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`Archives of Medical Research 31 (2000) 232–236
`
`REVIEW ARTICLE
`Neuromodulation: An Overview
`
`,
`**
`Francisco Velasco*
`*Unidad de Neurocirugía Estereotáctica y Funcional, Hospital General de México, México, D.F., Mexico
`**Unidad para Investigación Médica en Neurofisiología, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS),
`México, D.F., Mexico
`
`Received for publication October 12, 1999; accepted October 14, 1999 (99/167).
`
`For over two centuries, electricity has been known to induce modification of neural and
`nerve fiber activity and has been proposed to be used to treat some neurological dysfunc-
`tions. The new era of the use of electrical current in the treatment of neurological symp-
`toms began in 1967 with the use of totally implanted devices that deliver a controlled
`amount of electricity on a precise structure within the nervous systems and was first used
`to control pain. Extensive research has been carried out ever since to elucidate the mecha-
`nism of action of this treatment and extend its indication for the treatment of the other neu-
`rological symptoms. So far, there is evidence that the treatment is safe and efficient for
`long periods of time, as it does not induce permanent damage to the stimulated structure.
`Most likely, electrical current at the parameters used for therapeutic purpose induces an
`inhibition of the structure on which it is applied. However, this may be accompanied by
`either inhibition or excitation of anatomically related structures. For this reason, it seems
`more convenient to refer to this type of therapy as neuromodulation.
`A review of the historical development of this fascinating area is presented, with special
`attention to the evidence derived from experimental work on the parameters that electrical
`current must maintain to avoid damage to the underlying tissue. © 2000 IMSS. Pub-
`lished by Elsevier Science Inc.
`Electrical stimulation of nervous tissue, Neuromodulation, Pain, Involuntary move-
`Key Words:
`ments, Epilepsy, Spasticity.
`
`Introduction
`
`The experimental effects of electrical and chemical stimula-
`tion of the nervous system on various behavioral and/or
`electrophysiological responses led to their use for therapeu-
`tic purposes. To date, both electrical (ES) and chemical
`(CS) stimulation have been used to treat a number of neuro-
`logical symptoms such as pain, movement disorders, spas-
`ticity, epilepsy, stupor and coma, psychiatric disorders, neu-
`rogenic bladder, peripheral vascular insufficiency, and
`diaphragmatic palsy. They also have been used to design
`prototypes for visual and audiogenic prostheses to treat vi-
`sual and hearing loss.
`
`Address reprint requests to: Francisco Velasco, M.D., UIM Neurofisi-
`ología, Centro Médico Nacional Siglo XXI, IMSS, P.O. Box 73-032, Méx-
`1
`ico, D.F., México. Tel.: (525) 578-4238; FAX: (
`525) 761-6933; E-mail:
`fvelazco@netservice.com.mx
`
`This Special Issue focuses on the treatment of pain,
`movement disorders, spasticity, and epilepsy, as these are
`fields in which neurologists and neurosurgeons are mainly
`involved. Treatment of stupor and coma and psychiatric dis-
`orders are confined to a few reports that await confirmation
`derived from multicenter studies. Visual and auditory pros-
`theses are still in the developmental phase and bladder, dia-
`phragmatic, and vascular insufficiency treatment by ES has
`been undertaken by other specialties in medicine.
`
`Historical Notes
`
`There is evidence that mineral sources of electric and mag-
`netic energy such as amber and magnetite were used for
`therapeutic purposes as early as 9,000
` in the form of
`BC
`necklaces, bracelets, and amulets. For many centuries and
`throughout several cultures (Greek, Egyptian, Hebraic, Ro-
`man, etc.), the practice of electrotherapy was extended
`
`0188-4409/00 $–see front matter. Copyright © 2000 IMSS. Published by Elsevier Science Inc.
`PII S0188-4409(00)00063-1
`
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`Ex. 1013, p. 232
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`Velasco / Archives of Medical Research 31 (2000) 232–236
`
`233
`
`through the use of several sources, such as minerals, metals,
`and animals like the torpedo fish and the electric eel.
`During the Middle Ages, knowledge of electricity was
`advanced. Electricity was identified as a form of energy and
`primitive devices to induce electrical current were devel-
`oped. In 1745, the capacitator, i.e., a device to create and
`conserve energy, was simultaneously developed by Von
`Kleist and Musschenbroek (1).
`Experiments in neurophysiology utilizing electrical cur-
`rent began in 1786 when Galvani induced muscular contrac-
`tions in the legs of frogs by applying a pair of scissors along
`the trajectory of the sciatic nerve during an electric storm
`(2). With the design of the battery by Volta (1790) (3), ex-
`periences in neurophysiology using electrical current multi-
`plied. It is interesting that the earliest experiences were ob-
`tained in humans; for example, D. Larrey, a surgeon of
`Napoleon’s army, stimulated the popliteal nerve to induce
`contractions of the gastrocnemius muscle in the amputated
`leg of a soldier in 1793.
`In 1870, Fritsch and Hitzig (4) produced seizures by ap-
`plying electrical current in a dog’s brain, thus initiating the
`study of the central nervous system (CNS) with electricity.
`Electrical currents were extensively used to study spinal re-
`flexes and motor and sensory responses from the nervous
`system at the beginning of the 20th Century. Of particular in-
`terest is the book by Ferrier in 1886 that describes the topo-
`graphy of different areas in the cerebral cortex of animals,
`using ES to elicit various motor and sensory responses (5).
`In 1932, Hess (6) described antagonistic responses that
`could be obtained through stimulation of the same locus in
`the thalamus of the cat by varying the frequency of alternat-
`ing currents (AC). While low frequency stimulation induced
`sleep, high frequency currents induced arousal. In this man-
`ner, Hess demonstrated for the first time that nervous tissue
`response could be modulated according to the parameters of
`the ES applied.
`In 1942, Dempsey and Morrison (7) described a wide-
`spread synchronization of the cortical electroencephalo-
`gram (EEG) by stimulation of circumscribed loci in the
`brain stem and the thalamus, demonstrating the regulatory
`activity of subcortical structures upon the cerebral cortex. In
`1949, Hunter and Jasper (8) were able to correlate low fre-
`quency stimulation of the thalamus to behavioral and EEG
`patterns of sleep and petit mal epilepsy, while high fre-
`quency stimulation of the same area induced arousal and
`EEG desynchronization.
`With the publication of the book entitled
`Functional
`
`Anatomy of the Human Brain, in 1954 (9), Penfield and Jas-
`per provided invaluable information on the topography of a
`number of clinical and EEG responses induced by ES. The
`observations were made during surgical procedures per-
`formed under local anesthesia to treat epilepsy. Zanchetti et
`al. in 1952 (10) demonstrated an increase in the convulsive
`threshold of pentylene tetrazol seizures by simultaneous
`electrical stimulation of the vagal nerve.
`
`Cooke and Snider (11) in 1955 and Dow et al. (12) in
`1962 prevented seizures originating in the cerebral cortex
`by stimulation of the cerebellar cortex in animal models of
`epilepsy.
`In 1965, Melzak and Wall (13) proposed the gate control
`theory of pain. They considered a competitive input of
`small-diameter fibers associated with noxious information
`and large-diameter fibers associated with propioceptive and
`other forms of sensory information at the entrance of the
`dorsal roots to the spinal cord. Accordingly, pain perception
`would depend upon the balance between large- and small-
`fiber input. Melzak and Wall also suggested that activation
`of the dorsal column of the spinal cord would induce anti-
`dromic potentials of large-diameter fibers that could inhibit
`the input of small-diameter fibers and decrease pain percep-
`tion. In 1969, Reynolds (14) electrically stimulated the
`periventricular gray substance in the thalamus and mesen-
`cephalon and reduced painful perception in rats. He inter-
`preted this result as the activation of opioid receptors lo-
`cated in those areas.
`In 1972, Consieller et al. (15) demonstrated that mor-
`phine delivered to the spinal cord of cats inhibited the activ-
`ity of nociceptive neurons located in the dorsal horn. Dug-
`gan et al. (16) in 1977 suppressed the transmission of
`nociceptive input by delivering morphine in the substantia
`gelatinosa of the spinal cord.
`In regard to the treatment of involuntary movements, the
`history has been different. Observations made during ster-
`eotactic procedures to treat tremor and rigidity provided in-
`formation that some symptoms may be decreased by ES
`used transoperatively to assess the proximity of eloquent ar-
`eas to the stereotactic target before performing the lesions
`(17,18). More recently, the experiments by De Long et al. in
`1985 (19) provided evidence of the inhibitory influence of
`the subthalamic nucleus on the activity of the ventrolateral
`thalamic nucleus (VL), both directly and through the inter-
`nal globus pallidus, which led to the use of subthalamic nu-
`cleus stimulation to treat Parkinson’s disease and other in-
`voluntary movements.
`These are only some of the major experimental observa-
`tions that supported the use of neuromodulation in the treat-
`ment of difficult-to-control pain, seizures, involuntary move-
`ments, altered states of consciousness, and spasticity.
`Clinically, the use of neural tissue ES to treat neurologi-
`cal symptoms goes back to the past century in Europe and
`perhaps even more in the Oriental cultures. An interesting
`photograph was obtained from the photograph archives of
`the old School of Medicine in Paris; it was taken in 1852.
`The picture shows Dr. Duchenne applying an electrode
`along the trajectory of the facial nerve to treat a patient suf-
`fering from facial nerve palsy (20) by means of ES.
`ES of peripheral nerves by acupuncture or transcutane-
`ous electrical nerve stimulation (TENS) was used in the
`Western world to treat pain or to induce a state of analgesia
`several years before the initiation of chronic ES. The begin-
`
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`Velasco / Archives of Medical Research 31 (2000) 232–236
`
`Benabid et al. (31) used the thalamic target to treat tremor in
`the nucleus ventralis intermedius (Vim) of the thalamus to
`control tremor and rigidity in cases of Parkinson’s disease
`by ES. In the same year, Uthman et al. (32) initiated their
`experience in seizure control by ES of the vagal nerve and
`F. Velasco et al. (33) described the anticonvulsive effect of
`centromedian thalamic nucleus stimulation. In 1988, Suss-
`man et al. (34) presented a short communication on the
`treatment of seizures by ES of the ventralis anterior nucleus
`of the thalamus (VA).
`In 1991, Tsubokawa et al. (35) described the analgesia
`induced by ES of the motor—but not of the sensory—cortex
`of patients suffering from deafferentation pain. In 1995,
`Limousin et al. (36) reported the control of symptoms of
`Parkinson’s disease by ES of the subthalamic nucleus.
`Last year, Fisher provided experimental evidence of sei-
`zure control by VA nucleus stimulation and reported the
`success of the method in clinical cases. Velasco et al. (37)
`provided evidence that stimulation of the epileptic foci may
`induce decrease of seizure activity and seizure control. To-
`day, the same group presents evidence that stimulation of
`subthalamic fibers, termed prelemniscal radiation, induces
`improvement of Parkinson’s disease symptoms.
`Throughout this issue, we have had the opportunity of
`bringing together most of the outstanding experts in neuro-
`modulation who either have described some of the proce-
`dures to treat neurological symptoms or who have the great-
`est experience in the use of a particular procedure. For their
`assistance and participation, we would like to express our
`gratitude.
`Before going into the material of this issue, I would like
`to refer to an experimental work of utmost importance, i.e.,
`evidence provided concerning the ranges at which ES of
`neural tissue may be considered safe.
`Several experimental models have been used to study the
`effect of ES on the neurons themselves. One of the simplest
`models and perhaps the model that has provided the most
`evidence on this matter is the use of implanted electrodes in
`the motor cortex of the cat to perform controlled microstim-
`ulation while orthodromically induced potentials were be-
`ing recorded from the cerebral peduncle (38). The amount
`of current delivery measured as charge per phase, i.e., the
`amount delivered in each phase (positive/negative) of a bi-
`phasic stimulus, measured in nano Coulombs (nC) or micro
`m
`Coulombs (
`C), the charge density that is the charge per
`phase multiplied by the electrode’s surface expressed in C/
`2
`cm
`, the frequency of stimulation in Hertz, and the duration
`of stimulation in hours and the fragmentation of the metal
`used to build up the electrodes were varied in those experi-
`ments. The local effects on neurons by histology or electron
`microscopy subsequent to different forms of stimulation
`and related their observations to other experimental studies
`that dealt with lesions caused by chronic stimulation, pro-
`viding valuable information concerning the ranges of safety
`of ES have been analyzed (39–42).
`
`Figure 1. Combinations of charge density and charge per phase used in
`several studies of stimulation-induced neural injury. The occurrence of
`neural injury is indicated by filled symbols, absence of damage by open
`symbols. The broken line connects loci from the author’s most recent
`study, described in the text, using electrodes of various sizes. Loci in the
`upper left portion of the graph represent small electrodes, while those in the
`lower right portion represent large (8-mm diameter) disc electrodes. (From
`Agnew et al., 1989. In: Agnew WF, McCreery DB, editors, Neural prosthe-
`sis. Minneapolis, MN: Prentice Hall Biophysics and Bioengineering Series,
`by permission of the publisher).
`
`ning of the modern era of ES started with the introduction of
`totally implanted devices to stimulate nervous tissue in an
`attempt to interfere with mechanisms related to the physio-
`pathology of symptoms (21).
`Shealy et al. in 1967 (22) initiated the use of ES in the
`dorsal column to treat pain. Initially, the electrodes were
`placed subdurally and later, epidurally. The authors took ad-
`vantage of the technology developed for the cardiac pace-
`makers that had been in use by that time for over a decade
`(23). The new indication in the treatment of neurological
`disorders promoted the rapid development of totally im-
`planted devices, described subsequently in this special issue
`on instrumentation.
`In 1973, Mazars (24) and Hosobuchi (25) stimulated var-
`ious sites of the thalamus, the internal capsule, and periven-
`tricular gray to induce analgesia, perhaps by enhancing or
`interfering with opioid receptors and other anatomo-physio-
`logical mechanisms of pain perception. Also in 1973, based
`on the experiments by Cooke and Dow previously de-
`scribed, Cooper et al. (26) stimulated the cerebellar cortex
`to treat refractory epileptic seizures and described the addi-
`tional effects on muscular tone of patients suffering from
`spastic paraplegia.
`In 1974, Steude (27) described the analgesic effects of
`ES of the trigeminal nerve and Gasserian ganglion in cases
`of facial anesthesia dolorosa. Andy, in 1980 (28), described
`the effect of ES of centromedian nucleus of the thalamus on
`painful dyskinesia and in 1982, Bovie and Meyerson (29)
`attributed the analgesic effect of periventricular gray stimu-
`lation to the interference of neuronal activity in the parafas-
`cicular nucleus.
`In 1985, Heath et al. (30) reported the beneficial effect of
`cerebellar stimulation on behavioral disorders. In 1987,
`
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`Ex. 1013, p. 234
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`Velasco / Archives of Medical Research 31 (2000) 232–236
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`235
`
`Table 1.
`
`Effect of electical stimulation
`
`Current intensity
`
`Charge density
`
`Charge per phase
`
`Frequency of stimulation
`
`Neuronal excitation
`Neuronal inhibition
`Neuronal lesion
`
`m
`A
`5–15
`m
`40–80
`A
`m
`800–1,200
`A
`
`m
`2
`C/cm
`50–150
`m
`2
`400–800
`C/cm
`.
`m
`2
`800
`C/cm
`
`1.0–5.0
`0.5–1.0
`.
`2.0
`
`m
`C/ph
`m
`C/ph
`m
`C/ph
`
`10–40 Hz
`40–60 Hz
`.
`40 Hz
`
`Progressive lesion: it depends on the metals used to build up electrodes and current densities inducing fragmentation of the electrode.
`
`In Table 1, we presented the effects of subacute (min-
`utes) ES on evoked potentials and neuronal changes. Neu-
`ronal excitation (increase in pyramidal tract-evoked poten-
`tials) was obtained within a narrow, small intensity and
`current charge. A neuronal inhibition was obtained within a
`range 3–5 times greater than that necessary to induce excita-
`m
`tion. Neuronal lesion not exceeding 750
`m around the
`electrode was induced by currents over 10 times those nec-
`essary to produce inhibition. However, stronger current
`charges caused a progressively enlarging lesion dependent
`on fragmentation of the electrode’s metal (43). Lesions in-
`duced were principally neuronal shrinkage secondary to dis-
`ruption of their membrane, but local vascular changes
`mainly in the form of hypoxia and hypoglycemia were also
`1
`induced, as well as increments in [K
`] in the interstitial
`space (38).
`The safety of the procedure more clearly related in-
`versely to charge density and charge per phase and was in
`agreement with other experiments of ES in different areas
`of the brain and the cerebellum and different animal species
`(Figure 1). Chronic (hour) stimulation tends to induce pro-
`gressive inhibition of the stimulated tissue when other stim-
`ulation parameters are unchanged.
`From these studies, we may conclude that with the inten-
`sity currents and paradigms of stimulation used for clinical
`work, we are most likely to be inducing inhibition of the
`stimulated tissue. Therefore, the term neuromodulation
`seems more appropriate than that of ES.
`The objectives of this Special Issue would be to review
`the instrumentation used in clinical work and the indications
`and contraindications of each procedure, and to provide an
`outline of the surgical techniques used for implantation and
`the manner by which the results may be evaluated. Because
`all devices are used chronically, adequate monitoring of the
`functioning of the device and the effectiveness of neuro-
`modulation throughout the treatment period is imperative
`for all procedures. Finally, because most procedures are de-
`signed as alternatives to traditional lesion procedures used
`in neurosurgery, and in view of the expensive cost of instru-
`mentation, the evaluation of cost benefits of each particular
`procedure should be considered.
`There is no doubt that the use of neuromodulation is rap-
`idly expanding and that in addition to the benefit neuromod-
`ulation provides to our patients, these procedures also offer
`a unique opportunity to acquire knowledge concerning the
`physiology of the human brain. Consequently, information
`
`concerning the possible mechanisms of action of these pro-
`cedures will also be welcome.
`
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`Ex. 1013, p. 236
`
`