Deep brain stimulation for psychiatric diseases: an ethical approach

2013/2014

Lília Carlos Meireles Monteiro

Deep Brain Stimulation for psychiatric diseases:

an ethical approach

Mestrado Integrado em Medicina

Área: Psiquiatria e Saúde Mental

Trabalho efetuado sob a Orientação de:

Dra. Adelaide Costa

Trabalho organizado de acordo com as normas da revista:

Neuroethics

Lília Carlos Meireles Monteiro

Deep Brain Stimulation for psychiatric diseases:

an ethical approach

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Deep Brain Stimulation for Psychiatric diseases: an ethical approach

Authors:

Lília Monteiro

Medical School of the University of Oporto

Alameda Prof. Hernâni Monteiro, 4200 - 319 Porto, Portugal Correspondence to:

Email: lcmm545@gmail.com Telephone: +351 914709107

Address: Rua Camilo Castelo Branco nº34, hab 2.2, 4425-037 Águas Santas, Maia, Portugal

Adelaide Costa

Department of Clinical Neurosciences and Mental Health at the Medical School of the University of Oporto

Institute of Bioethics of the Portuguese Catholic University

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Deep Brain Stimulation for Psychiatric diseases: an ethical approach

Abstract

Mental diseases are responsible for a huge amount of morbidity and mortality among society. Despite the wide availability of psychotropic drugs and psychotherapy, there is a considerable amount of psychiatric patients that remain non-responsive to non-invasive therapies. It is in this context that Deep Brain Stimulation (DBS) emerges, a technology already used in neurologic disorders such us Parkinson Disease (PD) and neuropathic pain. This intervention is now in investigation for many psychiatric diseases, for example obsessive-compulsive disorder (OCD) and major depression, and has demonstrated its success in the treatment of severe ill patients, as well as for cognitive enhancement of healthy individuals. The hasty spread out of DBS medical indications, its applications in severely debilitated patients, its effects in patient’s personality and in the intimate relation between man and technology raise many ethical questions that claim for discussion. Indeed, these questions have rarely been addressed so far.

We explored DBS introduction in psychiatric practice, pointed its approved and investigational indications, its advantages and risks, and collected and discussed the ethical questions that surround its application in psychiatric field.

After thoroughly literature analysis, we gather the most presented ethical topics: risk-benefit ratio, autonomous decision, informed consent, responsibility, conflicts of interest, use to enhancement purposes and distributive justice.

Some authors offered guidelines to rule DBS investigation and clinical practice. These instructions are here presented, along with our own point of view. However, the ethical discussion is far from being finished. Further investigation on DBS risks and scope will contribute to this debate.

Keywords: deep brain stimulation, neuroethics, psychiatry, major depression, obsessive–compulsive disorder,

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Introduction: The neuroethics role

Neuroethics is a branch of ethics that emerged at the same time as the huge development of neuroscience over the last decades. During this time of enormous scientific and technologic expansion, it is required to consider carefully this expansion’s range and limits. Neuroscience is probably the fastest growing area of medicine and biotechnology, raising important ethical questions. Indeed, these questions are more significant than any other questions in any other area of bioethics [1]. It is in this context that neuroethics come to light, due to the imperious need of mediation between what we can do and what we should do.

The actual ability that neuroscience has to infer about subjective mental states, until now only accessible to the subject by observing cerebral physiology and physiopathology, will bring deep changes in society. The capacity to use technology to 'read minds', treat 'antisocial brains' and enhance cognitive skills of healthy subjects will challenge our concepts of free will and responsibility. Uncovering the molecules, receptors and signalization pathways that convert neuronal complex processes in human thought and behavior will make us believe that all human deeds can be precisely measurable and understood as linear consequences of brain physiology. This belief would ultimately guide us to deduce that mind is equal to brain. Beyond that, if every cognitive function could be translated in physiologic measurable processes, can we keep seeing human beings as specials? [2,3] Nevertheless, some believe that human thought will never be totally deciphered and that actions will never be precisely predicted, giving the complexity and plasticity of central nervous system [4].

Brain-computer interfaces

Unwitting, we attribute to the brain a unique statute, one that is different to any other organ statutes. It is due to this different valorization that we show more reluctance when intervening in the brain, either pharmacologically, or surgically. It is because we attribute to the brain the origin of our identity, the storage of our memories and the source of our behavior that we look at a brain stimulator with more apprehension than at a cardiac pace-maker device. Even among public awareness, being treated with an antidepressive drug raises more discussion than being treated with a proton bump inhibitor.

The first form of brain-machine interface was the cochlear implant 3 . Since then, many others have come and some were raised in psychiatric field for treatment purposes: the well-known electroconvulsivotherapy, transcranial magnetic stimulation, vagus nerve stimulation and deep brain stimulation. Cyborg, derived from cybernetic organism, is the concept that we use to designate the combination of human and technology. In fact, it is an easy way to delay the categorization of such combination in either human or machine. These familiar terms belong to our symbolic order, the cultural determined categories we use in everyday life in order to be understood in the world. Cyborgs challenge symbolic order by blurring the distinction between man and machine. But why is that distinction important? The answer is simple: it is important because we treat people differently from machines. People, and not machines, have moral requirements and can be held responsible for their actions. Thus, will brain-machine interfaces affect the moral status of people using them? 3

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The contention around psychosurgery can be demonstrated by the opposite views of J.R. Delgado (1915-2011) a Spanish professor of Physiology at Yale University that created the stimoceiver and Peter Breggin (born in 1936), an American psychiatrist. Delgado defends that one should use technology to escape from the random process of natural evolution towards a “future man with greater personal freedom and originality, a member of a psychocivilized society, happier, less destructive, and better balanced than present man”. Conversely, Breggin stated that psychosurgery would be used to control human spirit, threatening human freedom: “…If America ever falls to totalitarianism, the dictator will be a behavioral scientist and the secret police will be armed with lobotomy and psychosurgery. And by the way, lobotomy is still with us…Lobotomy and psychosurgery is an ethical, political and spiritual crime. It should be made illegal”. However, it is important to keep in mind that Bergin is not only against psychosurgery but also against electroconvulsivotherapy and any form of pharmacological intervention to treat mental diseases. Nevertheless, both opinions are extremists and contribute to complicate brain surgery debates more than to solve them. The philosopher Kenneth Schaffner names them as a “sweeping reductionism” 5 .

Between all new means to interfere directly in mental processing, DBS is the most widely used and effective technique 6,7 . DBS involves direct intervention in the brain. Electrodes are surgical implanted in precise brain regions and are connected to a battery-driven stimulator implanted in the chest near the collarbone, that can be switched on and off by pressuring in the skin above. This technique is adjustable and reversible: it is possible to alter the setting of the electrodes and the stimulator frequency. It is also possible to remove the device 6 .

DBS origins go back to the introduction of stereotactic surgery in 1947. Since then DBS was firstly used intraoperatively, for target selection prior to injuring, then as chronically implanted electrodes prior to deferred ablative surgery, and only subsequently as a therapy itself. Unlike serial statements reporting DBS set-out as a therapy for movement disorders, in the beginning DBS was, in fact, applied in the psychiatric and behavioral field, then for pain, then for epilepsy and only last for disorders as Parkinson Disease and Essential Tremor 8 .

The first psychiatric indication of DBS was treatment-refractory obsessive-compulsive disorder, approved by FDA (Food and Drug Administration) in 2009. It is considered a Class III device: high-risk device that poses a significant risk of illness and injury. CE (Conformité Européene) has recently also approved DBS for the same indication 9 .

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Deep brain stimulation: current and investigational applications

DBS is medical indicated for Parkinson Disease, chronic pain, essential tremor, Tourette syndrome, depression and obsessive–compulsive disorder, when these conditions are severe and have proven to be resistant to every other less invasive treatments. Brain targets differ depending on the diseases: for PD the electrodes target globus pallidus interna and subthalamic nucleus, for depression subtalamic nucleus and for OCD subcallosal cingulate gyrus and subgenual cingulate gyrus. Adverse effects include impulsive decision-making, hypomania, mania, intracerebral haemorrhage and infection in the electrodes area 6 . Other studies also report dysarthria, worsening of apathy, depression, cognitive impairments, walking disturbances, symptom recurrence in case of battery depletion, and severe disappointment with renewed desperation in case of non-responsiveness to DBS. This non-responsiveness predisposes patients to suicidal reactions 10 . These adverse effects can occur in up to 10% of individuals 9 .

DBS is also being studied in Alzheimer dementia, cluster headache, minimally conscious state, violent behavior, obesity and for enhancement purposes. In the enhancement field, it has been reported that stimulating the ventral striatum can induce emotions with positive valence and hypothalamic stimulation enhances associative memory (in cognitively intact persons). It can also ease anhedonia. Patients can selectively choose stimulations parameters depending on how they want to feel, eg. calm or ”revved up” 10 .

Ablative surgery and deep brain stimulation: What are differences?

DBS involves more risks than non-invasive forms of brain stimulation 6 , but giving the field of current application – severe diseases that are unresponsive to any other treatment - it’s necessary to compare it to the procedure that is usually applied in these situations: ablative surgery.

When comparing DBS and ablative surgery we observe that both have the same medical indications: severe diseases, which are refractory to other treatments. The decision-making process, with interdisciplinary teams and information on the patient to obtain informed consent, are similar too. So, in which aspects do they differ? First, the method to select target areas: ablative surgery selection is based on previous animal lesion experiments and patients studies; in DBS, target areas are based on extensive prior functional neuroimaging data. Another difference: ablative surgery causes irreversible lesions and the adjustment of the procedure according to his effects and side effects is impossible. DBS causes a reversible damage (you can remove the hardware) and can be remotely adjusted to maximize effects and reduce side-effects 10 .

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The ethics of application DBS in the treatment of psychiatry diseases

DBS for both neurological and psychiatric diseases is surrounded by many ethical issues. The most debated issues in present literature are: risk-benefit ratio, autonomous decision, informed consent, responsibility, conflicts of interest, use to enhancement and distributive justice 11,12].

1. Risk-benefit ratio

Concerning the risk-benefit ratio, we have previously pointed major DBS’s associated risks. The major question, when approaching DBS application risks, is whether or not DBS interferes and changes patient personality. To elucidate this question, we have to find a reasonable and useful concept of personality. Personality can be defined as a dynamic set of characteristics in a person that uniquely influences his cognitions, motivations and behavior. This concept bears not only cognitive and mood representations, but also sensorimotor and vegetative ones. Adopting this definition, we have to agree that DBS changes the patient’s personality, but psychopharmacological and psychotherapeutic treatments change it too. Moreover, if DBS did not change patient’s personality and if the mood and cognitive behavior did not change in obsessive compulsive disorder or major depression, the treatment would not be effective 10 .

As an interdisciplinary European group point out:

“Practically no intervention in the structure or functioning of the human brain can be undertaken in complete certainty that it will not affect mental processes, some of which may come to play a key role in a person’s self-concept” 6 .

Matthis Synofzik argues that the main question is not whether DBS changes personality or not, but whether it does so in a good or bad way from the patient’s own perspective 10 . Although the patient’s perspective usually praises DBS effects, some clinical trials reported that patients can have an unfamiliar sensation after DBS implantation, “I don’t feel like myself anymore”, “I haven’t found myself again after the operation” 13 .

2. Autonomy

We may now discuss autonomy. Many philosophers agree in these 3 general conditions of free will: 1) alternative possibilities to choice and action, 2) responsiveness to reasons for appropriate actions, and 3) being the genuine source of one’s actions. We can argue if DBS satisfy or not this third condition. It would probably depend on how patient sees the device itself. Since the stimulator regulates his thought and behavior outside of his conscious awareness, he could perceive it as a foreign body, as a threat to his experience of being in control. Yet, the psychiatry condition that led him to the DBS procedure probably prevented him of concretizing his own predispositions and wills, severely altering his mood, volition and usual behavior. Thus, he can see the device as an enabling tool that enhances his existing, though diminished capacities, and ensures him that he is the genuine source of his actions. This interpretation conceives DBS as an intermediary device between brain and mind that

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strengthens rather than impedes agency. It is therefore consistent with distinct philosophical conceptions of free will. 14

3. Informed consent

Regarding the informed consent issue, it may help exposing three conditions to fulfill it: 1) the patient has access to information on his disease, prognosis, potential risks and benefits of the therapy and alternatives; 2) the patient has the ability to understand the information; and 3) the patient is not being coerced or compelled. Since we are discussing psychiatric patients that suffer from major and debilitating diseases, one may argue whether the patient fulfills criterion 3. Some may say that the states of depression and the desperation for relief may undermine decisional capacity 15 . Nevertheless, many studies tried to assess this capacity, although they failed to find substantial impairment in people with psychiatric disorders to autonomous consent 16 .

4. Industry forces

Industry forces were the main impetus for DBS research in psychiatric diseases. This has been poorly addressed in the literature and brought important ethical implications. 9 There are multiple sources of conflict of interest such as sources of funding, intellectual property and reimbursement. DBS devices are essential to scientific inquiry, but giving their heavy costs, they are only available through industrial sources 16 . Cordelia Erickson-Davis pointed out many ethical concerns regarding commercialization of DBS for OCD. In this section we will summarize her conclusions 9 .

Medtronic is the world’s largest manufacture of DBS technology and is the owner of FDA approval of DBS for OCD. It gained this approval thanks to a study of 26 patients that undergone DBS targeting on the ventral anterior limb of the internal capsule and adjacent ventral striatum. They enrolled in studies conducted by investigators or at institutions that received support from Medtronic. In this study, 58% showed clinically significant improvement and 42.3% reported adverse effects. A study of 4 patients undergoing DBS for OCD concluded that DBS was not sufficiently well developed to replace current OCD therapies. This study was not included in Medtronic’s report. Cordelia Erickson-Davis quests why 9 . However, it may have been excluded due to its small sample.

When a study is sponsored by the industry, it may shift to accommodate a ‘market based approach to inquiry'. This means that trials will look for extended drug applications or device applications that can possibly reimburse the initial investment made by industry, meaning they are economically fruitful. This industrial approach, however, has resulted in the violation of ethical norms of research such us initial validity and transparency 9 .

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5. Responsibility

Neurophrothesis, such as DBS, raise some questions concerning patients’ responsibility for their actions. As previously seen, an individual undergoing DBS treatment can develop changes in his personality and decisional capacity, changes that can led him to commit actions that he would not perform before the stimulator implantation. Who should be morally and legally responsible for these actions? Should it be the patient himself, the stimulator manufacturer or the neurosurgeon who implanted and adjusted the device? 3 Later in this paper, we will try to point a solution to this problem.

6. Cognitive enhancement

Cognitive enhancement enfolds every method, internal or external, physical or psychological, that improve our intellectual and emotional capacities. Many of these methods are largely accepted and don´t raise ethical discussion over them: coffee, wine, theater visits, school education, sun baths, etc. However, DBS differs from these methods in many ways: risks, costs, accessibility and in the mean by which it interferes with mental states, improving them independently of individual effort or dedication, in a precise and fine regulated way.

Many argue that DBS should only be applied for diseases’ treatment or for improvement of non-pathologic features that are under the average level. However, it is not easy to distinguish between healthy and diseased without applying countless statistic variables and without making, even if in an implicit manner, normative assumptions. If we can´t separate normal from pathologic it is impossible to accurately discriminate between treatment and potentiation. Moreover, the notion of disease depends greatly on the individual’s expectations, the society that he is inserted, in his preferences and socio-economic support. Therefore it can´t be determined with sufficient clarity and general agreement, in order for it to become normative 10 .

DBS for enhancement purposes can raise artificial social inequalities, created not by merit, but by the access to technology. There is also worry that the access to intellectual progress without effort removes the value from the concretizations achieved and forecloses personal growth. Even so, some ethicists advocate that the claim to free will and autonomy supersede the previous arguments, so that, if the technology is available, anybody should be restrained from using it for potentiation 17 .

7. Allocation of funding

The allocation of funding for expensive therapies is one of the greatest issues in public health care systems. Health care providers will never have enough resources to satisfy all society demands. For that reason, the allocation of resources has to balance between not only the burden of diseases, but also the existence and costs of alternative treatments. DBS devices and procedures cost tens of thousands of dollars. The cost for the treatment of Parkinson disease was increased by 32% in the first year of DBS therapy, having then decreased by 54% in the second year when compared to preoperative expenses. However, in DBS for psychiatric diseases, this comparison is not done yet 11 .

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Ethical application: guidelines

Despite all the controversy, some practitioners and investigators came up with some guide points that should be followed in DBS application. It has been argued that there is no need for specific ethical criteria in DBS situation, the same criteria that are applied in any other biomedical intervention: beneficence, non-maleficence, and autonomy should be used. In this case, Synofzik argues that the actual lack of clear evidence proving DBS efficacy, allied with the severe short and long-term risks, poses DBS as an illegitimate tool for current application. Nevertheless, they argue that DBS is not intrinsically unethical, and might be ethically legitimate in the future 10 .

In autumn 2007, a consensus conference with participants from different centers in the US and Europe, bioethics, patient advocates, research policymakers, psychiatrists, neurologists and other experts brought some valuable points of view. They stated that DBS for disorders of mood, behavior and thought is at an early proof-principle stage and must be considered investigational. As there are no validated targets for DBS, it is premature to design large-scale trials, and optimal targets and electrode settings should be determined in small early-phase studies. It is necessary to further investigate the comparative efficacy and safety of DBS versus other treatments, such as ablative surgery. DBS trials have to be performed only at expert centers that work with the highest scientific, clinical and ethical standards, and that include multidisciplinary teams, with neurosurgeons, neurologists, psychiatrists, neuropsychologists and case managers. Outcomes should not only measure disease-specific symptoms, but also daily living activities, cognition, quality of life and global improvement, including family and patient perception. Concerning informed consent, assessment of capacity should be carried out for each subject. There should be no financial burdens to patients withdrawing from a study 18 .

Another group added some ethical guidance for the management of conflicts of interest in DBS research. They warned that investigators should always disclose and justify their conflicts of interest. Academics conducting research should not be employees of the companies sponsoring their work. Payments, royalties, fees and stock options should be determined prospectively according to the established institutional policy. Patients should be aware of the putative conflicts of interest in all informed consent discussions. Investigators should avoid the ‘therapeutic misconception’, not labeling a device as a ‘therapy’ while it remains investigational. Investigators should report all trial results, and they should never be precluded from publishing negative results because of a potential adverse market impact upon a corporate sponsor. Everyone enrolled in the investigational process should use their influence on industry to ensure that the exclusivity granted by patents does not make products so expensive that its access is compromised 19 .

Some authors suggested a solution to the responsibility problem pointed out above. When someone under DBS stimulation performs an action with adverse outcomes, which is believed to be incongruous with patient behavior prior to the introduction of the device, we should use the concept of “diachronic responsibility”. Diachronic responsibility implies that one can take responsibility for one’s future behavior by taking certain action is his past. Thereby, when consenting with DBS application in his brain, knowing its possible side effects, a subject assumes the responsibility for the actions he will perform, when the DBS device is implanted 3 .

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The Portuguese situation

The Hospital of São João, in Oporto, performs DBS for motor diseases since October 2002 20 . A few years ago, this hospital performed a DBS surgery in a 15-year-old-patient that suffered from severe Tourette syndrome. This patient suffered from comorbid compulsive and obsessive symptoms, anxiety and depression. The stimulation target was bilateral anteromedial internal pallid (AM-GPi). During the 2 years follow-up after the procedure, the patient’s motor tics have improved, and his psychiatry comorbidities have also ameliorated 21 . In 2009 there were 5 medical centers practicing DBS technology that implanted 73 DBS devices in the same year 20 .

However, it was only in 2010 that the first DBS implantation for psychiatric indication took place, in a patient suffering from obsessive-compulsive disorder, in Coimbra University Hospital. In 2013, the Hospital of São João performed its first procedure for the same indication. In Portugal, the procedure is already approved for OCD. Nevertheless, each case should be evaluated by Psychiatry National Committee before the surgery. After being referenced by their own physician, another 3 psychiatrics would study the case and decide if the indication for surgery is appropriated or not. personal communication Rui Vaz, MD PhD .

The criteria for application in OCD are the following: 1) OCD diagnosis according to CID-10 or DSM-IV; 2) a disease duration of over 5 years; 3) severe clinical condition with significant suffering for patient; 4) disabling disease with major repercussions in patient global functioning; 5) Yale-Brown Obsessive Compulsive Scale (Y-BOCS) ≥ 28 (american group) or ≥ 30 (european group) and Global Assessment of Function (GAF) scale ≤ 45; 6) Pharmacotherapy and Behavioral therapy refractoriness; 7) Understanding capacity and informed consent 20 .

Exclusion criteria are: 1) age 18 or 65 years; 2) Neurological or medical significant disease (except tics disorder and Gilles de La Tourette); 3) cerebral MRI anomalies; 4) Specific contraindication to DBS performance 5) Current or previous psychotic disorder; 6) Drug addiction or unstable abstinence state; 7) Severe Personality Disorder; 8) Suicidal risk; 9) In fertile woman, if pregnant or with absence of effective contraception 20 .

For the application of DBS in Major Depression Disorder, inclusion criteria are: 1) Hamilton Depression Rating Scale (HDRS- 24 items); 2) Major depression with at least 5 years duration; 3) Pharmacotherapy failure with at least three drugs of different categories (more than 5 weeks with each one); 4) Potentiation or combination pharmacologic therapy with one antidepressant with at least two different agents of the following (e.g. anti-psychotic, mood stabilizer, buspiron, tiroxin); 5) at least one adequate treatment with electroconvulsive therapy (at least 6 bilateral treatments); 6) at least one therapeutic attempt with psychotherapy 20 .

Exclusion criteria are: 1) medical or neurologic significant disorders (except Tourette syndrome); 2) significant psychiatric comorbidities that can interfere with post-operative care adherence; 3) Non affective psychosis; 4) Drug abuse; 5) Suicidal risk 20

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There are few cases of DBS in psychiatric patients up to today in the entire country but other hospitals are attempting to start the procedure and this number will probably increase in the near future. personal communication Rui Vaz, MD PhD .

Discussion

A pertinent question may be crossing the reader’s mind: Why are we discussing the legitimacy of appliance of DBS instead of attaching it with every other current medical treatments? Discussion is needed because it is a new device, invasive and highly risky, applied to a vulnerable population, and, moreover, it has the potential to be used far beyond his current indications. An example is its usage as a treatment of ‘antisocial brains’: imagine a future where criminals receive, in addiction or instead of his sentences, the possibility to be ‘cured’ from his tendency to antisocial behavior. Or, imagine once again, it could be applied to manipulate mental states, administrated from a dictatorial government to his people, promoting obedience and social cohesion. It could also be used for enhancing mental capacities of healthy individuals, that can, in some cases, make good intentions easier to fulfills, but in orders, ameliorate deception and spoliation. It is because we fear this and other applications of DBS in the future, that we are currently debating the limits of its use.

As we have seen, in some cases, DBS is a less risky alternative to ablative surgery. In these cases, it is quite easy to point out DBS as the best option, since it is adjustable and reversible. However, it is in patient’s groups that had not indication to open surgery that DBS poses his major ethical issue.

DBS can be inserted and switched off. However, if DBS perchance changes patients’ decisional capacity, how can he decide to alter or stop the stimulation? Perhaps some will argue that, given his change of decisional competency, the physician should turn off the device time to time, so that patient can return to his previous intellectual state and decide in favor or against the continuity of stimulation.

Regarding distributive justice the first question posed is simple: Do we really need better treatment options for our medication refractory and severe diseased patients? Sure we do. The tough question is how much benefit has a new treatment to achieve, so it can have the costs of its application justified; that is, so the allocation of a certain amount of resources, over the appliance of these resources in another health care ground, with another cost-effective equation can be justified in the end.

DBS designing costs millions of dollars, but now, there is an existing and rooted technology exploring its possible field of action, trying to expand it to more and more indications, to yield the investment made. Aren’t we shaping to the needs of technological development, instead of being technologically trying to meet our needs?

Now I would like to approach the personality debate. We have seen that DBS can change patient's personality, an effect that can be regarded as a part of the treatment for some, or as an unwelcome outcome for other’s perspective. If an individual suffers deep personality changes due to DBS stimulation in a way that the one that presents himself with compulsive behavior and depressive beliefs relieved is no longer the one that experienced obsessive or depressive thoughts, who has, in fact, profited with the treatment? In pure

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philosophical and metaphysical conception, the severe diseased patient doesn't exist anymore, and the one that has no psychiatric symptoms didn’t exist before. In the limit of this situation, by implanting DBS electrodes are we creating a person free of psychiatric complains but that has no continuity with his anterior mental being? His family can acclaim his improvements, physicians will register his progress in clinical validated parameters, but would the individual himself surely get better? 6

A different concern, when talking about DBS technology is its use for enhancement purposes. Even if we accepted the idea of improving human intellectual capacities through technology devices and without any effort, we are forced to admit that, in a scenario of limited access (given the procedure’s costs and the limited facilities where to perform it), not all would have opportunity to potentiate themselves, creating more social inequalities.

However, even if we imagine a scenario in which everybody could access to DBS, it will still raise social and ethical controversy. Intellectual capacities that we have today depend more or less from this 3 connected aspects: 1) natural evolution, that selected some characteristics in detriment of others and that are encoded in our genes, 2) environment, seen here as cultural and socioeconomic variables, and 3) person investment (school education, training). In a future where we choose each of our capacities we would only choose features that we already knew and that we had previously valuated as favorable in the light of certain context and beliefs. This would lead to an apparently more capable society but would foreclose the emergence of new attributes, because we could only program attributes that we already knew. Francis M. Kamm called it as "our lack of imagination as designers" 22 . However, even admitting that potentially some brain areas will difficult the development of the others, it is not clear that by this means, innovation will be absolutely precluded.

Furthermore, if cognitive enhancement was possible it would possibly become morally obligatory. Physicians, pilots, historians, architects and many other professionals have the duty to perform their work the best they can. If it is proven that DBS turns physicians more capable of making accurate diagnosis and that made them treat more patients with better outcomes, doesn’t it make DBS intervention a morally obligation?

In addition, if DBS for enhancement purposes were liberalized, some would still not want to use it for several reasons (desire for natural capacities, disagreement with effortless achievements, religion believes, fear of surgery). Even when making an autonomous and informed decision, these people who reject DBS devices would be hampered due to the increased gap of abilities that separate them from the ones who use DBS, in the competition to achieve common goods.

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Conclusion

DBS is a treatment tool ethically legitimate when posed as an alternative to ablative surgery, in patients that did not respond to any noninvasive treatments. However, since equipment, surgery and long-term monitoring costs are superior to ablative surgery costs, it still places concerns about distributive justice. Only a clearly better profit to a patient with DBS, when compared with ablative surgery, would justify the application of financial resources in this technology rather than in other health care areas.

In the other cases, when patient has no indication for ablative surgery, it is harder to advocate DBS procedure without constrains. We agree that DBS should still be applied only as a last resort in patients in whom every other option failed. Giving comprehensive information about benefits and risks to the patient or his proxy can ameliorate ethical conflict.

On the issue of responsibility for future actions, we accept the adoption of the concept of "diachronic responsibility". Nevertheless, we must bear in mind that even if we thoroughly inform the patient about the possibility of personality, mood and behavior modifications that can lead to illicit or detrimental actions, the patient can never predict all conduct possibilities with which he decides to tolerate or refuse. Giving that, we have to look at “diachronic responsibility” in a careful and sensible way. Imagine a hypothetic case, in which a person submitted to DBS commits a murder due to the impulsivity or due to mood changes carried out by stimulation. For having accepted, after thoroughly informed consent, to be treated with DBS, he would be legally responsible for the homicide, and he will be charged with, for example, 20 year in prison. Even if "diachronic responsibility" is simple to accept in theoretical terms, in practice it is not that clear. In this case, admitting that the murder was totally derived from the stimulation, we are condemning a man to 20 years in prison, not because he committed the murder, but because he has consented with DBS implantation.

Thus, to solve this debate, we suggest that patient’s personality should be thoroughly evaluated before the surgical procedure, taking into account pre-morbid personality, friends and family descriptions, and the application of validated personality tests. Then, in the months that follow the surgery, and every time that the patient or his cohabitants report significant behavioral changes, personality should be evaluated again with the same parameters. In the presence of significant personality modifications, the device should be turned off, even if the patient has accepted “diachronic responsibility”. It is easy to foresee that, after having his device turned off and the return of his symptoms, a patient may ask for the device to be turned on again, despite the adverse effects. This case is harder to solve. Being a free citizen in a society requires, among other things, being the responsible moral author of his acts. Admitting that such a big and profound personality change can make one to lose the ownership of his acts, and knowing that diachronic responsibility can’t be enforced in all range of situations, in the case described above, if patient desires to turn on the electrodes again, this should be attended. However, his freedom needs to be limited, for example, by interning the patient in a psychiatric institution. This is not an ideal solution, since it diminishes the patient’s liberty. One can argue that freedom is a fundamental and inalienable right, however, in our view, the right to one’s freedom shouldn’t be thought of in such a radical and absolute way. It should be thought of as a highly important value, that can, in uttermost cases, be exchanged, according to patients will, for another equally highly important values, such as health and happiness, values that can be jeopardized in severely mentally ill patient.

12

Concerning the use of DBS for cognitive enhancement purposes, we believe that it shouldn’t be regarded differently from other forms of cognitive enhancement. It is true that DBS is more invasive, more expensive and that actually, it has more risks, and it is also true that it is still in an early phase of study and development, but these limitations will probably be surpassed in the coming years. Ultimately, it won’t be these downsides that rule out DBS as an ethically illicit technique.

However, before DBS is largely implemented, it would be prudent to reanalyse the processes underlying DBS approval for OCD and eventually extend the clinical trials. Further investigation of DBS risks and clinical scope is needed, as it is also important to research and disclose its mechanism of action.

13

References

1 – Glannon, W. 2006. Neuroethics. Bioethics, 20(1), 37-52.

2 – Kalichman, M., Plemmons, D., & Bird, S. J. 2012. Editors' overview: Neuroethics: many voices and many stories. Sci

Eng Ethics, 18(3), 423-432. doi: 10.1007/s11948-012-9398-z

3 – Schermer, M. (2009). The Mind and the Machine. On the Conceptual and Moral Implications of Brain-Machine Interaction. Nanoethics, 3(3), 217-230. doi: 10.1007/s11569-009-0076-9

4 - Greely, H. T. 2012. What if? The farther shores of neuroethics: commentary on "Neuroscience may supersede ethics and law". Sci Eng Ethics, 18(3), 439-446. doi: 10.1007/s11948-012-9391-6

5 - Fins, J. J. 2004. Neuromodulation, free will and determinism: lessons from the psychosurgery debate. Clinical

Neuroscience Research, 4(1–2), 113-118

6 – Glannon, W. 2009. Stimulating brains, altering minds. J Med Ethics, 35(5), 289-292. doi: 10.1136/jme.2008.027789 7 - Clausen, J. 2010. Ethical brain stimulation - neuroethics of deep brain stimulation in research and clinical practice. Eur J

Neurosci, 32(7), 1152-1162. doi: 10.1111/j.1460-9568.2010.07421.x

8 - Hariz, M. I., Blomstedt, P., & Zrinzo, L. 2010. Deep brain stimulation between 1947 and 1987: the untold story.

Neurosurg Focus, 29(2), E1. doi: 10.3171/2010.4.focus10106

9 - Erickson-Davis, C. 2012. Ethical concerns regarding commercialization of deep brain stimulation for obsessive compulsive disorder. Bioethics, 26(8), 440-446. doi: 10.1111/j.1467-8519.2011.01886.x

10 - Synofzik, M., & Schlaepfer, T. E. 2008. Stimulating personality: ethical criteria for deep brain stimulation in psychiatric patients and for enhancement purposes. Biotechnol J, 3(12), 1511-1520. doi: 10.1002/biot.200800187

11 – Bell, E., Mathieu, G., & Racine, E. 2009. Preparing the ethical future of deep brain stimulation. Surg Neurol, 72(6), 577-586; discussion 586. doi: 10.1016/j.surneu.2009.03.029

12 - Clausen, J. 2011. Conceptual and ethical issues with brain-hardware interfaces. Curr Opin Psychiatry, 24(6), 495-501. doi: 10.1097/YCO.0b013e32834bb8ca

13 - Baylis, F. 2013. "I Am Who I Am": On the Perceived Threats to Personal Identity from Deep Brain Stimulation.

Neuroethics, 6, 513-526. doi: 10.1007/s12152-011-9137-1

14 - Lipsman, N., & Glannon, W. 2013. Brain, mind and machine: what are the implications of deep brain stimulation for perceptions of personal identity, agency and free will? Bioethics, 27(9), 465-470. doi: 10.1111/j.1467-8519.2012.01978.x 15 - Glannon, W. 2010. Consent to deep brain stimulation for neurological and psychiatric disorders. J Clin Ethics, 21(2), 104-111.

16 - Fisher, C. E., Dunn, L. B., Christopher, P. P., Holtzheimer, P. E., Leykin, Y., Mayberg, H. S., Appelbaum, P. S. 2012. The ethics of research on deep brain stimulation for depression: decisional capacity and therapeutic misconception. Ann N Y

Acad Sci, 1265, 69-79. doi: 10.1111/j.1749-6632.2012.06596.x

17 - Mendelsohn, D., Lipsman, N., & Bernstein, M. 2010. Neurosurgeons' perspectives on psychosurgery and neuroenhancement: a qualitative study at one center. J Neurosurg, 113(6), 1212-1218. doi: 10.3171/2010.5.jns091896 18 - Rabins, P., Appleby, B. S., Brandt, J., DeLong, M. R., Dunn, L. B., Gabriels, L., Mathews, D. J. 2009. Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought. Arch Gen Psychiatry, 66(9), 931-937. doi: 10.1001/archgenpsychiatry.2009.113

19 - Fins, J. J., Schlaepfer, T. E., Nuttin, B., Kubu, C. S., Galert, T., Sturm, V., Mayberg, H. S. 2011. Ethical guidance for the management of conflicts of interest for researchers, engineers and clinicians engaged in the development of therapeutic deep brain stimulation. J Neural Eng, 8(3), 033001. doi: 10.1088/1741-2560/8/3/033001

20 – Rui Vaz et al. 2011. Estimulação Cerebral Profunda: do tratamento da doença de Parkinson a uma nova visão do

funcionamento do cérebro. Bial

21 - Massano, J., Sousa, C., Foltynie, T., Zrinzo, L., Hariz, M., & Vaz, R. 2013. Successful pallidal deep brain stimulation in 15-year-old with Tourette syndrome: 2-year follow-up. J Neurol, 260(9), 2417-2419. doi: 10.1007/s00415-013-7049-1 22 - Kamm, F. M. 2005. Is there a problem with enhancement? Am J Bioeth, 5(3), 5-14. doi: 10.1080/15265160590945101

Agradecimentos

Aos pais, pelo apoio incansável há mais de duas décadas. Ao Sandro, pelas inúmeras conversas sobre estes temas.

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