Introduction

Neuromodulation means many things to many people – but essential to any point of view is that the term implies some type of intervention that interfaces on some level with the nervous system of the patient and modifies function so as to effect benefit for the patient. What remains important to the definition, however, is a deeper belief that this therapeutic approach itself has greater merit, when chosen, than any of the alternatives. As a field of study, and as a burgeoning market in the vast expanse of health care overall, neuromodulation has taken several routes in achieving its current position – a position that has been estimated to be increasing from $3.0 billion worldwide to $4.5 billion worldwide in 2010 . In contrast, the pharmaceutical industry has a market of approximately $20 billion/year in treating similar clinical conditions. This lopsided ratio is shifting in the direction of neuromodulation and, with continued innovation, favorable outcomes and a reasonable reimbursement context, neuromodulation stands to be one of the greatest sources of therapeutic intervention ever, in terms of numbers of people treated and overall contribution to quality of life.

It is not simply interesting, or honorable, to be involved in weaving the fabric of so widely applicable a cloth, but a responsibility as well. Our goals herein are to impart both basic and not-so-basic aspects of neuromodulation to the reader – in terms of design, application, revision and troubleshooting, the patient perspective, and the future. We focus primarily on electrical stimulation, with very limited discussions of other modulation therapies when they may support an important principle overall. Readers will be exposed not only to thorough descriptions of every facet of neuromodulation by some of the most expert names currently in the field, but also to commentary from additional experts on the same topics, lending perspective, raising questions. Whether design engineer, graduate student, post-doctoral fellow, resident, neurologist, pain specialist, neurosurgeon, or other interested party to neuromodulation, our goal is to provide the ability to carry that responsibility soundly into whatever endeavors they lead.

Advances and new applications continue apace, but it would not be out of order to consider what has happened in neuromodulation and call it a ‘paradigm shift’ in managing the clinical problems where it has been applied. This is a strong term, but emphasizes that, while previously the rampant belief has been that more and more precise pharmaceutical solutions could prevail for almost any clinical problem, this approach has had holes punched in it. Certainly, the success of the pharmaceutical paradigm over previous methods of treatment has been profound and has created its own paradigm. But it has also been shown to have weakness and outright failures, in the form of side effects, tolerances, and inability to account for the anatomical precision necessary in some cases to effect benefit. At the same time, surgical solutions for many of the same problems – specifically, using resections or lesions – have soared with some successes, and plummeted with failure as well in cases where morbidity, imprecision, or irreversibility have left patients without benefit and possibly harmed further.

Kuhn pointed out that: ‘a student in the humanities has constantly before him a number of competing and incommensurable solutions to these problems, solutions that he must ultimately examine for himself’ , but science is different in that, once a paradigm shift has occurred, one would find it completely incompatible to posit that flies spontaneously generate from rotting meat, the sun revolves around the earth, or that the principles of Darwinian natural selection have not replaced Lamarck’s. Because of the wide successes now in neuromodulation, practitioners must recognize that this same transition, this paradigm shift, is occurring, or has occurred. It would be, at this point, reprehensible not to consider deep brain stimulation for a child with DYT-1 positive dystonia, a dorsal column stimulator for refractory CRPS-I in an extremity, or motor cortex stimulation for post-stroke facial or upper extremity pain. And these are but a few examples of how the neuromodulation approach has altered the algorithms of care. Neuromodulation has achieved this shift in every single field of application tried so far. One does not continue to ask: ‘What do I try when other traditional approaches have failed for this patient?’, one now asks instead: ‘How can I use neuromodulation to help this patient?’ –– and this change in approach makes all the difference.

History

Several excellent reviews of our best knowledge of the history of therapeutic electrical stimulation describe an early recognition of the potential benefits that electricity applied to human tissue could impart. As these authors have also appreciated, two earlier scholarly studies of this history , have brought out the ancient Egyptian references in hieroglyphics from the 3rd millennium BC on the use of the potent Nile catfish in causing fishermen to ‘release the troupes’ when they felt its strong current. These freshwater fish, and saltwater varieties of electric fish (e.g. torpedo fish) can generate up to about 200 volts at a time! The roots of several words in English have come down to the present day because of such phenomena (e.g. torpor, from the Roman name of the fish as ‘torpedo’ and narcosis from the Greeks naming the fish ‘narke’ ). A Roman text from 47 AD has suggested that multiple ailments (e.g. gout) were all treated by using the shocks from a torpedo fish. This electro-ichthyotherapy, as it is termed, has been noted by Kellaway to have been used in various primitive African and American Indian tribes still into the 20th century.

To lend context to the development of therapeutic electrical devices, it is helpful to appreciate something of the development of more formal pharmaceutical therapies. The first drugstore as such is thought to have flourished from approximately 754 AD in Baghdad . Most current larger pharmaceutical companies known today consolidated out of the drug store format throughout the 19th century, as refined ability to manufacture certain chemicals reliably on a large scale materialized – mostly in the Philadelphia area, it turns out . This eventually completely displaced the owner/pharmacist with mortar and pestle individually filling his clients needs, and further allowed the widespread uniform access to standard formulations of pharmaceuticals and standards in the industry.

Further applications of electrical therapy however continued into the late 19th century, involving myriad devices that imparted shocks and other sensations to the ailing, including as mentioned above electro-ichthyotherapy, which was still used even in Europe into the mid-part of the century . Perhaps the first device to reliably create man-made electricity though can be ascribed to von Guericke who, in 1662, created a generator of electrostatic discharges, among many other accomplishments. Over a hundred years later, following on from seminal work by Benjamin Franklin around 1774, who explored the phenomenon of muscle contraction following electrical shocks (even before Galvani more thoroughly examined it in the frog in 1780), many were quick to imbue the ‘new’ entity of electricity with magical healing powers, just as magnetite and amber had for many ages previously. It has been suggested that Christian A. Krantzenstein, however, was really the first to use electrical stimulation in a therapeutic manner , and this was before Franklin and others’ observations. Somewhat of a polymath, Krantzenstein was appointed by the King of Denmark in 1754 (at the age of 31) to study electricity and the effects it might have on various ailments. (It seems the King of Denmark deserves some credit as well perhaps.) He had been already renowned for his studies of electricity and lectures in a wide range of subjects. The following is a description of the original Danish review of his work in 1924, from the British Medical Journal:

…he issued advertisements inviting all and sundry who hoped electricity might cure their ills to call at his lodgings between 4 and 6 in the evening, when ‘everyone would be served according to the nature of the disease.’ How he ‘served’ them is not quite clear. He used a rotatory apparatus with glass balls, and the sparks he drew out of his patients caused a penetrating pain which was worst in the toes; moreover, it was associated with a smell of sulphur, and he explained that the electrical vibrations put the minutest parts of the body in motion, driving out the unclean sulphur and salt particles; hence the smell. Treatment with electricity, he said, made the blood more fluid, counteracted congestions, induced sleep, and was more effective than whipping with nettles in the treatment of paralysis.

Clearly, the bar was not high, as the therapy was competing with being whipped with nettles, for example. Kratzenstein, tangentially, has also been suggested as the basis for the character of Dr Frankenstein in the novel by Mary Shelley, first published anonymously in 1818 – a modern version of the classic Prometheus legend, stealing fire, the source of all creativity – in this case electricity, life, a cure of impossibly terrible ailments – from the gods, and the ruin it brings upon him by doing so.

There were several further key clinical observations through the end of the 19th century though insidiously at the same time, magnetic and electrical quackery became rampant on main street. Fritsch and Hitzig showed that stimulating the cerebral cortex could elicit muscle contractions in dogs (1870) and then Bartholow found it could be done in an awake human 4 years later. Sir Victor Horsely, one of the first few documented to perform what is considered a reasonable facsimile of a modern craniotomy in the 1880s, apparently tried to stimulate tissue within an occipital encephalocele, finding it produced conjugate eye movements . This was one of the first real uses of an evoked response, remarkably prescient at the time, and a technique relied upon in so many ways today (see for review).

Despite these noble attempts to make use of what was the most advanced information and insight into neural function to aid in patient care, little was otherwise advanced for decades with regard to neuromodulation or electrotherapeutics. In parallel course, several inventions worked off of rudimentary knowledge of batteries and insights of Faraday (Faraday’s law which linked electricity and magnetism), and led to ‘electrical therapies’ such as the Inductorium, the Gaiffe electrical device, the Faradic Electrifier, and the Electreat, patented by Kent in 1919 . The later device, similar to the present-day TENS unit, actually sold around 250 000 units over 25 years! Of note, these were promoted in ads such as the following:

All cases of Rheumatism, Diseases of the Liver, Stomach and Kidneys, Lung Complaints, Paralysis, Lost Vitality, Nervous Disability, Female Complaints…are cured with the Electrifier.

Subsequently, Kent was the first person prosecuted under the new Food, Drug and Cosmetic Act in 1938, because of unsubstantiated medical claims. The Electreat Company was forced to limit their claims to pain relief alone . Early in the twentieth century, the maturing of a pharmaceutical industry and the disrepute of many practitioners of electrotherapy in general led to widespread abandonment in the use of electrical stimulation as a therapy.

That electrical stimulation has had detractors is an understatement, and early experience with dorsal column stimulators (first developed and implanted by Shealy in 1967 ) in the neurosurgical community up until the 1990s highlights this point of view. Shealy himself eventually abandoned the approach in 1973 apparently because of frustrations with technique and technology. Many were discouraged either by the lack of efficacy, or by the short duration of efficacy. Unlike magnetic therapy, however, there is a strong grounding in the underlying biophysics of modulating neural activity using electrical fields. As a contrast on this point, it has been calculated that a typical magnetic therapy pad will generate a movement of ions flowing through a vessel 1 centimeter away by less than what thermal agitation of the ion generated by the organism itself causes, by a factor of 10 million . Yet, claims of efficacy using magnetic therapy continue. An estimate of magnetic field strength required to produce potentially a 10% reduction in neural activity itself was calculated to be 24 Tesla . Electrical stimulation on the other hand benefits from a deeper investigation and support of its principles, and technological advances continue to be made in refining appropriate applications.

The further details of the more recent history of neuromodulation devices has been well-documented elsewhere but, importantly, the advances have come about by the continued collaborative efforts between industry and practitioners. This synthesis speaks to the current debates on conflict of interest that presently occupy much time and effort. In general, devices became more refined in terms of materials, handling characteristics, electrode design and implementation, power storage and management, and understanding of the mechanisms of action. They originally used RF transfer of power, and by the early 1980s had transitioned to multichannel and multiple-program devices. The first fully implantable generators (IPGs), however, came from advances in cardiac devices and, in 1976, Cordis came out with the model 199A that was epoxy-coated. It had limited capabilities and was marketed for treatment of spasticity primarily in MS for example. Eventually, a lithium ion-based battery was developed in their third generation device (the model 900X-MK1) and was hermetically sealed in titanium, ushering in what we now consider the standard platform of these devices. Rechargeability came about with competitive patents in the 1990s and all three major device companies (Medtronic, St Jude Medical, and Boston Scientific) make rechargeable IPGs for spinal cord stimulators that can last approximately 10 years with regular recharging. Closed-loop systems are being developed, wherein some type of real-time information about the system being stimulated can be incoroporated into the function of the device. For example, a device in trials now for treating epilepsy (NeuroPace, Inc – ) analyzes cortical activity and can stimulate cortical regions or deeper regions to limit or stop a seizure. Further closed-loop applications are sure to become available in the near future, in deep brain stimulators (DBS), peripheral nerve stimulators (PNS), motor cortex stimulators (MCS), or spinal cord stimulators (SCS), or in other yet to be distinguished ways. All of these refinements, advances, and properties of these systems will be better characterized and elaborated in subsequent chapters in this text.

History

Several excellent reviews of our best knowledge of the history of therapeutic electrical stimulation describe an early recognition of the potential benefits that electricity applied to human tissue could impart. As these authors have also appreciated, two earlier scholarly studies of this history , have brought out the ancient Egyptian references in hieroglyphics from the 3rd millennium BC on the use of the potent Nile catfish in causing fishermen to ‘release the troupes’ when they felt its strong current. These freshwater fish, and saltwater varieties of electric fish (e.g. torpedo fish) can generate up to about 200 volts at a time! The roots of several words in English have come down to the present day because of such phenomena (e.g. torpor, from the Roman name of the fish as ‘torpedo’ and narcosis from the Greeks naming the fish ‘narke’ ). A Roman text from 47 AD has suggested that multiple ailments (e.g. gout) were all treated by using the shocks from a torpedo fish. This electro-ichthyotherapy, as it is termed, has been noted by Kellaway to have been used in various primitive African and American Indian tribes still into the 20th century.

To lend context to the development of therapeutic electrical devices, it is helpful to appreciate something of the development of more formal pharmaceutical therapies. The first drugstore as such is thought to have flourished from approximately 754 AD in Baghdad . Most current larger pharmaceutical companies known today consolidated out of the drug store format throughout the 19th century, as refined ability to manufacture certain chemicals reliably on a large scale materialized – mostly in the Philadelphia area, it turns out . This eventually completely displaced the owner/pharmacist with mortar and pestle individually filling his clients needs, and further allowed the widespread uniform access to standard formulations of pharmaceuticals and standards in the industry.

Further applications of electrical therapy however continued into the late 19th century, involving myriad devices that imparted shocks and other sensations to the ailing, including as mentioned above electro-ichthyotherapy, which was still used even in Europe into the mid-part of the century . Perhaps the first device to reliably create man-made electricity though can be ascribed to von Guericke who, in 1662, created a generator of electrostatic discharges, among many other accomplishments. Over a hundred years later, following on from seminal work by Benjamin Franklin around 1774, who explored the phenomenon of muscle contraction following electrical shocks (even before Galvani more thoroughly examined it in the frog in 1780), many were quick to imbue the ‘new’ entity of electricity with magical healing powers, just as magnetite and amber had for many ages previously. It has been suggested that Christian A. Krantzenstein, however, was really the first to use electrical stimulation in a therapeutic manner , and this was before Franklin and others’ observations. Somewhat of a polymath, Krantzenstein was appointed by the King of Denmark in 1754 (at the age of 31) to study electricity and the effects it might have on various ailments. (It seems the King of Denmark deserves some credit as well perhaps.) He had been already renowned for his studies of electricity and lectures in a wide range of subjects. The following is a description of the original Danish review of his work in 1924, from the British Medical Journal:

…he issued advertisements inviting all and sundry who hoped electricity might cure their ills to call at his lodgings between 4 and 6 in the evening, when ‘everyone would be served according to the nature of the disease.’ How he ‘served’ them is not quite clear. He used a rotatory apparatus with glass balls, and the sparks he drew out of his patients caused a penetrating pain which was worst in the toes; moreover, it was associated with a smell of sulphur, and he explained that the electrical vibrations put the minutest parts of the body in motion, driving out the unclean sulphur and salt particles; hence the smell. Treatment with electricity, he said, made the blood more fluid, counteracted congestions, induced sleep, and was more effective than whipping with nettles in the treatment of paralysis.

Clearly, the bar was not high, as the therapy was competing with being whipped with nettles, for example. Kratzenstein, tangentially, has also been suggested as the basis for the character of Dr Frankenstein in the novel by Mary Shelley, first published anonymously in 1818 – a modern version of the classic Prometheus legend, stealing fire, the source of all creativity – in this case electricity, life, a cure of impossibly terrible ailments – from the gods, and the ruin it brings upon him by doing so.

There were several further key clinical observations through the end of the 19th century though insidiously at the same time, magnetic and electrical quackery became rampant on main street. Fritsch and Hitzig showed that stimulating the cerebral cortex could elicit muscle contractions in dogs (1870) and then Bartholow found it could be done in an awake human 4 years later. Sir Victor Horsely, one of the first few documented to perform what is considered a reasonable facsimile of a modern craniotomy in the 1880s, apparently tried to stimulate tissue within an occipital encephalocele, finding it produced conjugate eye movements . This was one of the first real uses of an evoked response, remarkably prescient at the time, and a technique relied upon in so many ways today (see for review).

Despite these noble attempts to make use of what was the most advanced information and insight into neural function to aid in patient care, little was otherwise advanced for decades with regard to neuromodulation or electrotherapeutics. In parallel course, several inventions worked off of rudimentary knowledge of batteries and insights of Faraday (Faraday’s law which linked electricity and magnetism), and led to ‘electrical therapies’ such as the Inductorium, the Gaiffe electrical device, the Faradic Electrifier, and the Electreat, patented by Kent in 1919 . The later device, similar to the present-day TENS unit, actually sold around 250 000 units over 25 years! Of note, these were promoted in ads such as the following:

All cases of Rheumatism, Diseases of the Liver, Stomach and Kidneys, Lung Complaints, Paralysis, Lost Vitality, Nervous Disability, Female Complaints…are cured with the Electrifier.

Subsequently, Kent was the first person prosecuted under the new Food, Drug and Cosmetic Act in 1938, because of unsubstantiated medical claims. The Electreat Company was forced to limit their claims to pain relief alone . Early in the twentieth century, the maturing of a pharmaceutical industry and the disrepute of many practitioners of electrotherapy in general led to widespread abandonment in the use of electrical stimulation as a therapy.

That electrical stimulation has had detractors is an understatement, and early experience with dorsal column stimulators (first developed and implanted by Shealy in 1967 ) in the neurosurgical community up until the 1990s highlights this point of view. Shealy himself eventually abandoned the approach in 1973 apparently because of frustrations with technique and technology. Many were discouraged either by the lack of efficacy, or by the short duration of efficacy. Unlike magnetic therapy, however, there is a strong grounding in the underlying biophysics of modulating neural activity using electrical fields. As a contrast on this point, it has been calculated that a typical magnetic therapy pad will generate a movement of ions flowing through a vessel 1 centimeter away by less than what thermal agitation of the ion generated by the organism itself causes, by a factor of 10 million . Yet, claims of efficacy using magnetic therapy continue. An estimate of magnetic field strength required to produce potentially a 10% reduction in neural activity itself was calculated to be 24 Tesla . Electrical stimulation on the other hand benefits from a deeper investigation and support of its principles, and technological advances continue to be made in refining appropriate applications.

The further details of the more recent history of neuromodulation devices has been well-documented elsewhere but, importantly, the advances have come about by the continued collaborative efforts between industry and practitioners. This synthesis speaks to the current debates on conflict of interest that presently occupy much time and effort. In general, devices became more refined in terms of materials, handling characteristics, electrode design and implementation, power storage and management, and understanding of the mechanisms of action. They originally used RF transfer of power, and by the early 1980s had transitioned to multichannel and multiple-program devices. The first fully implantable generators (IPGs), however, came from advances in cardiac devices and, in 1976, Cordis came out with the model 199A that was epoxy-coated. It had limited capabilities and was marketed for treatment of spasticity primarily in MS for example. Eventually, a lithium ion-based battery was developed in their third generation device (the model 900X-MK1) and was hermetically sealed in titanium, ushering in what we now consider the standard platform of these devices. Rechargeability came about with competitive patents in the 1990s and all three major device companies (Medtronic, St Jude Medical, and Boston Scientific) make rechargeable IPGs for spinal cord stimulators that can last approximately 10 years with regular recharging. Closed-loop systems are being developed, wherein some type of real-time information about the system being stimulated can be incoroporated into the function of the device. For example, a device in trials now for treating epilepsy (NeuroPace, Inc – ) analyzes cortical activity and can stimulate cortical regions or deeper regions to limit or stop a seizure. Further closed-loop applications are sure to become available in the near future, in deep brain stimulators (DBS), peripheral nerve stimulators (PNS), motor cortex stimulators (MCS), or spinal cord stimulators (SCS), or in other yet to be distinguished ways. All of these refinements, advances, and properties of these systems will be better characterized and elaborated in subsequent chapters in this text.