Major Safety and Ethical Concerns in Brain Stimulation

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Ethics in Biology, Engineering & Medicine - An International Journal, 2(4): 305–316 (2011)

Major Safety and Ethical Concerns in Brain Stimulation

Mulugeta Semework1* & Subrata Saha2,3

1Mahoney-Keck Center for Brain and Behavior Research, Department of Neuroscience,Columbia Uni-versity College of Physicians and Surgeons, New York, NY 10032; 2Program in Biomedical Engineer-ing, SUNY Downstate Medical Center, NY 11203; 3Department of Orthopedic Surgery and Rehabili-tation Medicine, SUNY Downstate Medical Center, 450 Clarkson Ave., Box 30, Brooklyn, NY 11203

*Address all correspondence to: Mulugeta Semework; 1Mahoney-Keck Center for Brain and Behavior Research, Depart-ment of Neuroscience, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; e-mail: [email protected], ir [email protected].

AbstrAct: Over the last few decades, a great deal of progress has been made in the therapeutic use of electrical stimulus in alleviating pain, in correcting heart, motor and autonomic nervous system control problems, and in many more applications. Deep brain stimulation has been successfully used in treating various psychiatric disorders and may even help improve cognitive impairments. However, although its benefits outweigh its perils, electrical stimulation, especially of the brain, has not been fully accepted. Some researchers, medical professionals, and a few skeptical members of the target community still question its validity. This article discusses the generally debated central safety and ethical issues. As similar points are commonly raised regarding its use in or on various body parts, problems and possible solutions are presented using the examples of the most widely used application of electrical stimulus, deep brain stimulation. Generally, side effects from system implant surgery or the actual activity of stimulating the targeted brain areas affecting symptoms, such as depression and lesions where they occur, are still major sources of concern. Large gaps exist among the challenges that have to be overcome, what is known, and what needs to be communicated. Major ethical dilemmas concerning side effects such as suicidal tendencies, cognitive impairment, even personal identity crises, remain to be addressed.

KEY WOrDs: Deep brain stimulation; DBS; microstimulation; brain stimulation ethics; somatosensory feedback; depression; mania; lesions; cognition, neuroethics

I. IntroduCtIon

From ancient stories that patients suffering from ailments such as gout or headache were directed to touch electric fish in the hope that the powerful jolt might cure them,1

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to the modern-day reality of using electrical stimulus to alleviate an array of illnesses, we have always been curious and adventurous in harnessing the power of electrically charged particles. Notable researchers like Dr. Wilder Penfield and others, who used this phenomena to electrically stimulate various areas of the human cortex to verify their roles, have provided us detailed functional maps of the brain. These somatotopic repre-sentations indicate parts or the body which, when stimulated, elicit unique behavioral responses. Such studies have made it possible to carefully excite chosen brain parts to control some ailments or to locate specific loci of an illness, such as epilepsy.

In a true but with an almost fictional Star-Trek quality, our lives have been made fuller by the tireless work of electrons that are carefully and therapeutically unloaded to specific body parts (Fig. 1). One of the greatest recent success stories recounts the use of electrical stimulus on the auditory nerve to replace lost hearing. In another area where a great deal of progress is being made, areas of the brain associated with vision are being stimulating to help blind people see. Brain stimulation is now being used to block sei-zures, and skin and back-muscle stimulation has been effective in relieving some pain. Fast becoming legendary therapies are direct electrical activation of paralyzed limb

FIGURE 1. The wide range medical uses of electrical stimulus.

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muscles to activate and coordinate movement, of bone to facilitate healing and growth, of autonomic nerves to control the bladder, even sexual organs to correct impotence, just to name a few. Other useful outcomes of these therapies include devices such as pacemakers that can detect whether a person’s heart rate is too slow and can respond by sending electrical signals to the heart to speed up, and others (implantable cardio-verter defibrillators) that can sense if the heart develops a dangerously fast or irregular rhythm and can deliver an electrical shock to restore a normal heartbeat.

No one can deny the benefits of these advances; however, it is inevitable that the ethical and safe application of these technological advances will be, or is already, one of the issues with which scientists, health professionals, and the general population are faced.

The first and main concern is that not all of the direct application of the technology is done by the inventors, researchers, or physicians. Therefore, the moral and danger issues can multiply greatly as the delicate task of applying the technology is passed to patients, nurses, technicians, and others. Due to neglect, lack of adequate knowledge, or mirroring the feelings of others, our propensity to err as human beings, is a cause of senseless worry in some unwarranted situations and of informed caution in standard circumstances.

Apart from our occasional natural tendencies to make mistakes, even the most well-intentioned approaches can include chances of misuse or of using this technology in an unethical. At the forefront of such questionable use, albeit unjustified more often than not, are the infamous weapons that are used for to incapacitate and subdue humans by electrically disrupting the functioning of superficial muscles. Stun guns, stun batons, electroshock belts, and tasers all send electrical shocks to a target, carrying enough charge to sometimes cause painful sensations. In one recent case a Florida man died after being shocked with a taser gun by a police officer; 2 side effects such as myocardial infarction have been recorded after taser exposure. 3,4 These instances and many others5 have been grounds for several law suits and pervasive worry. While extreme cases do not warrant complete paranoia about the use of electrical stimulus in general, some questions at the forefront remain to be answered. One very important electrical therapy, the use of this technology directly in or on the brain, has always been an issue for researchers, doctors, and patients. Because it is now possible to implant self-contained brain stimulation devices, there is a great concern about their efficacy and side effects. Although they are not expected to be curative, some studies have found that as many as 33% of implanted patients did not benefit from stimulation and had the electrodes removed.6 Even in cases in which it has been shown to be effective and to improve lives, brain-implant devices require the resolution of key safety issues and present a few totally new ethical challenges.7 For the outsider observer, the magnitude and diversity of these issues can be daunting. A systematic approach to identifying problems and a careful approach to solving them is urgent and imperative. Without attempting to work all of them out at once, especially the extreme cases, we can begin to address the notori-ous issues.


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This article discusses the most important issues related to electrical stimulation therapies with the aim of nurturing a healthy debate. Because the general safety issues remain the same whether one is stimulating the cortex, the peripheral nerves, or the heart, and because most of the research and success in this field is concentrated in this area, we draw our major points from the existing deep-brain stimulation (DBS) knowledge base.

DBS is very central to the prominent issues at hand because there have been numer-ous rumors regarding its psychiatric and behavioral side effects. Long-term efficacy and impact on life of these procedures is an area that remains open for discussion. Although there are increasing numbers of DBS procedures, there are not many controlled clinical trials that deal with the critical issues.8 Before we give a detailed enumeration of the landmark concerns, we first describe why and how DBS is performed.

I.A. Why do deep Brain Stimulation?

Several studies have proven the efficacy of stimulating the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) for the treatment of advanced Parkinson’s disease (PD).8,9 DBS is considered a surgical treatment alternative for patients with intractable tremor or for patients who are affected by long-term compli-cations of levodopa therapy such as motor fluctuations and severe dyskinesia.10 DBS is said to be more effective than medication in reducing the amplitude and increasing the frequency of resting and postural tremors to healthy physiological levels.11 Pallidal DBS is the best therapeutic option for patients with disabling primary generalized dys-tonia (PGD) that is refractory to medications and for which there are no intraoperative complications.12

Lately, DBS has been used for the treatment of various psychiatric disorders, such as obsessive compulsive disorder, Tourette syndrome, and severe depression.13

I.B. Mechanisms of Action of deep Brain Stimulation

Most of these deep-brain diseases cause dysrhythmic neural activities, and DBS is usu-ally administered as high-frequency stimulation (HFS) to affect local and distant spon-taneous neuronal activity. HFS as an extracellular stimulation is expected to activate subsets of both afferent and efferent axons, leading to antidromic spikes that collide with ongoing spontaneous spikes and orthodromic spikes that evoke synaptic responses in target neurons.6As has been shown in the globus pallidus internus (GPi), DBS causes a local and reversible inhibition of neuron firing rate with a simultaneous excitation of distant afferents and/or efferents. The combined effect is strong GPi inhibition without precluding increased outflow from the GPi. In a study using 100-Hz stimulations of the GPi to treat Lesch-Nyhan syndrome (LNS), 10% of the recorded neurons were unaf-fected, approximately 36% were inhibited, and 52% were excited. These effects lasted as long as the DBS, and inhibited neurons were situated lower than excited ones on the trajectory (1.25 and 4.65 mm above the center of GPi, respectively).14



HFS interferes with spontaneous pathological patterns by introducing regular activ-ity in several nodal points of the neural network.15 With the complex nature of local and distant network connections and their coordinated normal or affected functioning, HFS adds another layer of complication to the already compound neuronal activity. Only few studies, however, have focused on the non-motor effects of DBS.15 These perilous byproducts account for most of our safety and ethical concerns, and we categorize and discuss them in the following section.

I.C. Adverse Effects of Electrical Brain Stimulation that Influence Ethical and Safety Choices

1. Surgical Consequences

As mentioned above, interrupting biological processes and interfering abruptly with their current balance by means of a surgical intervention into their complex motor and cognitive and limbic functions can potentially cause severe problems. Because cogni-tive or emotional impairment may have an even stronger impact on quality of life than impairment of motor symptoms, surgery must be done very safely to exclude adverse effects in these domains.16 As the implantations are done deep in the brain and in very close proximity to areas that are vital for basic biological functions, extreme caution is needed so errors in localization of targets, introduction of infectious agents, and use of safe stimulation parameters are avoided.

2. Depression and Mania

Most of the literature dealing with the side effects of DBS is dedicated to depression and mania manifested in otherwise normal or susceptible patients. A research paper that analyzed several articles reported that antidepressant, depressant, and mania-induced ef-fects occurred in 16.7–76%, 2–33.3%, and 4.2–8.1% of patients treated with STN DBS, respectively. In general, this study found that most investigations indicate that subthal-mic nucleus (STN) DBS has an antidepressant effect in Parkinson’s disease (PD).17

3. Suicide

There are some reports of suicidal tendencies following DBS for PD18. By any standard, this side effect will cause the ultimate failure of the whole adventure of trying to treat the disease with this methodology. It will open the door for debates in legal circles about the possibility of homicidal actions on people who have been implanted with DBS stimula-tion systems. It is the responsibility of researchers and practitioners to consider of all of the worst scenarios and to work on correcting those they can.


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4. Apathy

Some studies have recorded significant worsening of apathy after STN-DBS in comparison with preoperative evaluation, probably caused by contribution of the surgical procedure. These same studies have alluded to the possibility of direct influence of STN-DBS on the limbic system by diffusion of stimulus to the medial limbic compartment of STN.9 Consid-ering what the limbic system does, one cannot help but wonder what other side effects are likely, and whether these patients should be evaluated for them. Soon researchers may ask about other behavioral and performance tests, including long-term memory and olfaction.

Another consideration is the fact that, in addition to the limbic system, other brain areas could also be indirectly affected by nearby stimulus.

5. Lesions

Brain tissue is very sensitive to damage by electrical stimulation, and this damage is manifested as a lesion. It is very common to induce lesions during monopolar HFS.19

6. HeartProblems

DBS is done under awake conditions, and some have postulated that this wakefulness can cause patients stress to the extent of having a heart vasospasm followed actual myocardial damage.20

7. Skin

Some DBS patients have been diagnosed with a hardware-related complications mani-fested as skin erosion.21 This eventually calls for a dermatological intervention to man-age the condition.

8. Cognition, Hypersexuality, and Other Problems

Indirect lessons learned from some studies not particularly involving DBS have led to the question of whether brain stimulation can interfere with cognition. The disruption of biological functions may cause transient blackouts in sustaining a thought. For instance, there is a real concern and ongoing research on the side effects of transcranial magnetic stimulation (TMS); it has been hypothesized to influence task performance in behavioral TMS studies.22

These investigations have tested the issue by assessing the discomfort caused by electrical stimulation during a verbal working memory task, mainly to investigate whether TMS side effects may bias task performance in cognitive neuroscience studies and may thereby lead to misinterpretation of the results. If such a side effect is found with TMS, the next natural direction is the same study with DBS which opens the door



to many important ethical questions. As such, it will not be long before we are faced with the moral choice between correcting motor deficits and lowered cognitive performance. We will have to determine whether DBS contributes to chronic forgetfulness normally associated with the ailments the procedure tries to alleviate in the first place.

Few other side effects are reported in the literature, although some in cases rare occurrences are reported in a single patient and only for a short time. For example, STN DBS has been documented to cause an unmanageable sexual urge despite a very conser-vative background and presurgery behavior, and this very strong behavior continued for up to 5 years if not restricted by drugs.23Others have reported rare stimulation-related adverse events, such as affected speech.12

II. AddrESSIng SoME CorrECtABlE SAfEty And EthICAl BrAIn StIMu-lAtIon ISSuES

II.A. Patient Screening for Mood and heart history

In the face of the aforementioned safety and ethical issues, it is imperative to start with a thorough patient screening prior to brain stimulation surgery. The patient’s health his-tory, including predisposing conditions for DBS side effects such as mood extremes and heart problems must be consdered. Despite its negative connotations and possible op-position from the patient or his or her family, a full psychiatric evaluation is imperative.

Once DBS is used, full patient monitoring should be mandatory and an anesthe-tist should be present throughout the procedures. In cases in which cardiac disease or vasospasm is reported in the patient’s history, the use of 5-lead ECG monitoring and premedication with beta-blockers and nitrates should be used.20

II.B. Safe Electrical Stimulation Parameters

1. Amplitude

In DBS, assuming that “bigger is better” or that a high energy of stimulation is more effective is not necessarily accurate. Clinical outcome does not depend on high energies of stimulation; low energies do not adversely affect clinical outcome but are associated with longer battery life in the case of implants.12 Therefore, many technical specifica-tions of the DBS stimulation should be individually tailored. Some parameters, such as those discussed in the following sections, are associated with clearly established guide-lines.In a study that investigated the excitability changes induced in cerebral cortical neurons during prolonged microstimulation with a spatially dense microelectrode array, all 16 microelectrodes were pulsed for 7 h at 50 Hz and at 4 nC/ph, the electrical thresh-old of approximately 50% of the single pyramidal tract axons in the medullary pyramid was elevated, and recovery of excitability required 2–18 days.24 Stimulation at higher amplitude (15 nC/ph) induced a much better reduction in excitability. The study implied that multiple processes mediate the stimulation-induced depression of neuronal excit-


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ability and that by maximizing the inherent spatial resolution of the array, depression can be minimized. In summary, it is possible to cause a long-lasting therapeutic effect using the appropriate stimulation parameters.

2. Pulse Type

As previously mentioned, monophasic electrical stimulation is prone to creating tissue damage manifested as a lesion, the extent of which increases linearly with the intensity and duration of stimulation. It is possible, but not always practical, to safely use mono-phasic pulses during short stimulation and at low intensities. Therefore, charge-balanced biphasic pulses are often preferred. HFS is safe when biphasic pulses are used for inten-sities as high as 2 mA and durations as long as 120 minutes.19

3. Frequency

Care must be taken with respect to stimulation frequency because some frequencies have deleterious effects. Thalamus stimulation at 10 Hz has been shown to increase tremor ac-tivity in the subthalamic nucleus in a patient with PD. This result indicates that pathologi-cal cerebral and cerebral-muscular communication in PD is mainly driven at 10 Hz. It is now accepted that a 10-Hz network is a pathophysiological key mechanism in the genera-tion of motor deficits in PD.25 This frequency and frequencies which are integer multiples of it, should be investigated so that the harmful mechanism is not activated in practice.

II.C. Safe Selection and Change of Stimulation target

Care should be taken in pinpointing the precise location for stimulation, and if possible targets should be tested and switched. Strict verification of stimulated regions in further investigations is needed to address this issue.17Target selection and change is needed to counteract adaptation and reduced efficacy. In at least one patient with a manic episode with psychotic features in which secondary STN DBS treatment of Parkinson’s disease was performed, increased efficacy was accrued by switching the stimulation target.26 Others have concluded that the best site of implantation of the HFS electrode may be in a region where the HFS-driven activity spreads to most of the identified, dysrhythmic, neuronal populations without causing additional side effects.15

High-frequency microstimulation in the central nervous system (CNS), when done for a long time in a specific area, can cause depression, which is defined as a persistent refractory state in the neurons and axons near the stimulating microelectrode that oc-curs in the absence of histologically detectable tissue injury. Because there is no lasting change in synaptic efficacy, the result is long-term depression (LTD). Although it is reversible after several days, LTD does not become more severe from day to day when the stimulation protocol is repeated on successive days. The design and use of these microstimulation systems should develop ways of minimizing this phenomenon.25



II.d. Magnetic resonance Imaging (MrI)

Although there have been no adequate clinical series regarding the safety profile of magnetic resonance imaging (MRI) in DBS patients,27 several risks of performing MRI in patients with neurostimulators that have been reported include those associated with heating, magnetic field interactions, induced currents, and the functional disruption of these devices. Failure to strictly follow safety recommendations can cause serious, tem-porary, or permanent injury to the patient, including the possibility of transient dystonia, paralysis, coma, or even death, and two recent accidents have been attributed to these oversights. It is thus obvious that with regard to the MRI pulse generator, leads, elec-trodes, operational conditions for the device, the positioning of these components, and the MR, the system-specific safety recommendations for neurostimulation must be care-fully followed.28

II.E. Electromagnetic Interference (EMI)

Although there is little research available in the literature regarding electromagnetic in-terference (EMI) on DBS, some authors have suggested that we should not exclude EMI as a potential health concern. In instances where stimulation is turned on or off by theft detectors and security screening devices, the switching act may create perceptions in some patients of momentary increase in the implant stimulation. Temporary malfunction may occur, interrupting the therapeutic benefit for persons who have the device.29

Active research to investigate the possible effects of devices such as global position-ing system (GPS) and global system for mobile (GSM) is ongoing, although no direct risks have been established.30 More research should be conducted in this area, and healthcare professionals should routinely educate their patients being treated with DBS regarding such possibilities.

III. SortIng out thE Myth And thE truth

Due to the lack of information and slow or nonexistent communication of what is al-ready known, some opinions persist in DBS, as in many areas of patient care. For exam-ple, while some31 insist that there is a high rate of suicide in patients treated with DBS, particularly with thalamic and GPi stimulation, others disagree.32 The former even sug-gested that, because of the high suicide rate, patients should be prescreened for suicide risk prior to DBS surgery. Additionally, they suggested that patients should be moni-tored closely for suicidal behavior postoperatively. These opposite views about such a critical matter should be immediately sorted out.

Another cautionary note is that hardware-related adverse events are infrequent,12 and not all first signs of side effects are long-lasting. For example, it is possible for mood changes to show subsequent adaptation with time, probably as a result of both the dis-appearance of the microtraumatic effect of the implantation procedure and the plastic changes induced by HFS.33


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IV. ConCluSIonS

A large knowledge gap exists between what is being done and what should be known. A review of 140 published articles investigated the mood and the behavior changes fol-lowing neurosurgery for movement disorders and reported that shortfalls remain in the published interpretation of results, of comparisons of limbic effects of DBS due to meth-odological limitations, small sample sizes, lack of control groups, as well as in the het-erogeneity in the data reported.34 The review called for collection and reporting of more standardized minimal data sets that will allow for future comparisons, and improve the power required to answer many of the questions raised in its review. We find this rec-ommendation to be important and apropos to the future of electrical stimulus therapies.

The success rate of DBS or other electrical stimulation applications used to solve real-life problems are not as advanced as we all would like them, and they all require improved communication of results and more research. As immediate goals, we should find ways to separate the truth from myths and develop ways of stimulating the brain without causing cognitive deficits and considerable psychological side effects.

Then we can begin to address the remaining questions. Some have asked: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during post-operative care?9 Some have said that brain stimulation could alter a person’s brain func-tion and hence his or her personal identity.12 This is one of the major ethical issues. If a personality can be changed by brain stimulation, the future of many clever approaches to improve our lives will be under scrutiny. With the rapidly growing interest in direct microstimulation of the human cortex to replace lost function or to correct breakdowns in normal brain activity (e.g., controlling seizures)35 or for sending sensory feedback to the brain (e.g., neuroprostheses), these concerns may become even more magnified. We recommend increased future support for such research so that DBS can be used safely and ethically and more effectively for our patients.

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Major Safety and Ethical Concerns in Brain Stimulation

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