DEEP BRAIN STIMULATION

Electrical stimulation of the brain is an important therapy for refractory neurological disorders such as drug resistant Parkinson's disease and severe tremor and has become an area of active clinical research in both neurology and psychiatry. Using a technique called deep brain stimulation (DBS), small electrical leads are placed into the brain using stereotactic localization. A special head frame is attached to the skull under local anesthesia, and electrodes are implanted using internal brain targets located with reference to anatomical landmarks determined by brain imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). This technique allows for the precise targeting of specific brain sites or nuclei. Insertion of electrodes can be done without damage to adjacent tissue. These electrodes are connected by a wire to a pacemaker implanted in the chest that generates electrical stimulation. Stimulation parameters can be modified by manipulation of the pacemaker.

Unlike ablative surgery that results in irreversible damage of brain tissue from the intentional destruction of targeted areas, the effects of DBS are reversible. The stimulator can be turned off, and the electrodes can generally be removed without any significant aftereffects. DBS differs from other methods that employ electrical stimulation of the central nervous system. Electroconvulsive therapy (ECT), primarily used to treat severe depression, stimulates the brain using electrodes placed on the scalp. Transcranial magnetic stimulation induces electrical currents in the brain using external magnetic coils. Electrical stimulation in the neck of the vagus nerve has been demonstrated to reduce epileptic seizures. Cortical stimulation of the brain is also employed as a treatment for chronic pain disorders (Greenberg).

Electrical stimulation of the brain is also used as a diagnostic tool in the treatment of epilepsy and as a means to localize specific brain areas in order to avoid injury during surgical procedures. Electrical stimulation has also been applied within the peripheral nervous system for neuroprosthethic applications such as reconstituting motor function in a paralyzed limb.

Historical Considerations

The modern history of electrical stimulation of the brain dates to the nineteenth century During this period the French surgeon and anthropologist Paul Broca (1824–1880) correlated speech with an area in the left hemisphere that is known as Broca's area, and the English neurologist John Hughlings Jackson hypothesized that electrical activity in the cortex could result in seizures. In tandem with these efforts to correlate cerebral structure and function, early neurophysiologists engaged in animal experimentation using electrical stimulation In 1870 the German neurologists Eduard Hitzig and Gustav Fritsch demonstrated motor activity in a dog following stimulation (Thomas and Young). In 1873 the Scottish neurologist David Ferrier induced contralateral seizures in a dog after unilateral hemispheric stimulation.

The first known electrical stimulation of the human brain was conducted by the American neurosurgeon Roberts Bartholow in Cincinnati, Ohio, in 1874 on a terminally ill woman with locally invasive basal cell carcinoma that had eroded her skull and left her brain exposed. Bartholow demonstrated that the dura mater covering the brain was insensate, that motor activity on one side of the body could be induced by stimulation of the opposite hemisphere, and that electrical stimulation of the brain could induce localized seizures and transient loss of consciousness when the amount of current was increased. The patient subsequently died from recurrent seizure activity. Contemporaries harshly criticized Bartholow on ethical grounds because of the fatal complications of the intervention, the uncertain nature of the patient's "consent," and the suffering that she experienced (Morgan).

Early electrical stimulation of the brain was used as a method of mapping cerebral cortical function, matching the site of stimulation of the brain's surface with the patient's response during operations under local anesthesia. Pioneering work was done by two American neurosurgeons: Harvey Cushing in the early twentieth century and Wilder Penfield, who later in the century used electrical stimulation in his study of epilepsy and the mapping of cognitive function. An important advance was the development in 1947 of stereotactic surgery, which enabled brain targets to be precisely located in three dimensions. With this technique, electrodes could now be inserted in the brain without the completion of a full craniotomy in which the entire skull needs to be opened (Gildenberg, 1990).

Robert G. Heath first described electrical stimulation for the control of chronic pain in his 1954 book, Studies in Schizophrenia. In the 1960s and 70s investigators demonstrated that deep stimulation of selected targets within the brain was demonstrated to relieve pain In 1985, the Swiss neurosurgeon, Jean Siegfried noted that stimulation of the thalamus for pain control could improve tremor in a patient with Parkinson's disease (Gildenberg, 1998).

The Psychosurgery Debate

Research involving electrical stimulation of the brain was closely linked to the broader debate over psychosurgery in the 1960s and 1970s (Fins, 2003). Commentators from that era worried about the use of electrical stimulation of the brain as a means of behavior control to address social problems such as crime and civic unrest. These concerns were prompted, in part, by the work of José M. R. Delgado who advanced the idea of "psychocivilizing society" using a brain implant that could be operated by remote control. Delgado came to international attention in 1965 when he stopped a charging bull in a bullring using a "stimoceiver" he had developed. Speculation was enhanced by popular novels such as Michael Crichton's The Terminal Man whose main character underwent electrical stimulation of the brain to treat violent behavior.

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, authorized by the National Research Act of 1974, was specifically ordered by the U.S. Congress to issue a report on psychosurgery (National Research Act of 1974. U.S. Statutes at Large). The National Commission, which issued its report in 1977, included electrical stimulation of the brain under its definition of psychosurgery, noting that "psychosurgery includes the implantation of electrodes, destruction or direct stimulation of the brain by any means" when its primary purpose was to "control, change, or affect any behavioral or emotional disturbance" (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research). The National Commission's definition of psychosurgery excluded brain surgery for the treatment of somatic disorders such as Parkinson's disease or epilepsy or for pain management.

Of the National Commission, the Behavioral Control Research Group of the Hastings Institute (Blatte), and the American Psychiatric Association's Task Force on Psychosurgery (Donnelly), none found reliable evidence that psychosurgery had been used for social control, for political purposes, or as an instrument for racist repression as had been alleged. Contrary to expectations of the day, the National Commission did not recommend that psychosurgical procedures be banned. Instead, it found sufficient evidence of efficacy of some psychosurgical procedures to endorse continued experimentation as long as strict regulatory guidelines and limitations were in place.

Although allegations of mind control were never substantiated, contemporary media reports about modern deep brain stimulation often allude to these earlier fears This misuse of historical analogy has the potential to distort current policy regarding the regulation of this novel technology (Fins, 2002).

Clinical Applications in Neuromodulation

The modern era of neuromodulation began in 1987 when the French neurosurgeon Alim Benabid noted improvements of parkinsonian tremor following stimulation of the thalamus (Speelman and Bosch). While engaged in mapping with electrodes prior to ablative surgery for Parkinson's disease, Benabid discovered that electrical stimulation of specific targets could modulate motor symptoms and tremor—a technique that came to be known as neuromodulation. These observations inspired him to develop the modern deep brain stimulator in use today (Fins and Schachter).

Deep brain stimulation is viewed as the standard of care for the treatment of refractory Parkinson's disease and is no longer investigational. In 1997 the U.S. Food and Drug Administration (FDA) approved use of the deep brain stimulator for refractory Parkinson's disease and essential tremor (Blank). DBS has been found effective in prospective, double-blind studies in patients with advanced Parkinson's disease (Deep-Brain Stimulation, 2001; Kumar et al.).

Complications can be related to the procedure, device, or stimulation, and they include hemorrhage, infection, seizures, and hardware-related complications. Such complications can necessitate revision or removal of the device at a rate per electrode year of 8.4 percent (Oh et al.). In one large series of patients, there were no fatalities or permanent severe neurological complications, although 6 percent of patients had some persistent neurological complication (Beric et al.).

In addition to being used to treat Parkinson's disease, neuromodulation using DBS has been used to treat chronic pain and manage epilepsy (Kopell and Rezai). Cortical mapping continues, with more electronic sophistication. Such mapping is being used to guide neurosurgical procedures; to prevent injuries to critical areas, such as those associated with speech or movement, during operations on the brain; and to precisely locate areas of the brain involved with epilepsy, occasionally by provoking seizures through stimulation (Feindel).

Investigational Applications

Research in deep brain stimulation is blurring the disciplinary boundaries between neurology and psychiatry. French investigators have discovered that DBS caused transient acute depression in a patient with Parkinson's disease whose motor function had improved markedly through DBS intervention (Bejjani et al.). Investigators are conducting clinical trials for the use of DBS for severe psychiatric illnesses such as obsessive–compulsive disorder using techniques pioneered in the treatment of movement disorders (Roth et al.; Rapoport and Inoff-Germain). Nicholas D. Schiff and colleagues have proposed the use of DBS for the modulation of consciousness after severe traumatic brain injury (Schiff, Plum, and Rezai).

Ethical Considerations

Deep brain stimulation raises special concerns because neuromodulation techniques deal with the direct stimulation of the brain. No other organ is so closely involved with concepts of mind or self, self-determination and consent.

POTENTIAL ALTERATION OF THE SELF. Interventions involving brain structure or function may result in alterations in cognition, memory, or emotions that may have a bearing on personhood. The potential of DBS to alter brain function may lead some to argue categorically against these interventions. This position would fail to appreciate that psychoactive drugs and cognitive rehabilitation alter brain states and that DBS can be used to restore brain functions that had themselves been altered by injury or disease.

The use of DBS as a potential agent of cognitive rehabilitation raises the question of whether helping a patient regain self-awareness is always an ethical good (Fins, 2000). Partial recovery of cognitive function could theoretically lead to greater awareness of impairment and increased suffering. These perceptions, which may also accompany improvement from more conventional rehabilitation, might be reversed with cessation of stimulation or be treated with antidepressant therapy.

THERAPEUTIC VERSUS INVESTIGATIONAL USE. Given the rapid development of this field, it is important to determine whether the application of deep brain stimulation to a particular disease is therapeutic or investigational. Historically, a treatment has moved from investigational use to therapeutic use when it is shown to relieve the symptoms it is intended to relieve with an acceptable degree of risk and when a significant proportion of physicians, especially those working in the field, are convinced that the intended outcome will appear without adverse long- or short-term effects that outweigh the benefits. This delineation between research and therapy has implications for the informed-consent process and the ability of surrogates to provide consent for DBS when a patient or subject lacks decisionmaking capacity. In the early twenty-first century DBS is recognized as therapeutic for the management of chronic pain, Parkinson's disease, and other movement disorders. It remains investigational for other indications.

Today, the use of a device such as the deep brain stimulator goes through several investigational stages before it is accepted as therapeutic. Formal mechanisms are in place to codify this transition. The FDA uses the investigational device exemption process to regulate devices that pose significant risk, such as the deep brain stimulator (Pritchard, Abel, and Karanian). FDA procedures, which supplement institutional review board (IRB) oversight of clinical trials, are designed to establish the safety and efficacy of devices and are required by law.

Once a device has been approved for use in humans, a clinical trial can proceed to assess the safety and efficacy of the device for a particular indication. Use of a device is deemed therapeutic when its safety and efficacy have been demonstrated in prospective trials, the most rigorous being ones that are double-blinded and randomized (a double-blinded study is one in which during the course of the study neither the subjects nor the conductors of the study know which subjects are in the active therapy or placebo group). Blinded studies can be conducted in the evaluation of DBS. Once the electrodes have been implanted, patients can be blinded to whether they are receiving stimulation, and their responses can be evaluated. Such methodological rigor is essential in the assessment of DBS because of the potential for a powerful placebo effect. The placebo effect has been shown to improve motor performance of patients with Parkinson's disease who were led to believe that they were being stimulated (Pollo et al.).

Demarcating the therapeutic use of DBS from the investigational may be difficult. For example, the use of an approved device does not, in itself, mean that an intervention is therapeutic. In these cases, the intent of the physician or clinical investigator may be important. Many would assert that if the physician's intent is to produce effects generally beneficial to the patient that have previously been demonstrated in similar cases, the intervention can be considered therapeutic. But when the investigator intends to use an approved device to increase knowledge of safety or efficacy for an approved indication or use the device at a new anatomical site or for a new indication, such interventions should be considered to be investigational and undergo review by an IRB.

Because investigational uses of DBS require more regulatory oversight, clinicians might be biased to classify borderline uses of DBS as therapeutic When it is unclear whether the use of DBS is therapeutic or investigational, clinicians should seek the guidance of their local IRB to mitigate this potential conflict of interest.

INFORMED CONSENT. The delineation of DBS as either therapeutic or investigational is also critical given ethical norms that govern informed consent. Given the ongoing investigational nature of many DBS procedures, potential candidates for stimulation need to be informed of whether the proposed procedure is therapeutic or experimental. Physicians who obtain consent from patients for therapeutic procedures should explain the risks, benefits, and alternatives so that the patient, or a surrogate authorized to consent for medical treatment, can provide consent.

Clinicians should seek to maintain the patient's voluntariness and ability to make an informed and reasonable decision about treatment with DBS. Those obtaining consent should appreciate that the chronic nature of the illness and desperation may lead a patient to consent to any treatment that promises symptomatic relief.

When individuals are approached for enrollment in an IRB-approved clinical trial, it is especially important to state the investigational nature of the intervention. Investigators should be careful to avoid the suggestion of a "therapeutic misconception" that falsely equates a clinical trial with safe and effective therapy (Applebaum et al.).

DBS RESEARCH IN THE DECISIONALLY INCAPACITATED. Individuals with severe psychiatric illness or head trauma, who may become candidates for enrollment in DBS clinical trials, may lack decision-making capacity. When these individuals are unable to engage in the informed-consent process, they are considered a vulnerable population and in need of special protections. While surrogates are generally allowed to consent to therapeutic procedures, their authority is more constrained when permission is sought for enrollment in a clinical trial unless they have been authorized through an advance directive for prospective research.

The National Bioethics Advisory Commission (NBAC), in its 1998 report, Research Involving Persons with MentalDisorders That May Affect Decisionmaking Capacity, proposed guidelines to regulate the conduct of research on individuals who are unable to provide consent. While the NBAC recommendations were never enacted into law, they do point to the ethical complexity of neuromodulation research in several cases: when subjects lack decision-making capacity, when the research has yet to demonstrate the prospect of direct medical benefit, and when the research poses more than minimal risk.

BALANCING THE PROTECTION OF HUMAN SUBJECTS WITH ACCESS TO RESEARCH. When considering the balance between the protection of human subjects and access to neuromodulation research, it is important to ask whether current ethical norms deprive decisionally incapacitated individuals of interventions that have the potential to promote self-determination by restoring cognitive function (Fins, 2000). While the ethical principles of respect for persons, beneficence, and justice require that decisionally incapacitated subjects are protected from harm, these principles can also be invoked to affirm a fiduciary obligation to promote well-designed and potentially valuable research for this historically underserved population (Fins and Miller; Fins and Schiff). This justice claim becomes especially compelling as developments in neuromodulation demonstrate growing clinical potential (Fins, 2003).

joseph j. fins

SEE ALSO: Behaviorism; Behavior Modification Therapies; Electroconvulsive Therapy; Emotions; Freedom and Free Will; Informed Consent: Issues of Consent in Mental Healthcare; Neuroethics; Psychosurgery, Ethical Aspects of; Psychosurgery, Medical and Historical Aspects of; Research Policy: Risk and Vulnerable Groups; Technology

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