal. Another center, also funded by the SRS, was at the University of Ljubljana (Slovenia), home institution of Vodovnik and Kralj. These three institutions were the early leaders that developed the directions of the field, supported by the early vision of these two federal agencies. In Cleveland, Mortimer took up the leadership in Reswick’s absence. In Ljubljana and Downey the focus was largely on pioneering clinical applications that utilized external surface stimulation, including lower-extremity walking in stroke, cerebral palsy, SCI, and urinary and fecal control, and early investigations into a whole new field that has become known as neural plasticity, studied as a “carry-over” of the effects of stimulation in children with cerebral palsy.

At Rancho, McNeal was instrumental in developing the first computational model for understanding electrical activation of peripheral nerves ( ). His mathematical model of the nerve membrane was used to describe the initiation of an action potential in a nerve following stimulation activation. This tool became essential for development of new stimulation techniques.

As reported by , “Most serious FNS investigators soon became convinced that the future of FNS required the abandonment of skin-surface stimulating electrodes except for short-term laboratory investigations. The alternative was implanted electrodes. At Case Western Reserve, implanted systems became the early focus of studies. Studies of my colleagues and I investigated the fundamental limitations of neuromuscular stimulation, primarily through the contract support of the NIH-Neural Prosthetics Program. These fundamental limitations were barriers to the development of electrode designs that would withstand stress of chronic use, defining safe levels of chronic stimulation, and muscle weakness and fatigue secondary to electrical stimulation.”

Studies of Mortimer et al. resulted in the development of a family of electrode lead designs that would sustain the tortuous loads of repeated flexing in the body and allow a safe chronic skin interface to form. One of the earliest technical developments was the “Caldwell electrode,” a fine wire coil that allowed penetration through the skin and was resistant to breakage ( ). The Caldwell electrode demonstrated that it would give chronic percutaneous penetration for years in human subjects. This was a critical development, as it allowed clinical exploration of subskin electrodes without the use of an implanted pulse generator, which at that time only existed for the pacemaker.

Subsequent electrode design derivatives developed by ) and have been extensively used with percutaneous and implanted versions, and have been the primary means for chronic human studies on eliciting controlled movement in paralyzed muscles with implanted electrodes. These electrodes are presently used in products approved by the United States Food and Drug Administration (FDA) for pain relief (SPR Therapeutics) and breathing (Synapse Biomedical).

Mortimer et al. elucidated the safe levels of chronic electrical stimulation for implanted neuromuscular electrodes that enabled human research to proceed with percutaneous implantable systems ( ). Peckham et al. demonstrated that muscle phenotype is changed by low-frequency (10 Hz) stimulation and could lead to both increased muscle strength and endurance in atrophied muscles ( ). This fundamental physiological finding, coupled with the use of the Caldwell electrode and its derivatives, provided the ability to stimulate muscles chronically in human subjects and begin discoveries leading to functional restoration.

The clinical focus in Cleveland was demonstration of function in both upper and lower extremities of people with SCI. Research laboratories established in the SCI centers at MetroHealth Medical Center (Peckham and Michael Keith) and the Cleveland VA Medical Center (Byron Marsolais) were coled by an engineer and a physician, and their patients immediately participated in research activities as an integral part of their rehabilitation. They developed and implemented percutaneous neuroprosthetic systems in people with SCI, demonstrated the control of multiple grasp-release patterns, and introduced functional systems for home use over years ( ). An early multicenter study involving five centers, the first multicenter study of a neuromuscular control neuroprosthesis, was conducted and demonstrated the potential for the technology ( ). used the same technology to demonstrate functional walking in people with SCI and stroke survivors. The first implanted multichannel stimulator was developed in Cleveland ( ), implanted in the pioneering research subject Jim Jatich in August 1986, and used until his death in 2013, 27 years later. These clinical experiences demonstrate the importance of enlisting the participation of the user community in the design of the systems and the functions they are intended to provide. Jim was a valuable contributor in the program, participated at the level of a coinvestigator, and was included in authorship in a scientific publication ( ).

Jim Jatich’s implant and subsequent implants led to the founding of the NeuroControl Corporation to commercialize the technology. NeuroControl sponsored the multicenter clinical trial that led to the approval of the Freehand System, still the only FDA-approved neuroprosthesis for functional restoration ( ); 312 people were implanted with this system before the company went out of business ( ). The applications in this area are described more completely in Chapter 96 , Chapter 97 .

Many important investigative teams were formed during this time and have made important contributions to the field of neuromuscular stimulation. In Cleveland the Functional Electrical Stimulation Center consortium was formed in 1990 with CWRU, the Louis Stokes Veterans Affairs Medical Center, and MetroHealth Medical Center. Hunter Peckham was the first executive director, and Byron Marsolais the medical director. This consortium focused on translational activities to move project concepts into human feasibility testing. Technology development was mainly done at CWRU, and clinical studies at the medical centers. Other teams were formed around North America and Europe as well. While it is dangerous to be exclusionary, the teams led by Thomas Sinkjaer et al. in Aalborg, Denmark, Richard Stein in Edmonton, Alberta, Ian Swain and Paul Taylor in Salisbury, UK, and Herwig Thoma et al. in Vienna, Austria are particularly noteworthy.

Again quoting Hambrecht, “The term functional neuromuscular stimulation (FNS) was coined as a subcategory of functional electrical stimulation (FES) at the first international workshop devoted exclusively to FNS, which was held at the US NIH, April 27–28, 1972.” This meeting brought together most of the leading investigators in the field ( Chapter 1 ). Over time, workshops and meetings related to the topic of FNS were held in conjunction with the annual NIH NPP Workshop and workshops sponsored by the Engineering Foundation, and finally resulted in the founding of the International Functional Electrical Stimulation Society.

The NIH NPP Workshop has been restructured into a workshop format called the Neural Interfaces Conference, to investigate fundamental barriers facing neural prostheses and bring new concepts, science, and investigators into the neural interfacing field of neuromodulation. The participation of interested scientists, engineers, and clinicians in the numerous meetings on this topic demonstrates the considerable interest in the field of FNS and neuromodulation.

It can be argued that the field has been unsuccessful in bringing forward viable products that benefit people with neuromuscular disorders. It is scarcely remembered that some large medical device companies investigated FNS. In the early 1970s Medtronic and Rancho Los Amigos developed an implantable prototype for restoration of ankle dorsiflexion in stroke survivors. The implant was a single-channel, radiofrequency, externally powered stimulator with a cuff electrode placed around the peroneal nerve. Control was from an insole switch that detected heel-off in the gait cycle. This system was tested in a multicenter trial but was never commercialized ( ). Medtronic also explored correction of scoliosis with implantable technology, but again did not bring the product to market ( ). In the early 2000s Neopraxis, a spinoff of the Cochlear Corporation (Sydney, NSW, Australia), developed a multichannel implantable system and tested it for walking applications, but never commercialized the product ( ).

Although the field has expressed excitement at the interest of some of the larger neurotechnology companies, the clinical, technical, and market challenges have been substantial. In the 1990s NeuroControl Corporation, which had achieved FDA premarket approval for Freehand and a Human Device Exemption approval for the Vocare bladder system, left the market, demonstrating the market challenges that face products in this area even after FDA approval.

One can, however, look to Synapse Biomedical (Oberlin, OH) as an inspiring demonstration that a small company only 15 years old can receive FDA approval for a viable implanted product that meets an important unmet clinical need—respiratory control. Synapse’s NeuRx-DPS product provides inspiratory control for people with SCI and amyotrophic lateral sclerosis; it is marketed in 26 countries, and approximately 1700 systems have been implanted.

Another company with a similar story is Finetech Medical (Hertfordshire, England), which is distributing the Brindley–Finetech bladder control system and STIMuSTEP foot-drop stimulator. These small companies are having success in the market today, but their growth is challenging. They do not attract the large companies interested in acquisition or the major venture investment that is required for large market opportunities—particularly in an unproven market.

What does the future hold for FNS? There remains a substantial unmet clinical need, and no approaches other than neuromodulation and neurotechnology are close to a solution. The success of Synapse, Finetech, and other evolving companies (for example Neuros Medical and SPR Therapeutics, both in Cleveland, OH) demonstrates the impact of neurotechnology for patients with pain and neuromuscular disabilities. There is acceptance by patients in need and the clinicians who treat them. Clinicians have considerably more understanding of technology and experience with neural implants in their training than was the case only a decade ago, and largely accept neurotechnology. Nevertheless, while neurotechnology has become an indispensable aspect of medicine, its availability to clinicians for treating neuromuscular disabilities is limited.

In the neuromuscular area, the needs are many and include restoration of motor function, restoration of sensory function, central and peripheral pain suppression, reduction of spasticity, and control of autonomic dysreflexia, just to name a few. When taken as a whole, the population of patients with these treatable disorders is large and includes SCI, stroke, cerebral palsy, ALS, traumatic brain injury, multiple sclerosis, and limb loss. Many of the people suffering from these disorders have broad compromise of their nervous systems affecting many of their body functions, limbs, sensation, and autonomic function. Patients present with manifestations that are highly heterogeneous, and thus there is a need to “customize” the applications.

While it must be acknowledged that adequate technology is only one aspect of a successful product, in the field of FNS there has been a mismatch between the technology that is available and the technology that is required to address the clinical need. All the technologies address a single function and have limited customization capabilities. Two approaches that attempt to bridge this technological mismatch are the Bion technology (A.E. Mann Foundation, Sylmar, CA) and the Networked Neuroprosthesis System (CWRU, Cleveland, OH). While these devices take different technological approaches, they both have the concept of using a modular approach in which the system is expandable and allows “mix and match” of components to achieve a functional outcome through programming the coordination of individual components of the system. These technologies, described in Chapter 35 , offer a technology platform for growth of neuromuscular applications.

Effective delivery of products to the neuromuscular rehabilitation population will need the success of smaller companies to demonstrate the viability of products and their delivery into the market. Additionally, however, given the identified challenges of market uncertainty and regulation of invasive implanted technologies, it is likely that more innovative actions and approaches will be needed to bring products to the market. It will be necessary to incubate new indications for neuroprosthetic technologies through clinical trials so that a market for these technologies can be established. One approach being trialed at CWRU is the Institute for Functional Restoration (IFR) ( https://vimeo.com/album/4252235/video/192342932 ). The IFR is a team of scientists, engineers, and clinicians focused not on innovative discovery but on product translation and clinical trials to deliver neurotechnology products into orphan markets. The IFR is doing much of what a start-up company would do, incubating the transfer of the networked neuroprosthesis technology to companies and supporting clinical trials that will lead to FDA approval and CMS reimbursement decisions, thus reducing risk for a commercial entity. History has a great deal to offer in this regard. Certainly, much of the approach to clinical and technical issues taken by NeuroControl was successful, but the business model was flawed. The approach of the IFR is to build on the successful aspects of companies such as NeuroControl and avoid the unsuccessful aspects. This approach and others will be needed to facilitate the translation of neuromuscular stimulation technology into the marketplace and make it available to patients and their clinicians.