Deep Brain Stimulation between 1947 and 1987: The Untold Story

Marwan I. Hariz, M.D., Ph.D.; Patric Blomstedt, M.D., Ph.D.; Ludvic Zrinzo, M.D., M.Sc.

Disclosures

Neurosurg Focus. 2010;29(2):e1 

In This Article

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Origins of DBS

In 1947, at Temple University in Philadelphia, neurologist Spiegel and neurosurgeon Wycis described a stereotactic apparatus and its use in humans to perform ablative procedures.[98] This collaborative paper heralded the era of human functional stereotaxy, initially labeled "stereoencephalotomy" by its authors.[97] Their efforts were explicitly aimed at avoiding the side effects of the all-too-crude and commonly performed frontal lobotomy. In the last paragraph of their pioneering paper, the authors wrote, "This apparatus is being used for psychosurgery … Lesions have been placed in the region of the medial nucleus of the thalamus (medial thalamotomy) …."[98] According to Gildenberg,[37,38] who was a fellow of Spiegel and Wycis in the 1950s, intraoperative electrical stimulation was used from the very beginning as a mean of exploring the brain target prior to lesioning. Thus, from its very beginning, functional stereotactic neurosurgery was multidisciplinary, was directed at the treatment of psychiatric illness, and used electrical stimulation as a physiological means of assessing and corroborating the subcortical anatomical brain target. Spiegel and Wycis soon shifted their focus to the treatment of movement disorders, starting with Huntington chorea and choreoathetosis, then PD, by performing pallidoansotomies, stereotactically ablating the same areas that had been lesioned by Meyers, Fenelon, and Guiot via an open nonstereotactic approach.[96]

In 1952, neurophysiologist and neurobehaviorist Delgado and his colleagues[23] proposed a technique of electrode implantation for chronic recording and stimulation to evaluate "its possible therapeutic value in psychotic patients." The following year, the Proceedings of the Staff Meetings of the Mayo Clinic published a symposium on "intracerebral electrography" including a paper on "Neurosurgical and neurologic applications of depth electrography" containing the following statement: "An observation that may have some practical significance was that several of our psychotic patients seem to improve and become more accessible in the course of stimulation studies lasting several days."[14] The authors speculated that a likely explanation for this effect "was that the local stimulation was having a therapeutic effect comparable to that of electroshock" and concluded, "… this aspect of localized stimulation studies requires further investigation since it may lead to a most specific, less damaging, and more therapeutically effective electrostimulation technic than can be achieved by the relatively crude extracranial stimulation methods in use at present."[14]

Meanwhile, a team at Tulane University in New Orleans led by psychiatrist Heath[47] had started depth electrode studies in patients in 1950, including chronic stimulation of the septal area in psychotic patients. Also, in 1961, a book entitled "Electrical stimulation of the brain – An interdisciplinary survey of neurobehavioral integrative systems", edited by Daniel Sheer Professor of psychology at the University of Houston, was published.[94] This multiauthored book was devoted to animal and human work on subcortical recording and stimulation in epilepsy, obesity, aggressive behavior, and other neurological and behavioral conditions. Hence, from its very beginning, the technique of chronic stimulation of deep brain structures was applied in behavioral and psychiatric studies and eventually in treatment of mental disorders (see further below).

Frequency of the Electrical Current Used for Stimulation

In a review paper published in 2009, Benabid et al.[10] wrote, "In 1987, the discovery that high-frequency deep brain stimulation (DBS) was able to mimic, in a reversible and adjustable manner, the effects of ablation of functional targets has revived functional neurosurgery of movement disorders …" The Grenoble group was certainly the first to systematically study the therapeutic role of high frequency electrical current in DBS and established 130 Hz as the "ideal" frequency now commonly used worldwide in pallidal and subthalamic DBS. A review of prior stereotactic literature reveals that frequency of the applied current during intraoperative stimulation of the brain target prior to stereotactic lesioning was often a matter of debate with several authors exploring this issue. In his review on evolution of neuromodulation, Gildenberg stated,[37]

There was considerable discussion on 'low frequency' versus 'high frequency' stimulation, but those terms were not consistently defined. Low frequency might be anywhere from 6 to 60 Hz. High frequency might be 50–100 Hz, but rarely above …. When I first worked with Spiegel and Wycis from 1955 to 1959, routine stimulation was 6 and 60 Hz. When I returned in 1963, a more sophisticated Grass laboratory stimulator was used, and the parameters were 5, 50 and 100 Hz. There was a general feeling that low frequency stimulation might drive or increase involuntary movements, especially tremor, and high frequency stimulation might mimic the therapeutic effect, but such observations were inconsistent. [37]

In 1961, Alberts et al.[3] studied stimulation thresholds in various parts of the internal pallidum and ventrolateral thalamus in 62 patients with PD prior to lesioning. They stimulated at 60 Hz and could elicit or disrupt tremor. Walker[110] defined the optimal parameters of intraoperative stimulation as being a current of 50–100 Hz, stating that arrest of tremor had better predictive value than facilitation or initiation of tremor. Common observations reported by several authors in the process of performing thalamotomies and subthalamotomies in awake patients were that "low-frequency" stimulation could exacerbate tremor whereas "high-frequency" stimulation resulted in an improvement of that symptom.[2,46,53,73,83,95] In 1963 in France, neurophysiologist Albe-Fessard,[2] who pioneered the technique of subcortical semimicrorecording, reported that stimulation in the region of the ventrointermediate nucleus of the thalamus at frequencies of 100–200 Hz would effectively inhibit tremor in parkinsonian patients. In the same year, psychiatrist Robert Heath from Tulane University in New Orleans published a paper, "Electrical self-stimulation of the brain in Man;"[48] electrodes were implanted in the caudate, septal area, amygdala, central medial thalamus, and various areas of the hypothalamus to study "rewarding" and "aversive" reactions at various current intensities. In all these stimulations, Heath used a fixed frequency of "100 pulse/sec." In 1969, Blaine Nashold and his colleagues[73] stimulated various subcortical structures including the ventrolateral thalamus, the subthalamic nucleus, and the zona incerta and reported that tremor suppression occurred at frequencies of 120–300 Hz. In 1973, Bechtereva et al.[7] advocated the use of "electric stimulation with high-rate pulses" of subcortical structures, however, without specifying what she meant by high-rate pulses. In 1979, Laitinen[58] studied emotional responses to subcortical electrical stimulation in 135 psychiatric patients. The targets were the rostral and middle cingulum, the anterior internal capsule, and the subcaudate region of the "substantia innominata." He noted that stimulation frequency played an important role with "high frequency (60 Hz)" being by far the most effective in producing emotional responses while "low frequency stimulation (3–6 Hz) seldom caused such responses."[58] In almost all these instances, stimulation was performed intraoperatively as a means of physiological evaluation of the brain target prior to lesioning.

Deep Brain Stimulation in Psychiatry and Behavior

As stated earlier, chronic subcortical stimulation through chronically implanted electrodes was first tested in psychiatric patients. Three key individuals, a neurophysiologist, a neurophysiologist/psychiatrist, and a psychiatrist, working independently of each other, devoted much of their career exploring this method.

José Delgado, a Spanish neurophysiologist and neurobehaviorist who moved to Yale University in 1950 and worked there with Fulton, is probably best known for a motion picture showing his experiment with a bull whose charge in the arena could be stopped through remote brain stimulation.[40,105] Delgado worked extensively with chronic subcortical stimulation in rats, goats, monkeys, and humans. In a lecture delivered in 1965 titled "Evolution of physical control of the brain," he reported, "Monkeys may learn to press a lever in order to stimulate by radio the brain of another aggressive animal and in this way to avoid his attack. Heterostimulation in monkey colonies demonstrates the possibility of instrumental control of social behavior."[25] He concluded, "Autonomic and somatic functions, individual and social behavior, emotional and mental reactions may be evoked, maintained, modified, or inhibited, both in animals and in man, by electrical stimulation of specific cerebral structures. Physical control of many brain functions is a demonstrated fact…."[25] Delgado's enthusiasm for this new technology led to a belief that there were no limits to its potentials. In 1969 he published a book titled "Physical control of the mind: towards a psychocivilized society."[26] Despite the book's provocative title, Delgado took great pains to negate the impression that mind control could be achieved by electrodes wired into people's brain and emphasized that the technique of "Electrical Stimulation of the Brain (ESB)" was meant as a research tool to study and understand the Human mind. Delgado developed a technique of subcortical stimulation using chronically implanted electrodes connected to a subcutaneous receiver implanted in the scalp, a "Stimoceiver," that could be controlled by radio waves. This technique of "radio communication with the brain" was initially developed for use in psychiatric patients.[24,27,28] Following his return to Spain, Delgado worked with Obrador and Martin Rodriguez. They implanted chronic electrodes bilaterally in the head of the caudate and septal nuclei of a patient with postplexus avulsion pain, which was probably the first implantation of a DBS device in Europe.[40]

Carl-Wilhelm Sem-Jacobsen was a Norwegian neurophysiologist and psychiatrist. He pursued a fellowship in physiology at the Mayo Clinic where his main interests were "depth electrography and depth stimulation and their application in psychiatric patients."[14] In 1963, he published an article about depth-electrographic observations in psychotic patients.[90] He stated, "electrical stimulation in some regions of the ventro-medial part of the frontal lobe resulted in a temporary improvement to complete freedom from symptoms." The specific aim of his studies was "to use chronic implanted electrodes in the target area in an attempt to improve the leucotomy operation."[93] In 1972 he reported that since 1952 in Rochester, and later in Oslo, 213 patients had been treated with his "depth-electrographic stereotactic neurosurgical technique;" of these, 123 patients were suffering from mental disorders.[93] Sem-Jacobsen's technique using chronically implanted electrodes aimed merely to study brain activity and perform intermittent chronic stimulation of various brain targets prior to subsequent lesioning. His concept of chronic stimulation was that it was not the final goal of the treatment but a means to evaluate the target area and its response to stimulation before the chronic electrodes were used to produce incremental therapeutic permanent lesions. Sem-Jacobsen eventually shifted his interest to the surgical treatment of Parkinson disease using this same technique and concept (see further below).

Robert Heath was a psychiatrist at Tulane University, New Orleans. He implanted a multitude of electrodes in several subcortical nuclei and pathways to study the effect of stimulation on behavior and probably pioneered the concept of electrical "self-stimulation."[48] Heath started a program of DBS to treat schizophrenia as well as pain and epilepsy in the early 1950s.[6] Benefits of stimulation in schizophrenic patients turned out to be scarce, but Heath made the interesting observation that some patients described the experience of self-stimulation as "pleasant," "jovial," or "euphoric." In these patients the electrodes were located in the septal area.[6,105] This pleasurable response obtained from the "septal area" came to dominate Heath's further research on DBS applications. He reported relief from physical pain by stimulation of "this pleasure-yielding area of the brain" and extended studies of this brain area during sexual arousal and orgasm.[6,50,105] In 1972 Moan and Heath[70] described the use of septal stimulation to induce heterosexual behavior in a homosexual man. The individual was shown a pornographic video, then a female prostitute was introduced to him in the laboratory and following stimulation to his septal area, the individual and the woman had a sexual intercourse culminating in the subject's orgasm and description of the experience as "pleasurable." The authors wrote that during these sessions the individual "stimulated himself to a point that he was experiencing an almost overwhelming euphoria and elation, and had to be disconnected, despite his vigorous protests."[70] Two electrodes, each with 6 contacts, had been implanted in this individual and the paper contains 2 figures from the Atlas of Schaltenbrand and Bailey[85] depicting their location: one electrode lay in the "septal area" (close to the nucleus accumbens) and the other in the region of the centromedian nucleus of the thalamus.[70] Heath pursued similar and other experiments through the 1970s. One of his last publications from that decade was "Modulation of emotion with a brain pacemaker. Treatment for intractable psychiatric illness"[49] featuring an illustration showing the commonly used DBS system at the time consisting of a pulse sender with an antenna placed above the skin of the pectoral area where the receiver was implanted (the Xtrel Medtronic system). "Modulation of emotion" by DBS, an issue widely criticized in the 1970s,[105] reemerged 30 years later from the pen of another psychiatrist, Luc Mallet from Salpêtrière hospital in Paris who published a paper titled: "La stimulation cérébrale profonde: un outil pour la modulation thérapeutique du comportement et des emotions" (Deep brain stimulation: a tool for therapeutic modulation of behavior and emotions).[63]

Heath's experiments were analyzed in depth by psychologist Baumeister[6] in the paper "The Tulane Electrical Brain Stimulation Program a historical case study in medical ethics," published in Journal of the History of the Neurosciences in 2000. Baumeister reviewed 3 decades of DBS work performed at Tulane university and concluded, "… the Tulane electrical brain stimulation experiments had neither a scientific nor a clinical justification…. The conclusion is that these experiments were dubious and precarious by yesterday's standards."[6]

In 1977, Finnish neurosurgeon Laitinen[59] had already commented on the questionable ethic of one of Heath's papers,[50] concluding that: "There is no doubt that in this study all standards of ethics had been ignored. The ethical responsibility of the editors who accept reports of this kind for publication should also be discussed."[59] Laitinen was not against the use of DBS as a therapeutic tool in psychosurgery; in that same paper he wrote, "After implantation of chronic electrodes, long-term depth recordings and repeated electrical stimulations enable the psychosurgeon to accumulate knowledge about the pathophysiology of the brain and to improve the treatment of the patient in question. It may even be possible to treat the patient with repeated electrical stimulation without macroscopic destruction of brain tissue."[59] Laitinen proposed a "model of controlled trial," whereby eligible patients are randomized to either receive best available conservative therapy or stereotactic surgery and stated, "Psychosurgery will remain an experimental therapy for years. Therefore its use should be concentrated and restricted to psychosurgical research units having strong and intimate affiliation with scientists from many disciplines."[59]

Meanwhile, the 1970s saw few clinical applications of DBS in the treatment of psychiatric symptoms. In 1972, Escobedo et al.[33] implanted quadripolar electrodes bilaterally in the head of the caudate nucleus in 2 patients with epilepsy, mental retardation, and destructive aggressive behavior and described vegetative, motor, and behavioral responses to stimulation. In 1979, Dieckman[31] performed unilateral stimulation of the nondominant thalamus using a quadripolar Medtronic "deep brain stimulation electrode" to treat a woman with phobia. The electrode contacts extended over 12 mm and were located in the parafascicular and rostral intralaminar areas. Stimulation was intermittent at a low frequency (5 Hz) and resulted in disappearance of the phobias, while attempts at stimulation with 50 Hz "was experienced as being very disagreeable."[31]

Deep Brain Stimulation in Pain and Epilepsy

As stated above, early attempts were made in the 1950s to treat chronic pain with DBS. Heath, Delgado, Bechtereva, and others performed chronic stimulation of various brain targets including the septal area, the caudate, the cingulum and the sensory thalamus. Deep brain stimulation for pain was not as "sensational" as DBS for psychiatry and behavior, or indeed in later years, as DBS for movement disorders. There was a surge in the use of DBS for pain in the 1970s initiated by 2 teams independently of each other (Mazars et al. in France[66–68] and Hosobuchi et al.[52] in the US). The authors targeted the sensory thalamus to treat various conditions of deafferentation pain. Subsequently, Adams et al.[1] reported on internal capsule DBS for pain, but this target never gained popularity. Another target, the periventricular and periaqueductal gray matter was introduced in 1977 by Richardson et al.[80,81] Hosobuchi et al.[51] demonstrated that pain relief of periventricular and periaqueductal gray matter DBS could be reversed by the opioid antagonist Naloxone. Deep brain stimulation for chronic pain, both in thalamic targets and central gray targets, became such a popular procedure that Medtronic trademarked the term "DBS" with respect to chronic subcortical stimulation for pain in the mid-1970s.[18] Despite this, DBS for pain was never approved by the US Food and Drug Administration, probably due to lack of controlled trials to prove its efficacy.[18] Deep brain stimulation for chronic pain along with occasional stereotactic ablative surgery continued to be used in Europe,[43] and interest has resurged in recent years, riding on the wave of success of DBS in movement disorders.[16]

Epilepsy was another indication that caught the early interest of the DBS pioneers listed above. The exploration and identification of epileptic foci rapidly adopted the technique of stereotactic chronic electrode implantation for recording and intermittent stimulation.[94] Indeed, one of the first human stereotactic apparatuses, designed by Jean Talairach in 1947, was fitted with a double grid system to allow precise implantation of chronic electrodes in medial temporal structures for recording and stimulation in patients with epilepsy.[69,101,102] Therapeutic chronic stimulation as treatment for epilepsy was subsequently introduced, in cerebellar as well as in thalamic and other brain structures. One of the early DBS targets was the anterior nucleus of the thalamus,[22,82,104] the very same target that has reemerged recently and shown benefit in a multicenter blinded randomized controlled trial of DBS for epilepsy.[36] According to Rosenow et al.,[82] Cooper had implanted DBS electrodes in the anterior nucleus of the thalamus in patients with refractory complex partial seizures as early as 1979. Of the 6 initial patients, 5 showed a more than 60% reduction of seizure frequency with stimulation at 3.5 V and 60–70 Hz.[82] Velasco et al.[108] published in 1987 their results of DBS for epilepsy targeting the center median thalamic nucleus. These documented historical facts challenge contemporary statements about DBS being "a new approach" to the treatment of epilepsy.[88]

Deep Brain Stimulation in Movement Disorders

Chronologically, DBS for PD and other movement disorders was the last indication of the older era of chronic subcortical stimulation. Initially, chronic stimulation of thalamic and other basal ganglia targets was used intermittently for days or weeks to ensure satisfactory results prior to lesioning via the chronically implanted electrodes. The first detailed account of this technique was provided by the aforementioned Norwegian neurophysiologist Sem-Jacobsen[91,92] in 1965 and 1966. Multiple electrodes were implanted in the thalamus around a point "midway between the foramen of Monro and the corpus pineale."[91] Chronic stimulation allowed identification of the optimal lesioning site. Sem-Jacobsen wrote, "The electrodes could be kept in for several months without any undesirable irritation around the electrode leads…. It is possible for the patient to go home for a week, on vacation, with electrodes in his head."[91] The electrode(s) yielding the best stimulation results could then be used to make incremental lesions. This recently rediscovered technique[30,79] was not uncommonly used in the past.[73,106]

The idea of using chronic subcortical stimulation as a "permanent" therapy for movement disorders was first presented in the early 1970s by Bechtereva,[7–9] who was a neurophysiologist at the Institute of Experimental Medicine in Leningrad, Union of Soviet Socialist Republics. Electrodes were implanted into the ventrolateral and the centromedian thalamus allowing intermittent sessions of "electric stimulation with high-rate pulses of suprathreshold current."[7] Bechtereva[8] coined the term "therapeutic electrostimulation" to describe this technique. Since the Union of Soviet Socialist Republics did not have access to implantable neurostimulators at that time, the last steps of the treatment were ultimately small lesions performed through the electrodes yielding the best stimulation responses[7] (Nathalia Bechtereva [July 7, 1925–June 22, 2008], personal communication to Patric Blomstedt, April 6, 2008).

In 1977, Mundinger[71] reported his experience in DBS for cervical dystonia. Electrodes were implanted unilaterally in the ventral oral anterior and ventral oral internal nuclei of the thalamus as well as the zona incerta allowing intermittent stimulation with frequencies of up to 390 Hz. In 1982 he wrote: "Stereotactic implantation of stimulation systems for autostimulation in subcortical deep brain structures (deep brain stimulation, DBS) for control of chronic pain and motor diseases is a functional and a reversible treatment which is characterized by the lack of complications involved. The advantages over dissection coagulation with irreparable destruction of nerves, nuclei or neuronal structures are obvious."[72]

Cooper[21,22] performed chronic stimulation in the thalamus and the internal capsule for various movement disorders. It is interesting that his paper from 1980 was titled "Reversibility of chronic neurologic deficits. Some effects of electrical stimulation of the thalamus and internal capsule in man."[22] "Reversibility", a hallmark of modern DBS, was an acknowledged value since the technique's inception. Cooper was probably the first to use the term "Medtronic deep brain stimulation (DBS) electrodes" in the context of surgery for movement disorders. Cooper described stimulation in the internal capsule in a patient with torticollis and illustrated the improvement of the position of the patient's head and neck after the operation.[22]

Brice and McLellan[17] from Southampton, United Kingdom, published in 1980 a paper on "deep brain stimulation" of the subthalamic area in 3 patients with intention tremor due to multiple sclerosis. In 2 of these patients stimulation continued to provide benefit at 6-month follow-up using stimulation frequencies between 75 and 150 Hz. McLellan had previously worked with Cooper with whom he published a paper in 1977 related to safety and efficacy of chronic stimulation in the brain.[20]

In 1983, Andy[4] published a paper on DBS in 9 patients with movement disorders, 5 of whom had parkinsonian tremor. Andy targeted the ventral intermediate nucleus and other areas of the thalamus and subthalamus. He reported effective stimulation frequencies ranging from 50 to 200 Hz and wrote that DBS "… in contrast to thalamic lesion … is preferred for the treatment of intractable motor disorders in high-risk elderly patients and patients with diffuse lesions secondary to trauma … the beneficial effects are reversible even after several months of applied therapeutic stimulation …. Lesion studies indicate that optimum sites for alleviating Parkinson tremor and other movement disorders are the Vim and other thalamic and subthalamic areas. Optimum sites for stimulation electrode implants tend to parallel those findings."[4]

Deep Brain Stimulation in Minimally Conscious States

In August 2007, a paper was published in Nature by Schiff et al.[86] describing how bilateral central thalamic DBS improved conscience levels in a patient who had been in a minimally conscious state for 6 years following traumatic brain injury. The printed issue of this groundbreaking paper, much publicized in the lay press at the time, quoted 23 references, none of which referred to any of the several previous studies on DBS for decreased consciousness, published by various workers between 1969 and 1993 in Germany,[45,100] in France,[19,29] and in Japan.[54,103,111]

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