Frederic Gilbert

Target Populations for First-In-Human Embryonic Stem Cell Research in Spinal Cord Injury

Geron recently announced that it had begun enrolling patients in the worlds first-in-human clinical trial involving cells derived from human embryonic stem cells (hESCs). This trial raises important questions regarding the future of hESC-based therapies, especially in spinal cord injury (SCI) patients. We address some safety and efficacy concerns with this research, as well as the ethics of fair subject selection. We consider other populations that might be better for this research: chronic complete SCI patients for a safety trial, subacute incomplete SCI patients for an efficacy trial, and perhaps primary progressive multiple sclerosis (MS) patients for a combined safety and efficacy trial.

The burden of normality: from ‘chronically ill’ to ‘symptom free’. New ethical challenges for deep brain stimulation postoperative treatment

Although an invasive medical intervention, Deep Brain Stimulation (DBS) has been regarded as an efficient and safe treatment of Parkinsons disease for the last 20 years. In terms of clinical ethics, it is worth asking whether the use of DBS may have unanticipated negative effects similar to those associated with other types of psychosurgery. Clinical studies of epileptic patients who have undergone an anterior temporal lobectomy have identified a range of side effects and complications in a number of domains: psychological, behavioural, affective and social. In many cases, patients express difficulty adjusting from being chronically ill to their new status as ‘treated’ or ‘seizure free’. This postoperative response adjustment has been described in the literature on epilepsy as the ‘Burden of Normality’ (BoN) syndrome. Most of the discussion about DBS postoperative changes to self is focused on abnormal side effects caused by the intervention (ie, hypersexuality, hypomania, etc). By contrast, relatively little attention is paid to the idea that successfully ‘treated’ individuals might experience difficulties in adjusting to becoming ‘normal’. The purpose of this paper is (1) to articulate the postoperative DBS psychosocial adjustment process in terms of the BoN syndrome, (2) to address whether the BoN syndrome illustrates that DBS treatment poses a threat to the patients identity, and (3) to examine whether the current framework for rehabilitation after DBS procedures should be updated and take into account the BoN syndrome as a postoperative self-change response.

Deep Brain Stimulation in the Media: Over-Optimistic Portrayals Call for a New Strategy Involving Journalists and Scientists in Ethical Debates

Deep brain stimulation (DBS) is optimistically portrayed in contemporary media. This already happened with psychosurgery during the first half of the twentieth century. The tendency of popular media to hype the benefits of DBS therapies, without equally highlighting risks, fosters public expectations also due to the lack of ethical analysis in the scientific literature. Media are not expected (and often not prepared) to raise the ethical issues which remain unaddressed by the scientific community. To obtain a more objective portrayal of DBS in the media, a deeper collaboration between the science community and journalists, and particularly specialized ones, must be promoted. Access to databases and articles, directly or through science media centers, has also been proven effective in increasing the quality of reporting. This article has three main objectives. Firstly, to explore the past media coverage of leukotomy, and to examine its widespread acceptance and the neglect of ethical issues in its depiction. Secondly, to describe how current enthusiastic coverage of DBS causes excessive optimism and neglect of ethical issues in patients. Thirdly, to discuss communication models and strategies to enhance media and science responsibility.

Deep Brain Stimulation and Postoperative Suicidality Among Treatment Resistant Depression Patients: Should Eligibility Protocols Exclude Patients with a History of Suicide Attempts and Anger/Impulsivity?

Recently, there has been a surge of interest in using deep brain stimulation (DBS) to treat patients suffering from treatment-resistant depression (TRD). While DBS has been regarded as an efficient and safe treatment for many conditions over the last 20 years, and although DBS research trials involving TRD patients show encouraging evidence of remission, recent DBS TRD follow-up studies have reported significant rates of postoperative suicidal ideation, as well as suicide attempts and deaths. Given the vulnerable nature of TRD patients with respect to suicide, if the postoperative DBS adjustment process contributes to an increased risk of suicidality among them, then there is a pressing need to investigate this problem. Based on current clinical trial follow-up data, does the suicidality risk-versus-remission benefit ratio favor the use of DBS in TRD patients? The purpose of this article is to examine whether adjusting enrollment criteria, such as excluding TRD patients with a history of suicide attempts or anger/impulsivity, could diminish DBS trial research suicidality, given the absence of uniformity in DBS trial eligibility protocols.

Controlling brain cells with light: ethical considerations for optogenetic clinical trials

Optogenetics is being optimistically presented in contemporary media for its unprecedented capacity to control cell behavior through the application of light to genetically modified target cells. As such, optogenetics holds obvious potential for application in a new generation of invasive medical devices by which to potentially provide treatment for neurological and psychiatric conditions such as Parkinsons disease, addiction, schizophrenia, autism and depression. Design of a first-in-human optogenetics experimental trial has already begun for the treatment of blindness. Optogenetics trials involve a combination of highly invasive genetic and electronic interventions that results in irreversible and permanent modifications of an individuals nervous system. Given its novelty, its uncertain benefit to patients, and its unique risk profile of irreversible physiological alteration, optogenetics requires a reassessment of the ethical challenges for protecting human participants in clinical trials, particularly at formative stages of clinical evaluation. This study explores the evolving ethical issues surrounding optogenetics’ potential harm to participants within trial design, especially focusing on whether Phase 1 trials should incorporate efficacy as well as safety endpoints in ways that are fair and respectful to research trial participants.

The Impact of American Tackle Football-Related Concussion in Youth Athletes

Postmortem research on the brains of American tackle football players has revealed the presence of chronic traumatic encephalopathy (CTE), a degenerative brain disease caused by repeated head trauma. Repeated concussion is a risk factor for CTE, raising ethical concerns about the long-term effects of concussion on athletes at risk for football-related concussion. Of equal concern is that youth athletes are at increased risk for lasting neurocognitive and developmental deficits that can result in behavioral disturbances and diminished academic performance. In this article, we consider evidence of the effects of concussion in youth athletes, and discuss ethical duties to youth athletes and how these duties might be satisfied, given the intrinsic risks of football. Finally, we evaluate potential strategies for reducing concussions in junior football, and recommend the optimal strategy for reducing brain injury to an acceptable level while still making available the benefits of football participation for youth athletes.

Ethical considerations for deep brain stimulation trials in patients with early-onset Alzheimer’s disease

Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimers disease, with several recruiting participants <65 and thus have early-onset Alzheimers disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

Prognostic Implication of Preoperative Behavior Changes in Patients with Primary High-Grade Meningiomas

High-grade meningiomas are rare extra-axial tumors, frequently causing brain invasion and prominent brain edema. Patients harboring high-grade meningiomas occasionally present with behavior changes. Data about frequency and prognostic importance of preoperative behavior changes in patients with high-grade meningiomas is missing. 86 patients with primary high-grade meningiomas were analyzed. Statistical analysis was performed to determine correlation of preoperative behavior changes with tumor location, preoperative brain edema, tumor cleavability, tumor grade, Ki67 proliferation index, and microscopic brain invasion. Survival analysis was performed. 30 (34.9%) patients presented with preoperative behavior changes. These changes were more frequent with male patients (P = 0.066) and patients older than 55 years (P = 0.018). They correlated with frontal location (P = 0.013), tumor size (P = 0.023), microscopic brain invasion (P = 0.015), and brain edema (P = 0.006). Preoperative behavior changes did not correlate with duration of symptoms, tumor cleavability, tumor malignancy grade, and Ki67 proliferation index. They were not significantly related to overall survival or recurrence-free survival of patients with primary high-grade meningiomas. Preoperative behavior changes are frequent in patients harboring primary high-grade meningiomas. They correlate with tumor size, microscopic brain invasion, and brain edema. Preoperative behavior changes do not predict prognosis in patients with primary high-grade meningiomas.

The need to tackle concussion in Australian football codes

Postmortem evidence of chronic traumatic encephalopathy (CTE) in the brains of American National Football League players who suffered concussions while playing have intensified concerns about the risks of concussion in sport.1 Concussions are frequently sustained by amateur and professional players of Australia’s three most popular football codes (Australian football, rugby league, and rugby union) and, to a lesser extent, other contact sports such as soccer. This raises major concerns about possible long-term neurological damage,2-4 cognitive impairment and mental health problems5 in players of these sports.

Rethinking responsibility in offenders with acquired paedophilia: punishment or treatment?

This article reviews the current neurobiological literature on the aetiology of developmental and acquired paedophilia and examines what the consequences could be in terms of responsibility and treatment for the latter. Addressing the question of responsibility and punishment of offenders with acquired paedophilia from a neurobiological perspective is controversial. Consequently it is essential to avoid hasty conclusions based strictly on neurobiological abnormality justifications. This study establishes a distinction between developmental and acquired paedophilia. The article investigates whether offenders who fulfil the diagnosis of acquired paedophilia should be held fully responsible, particularly in cases where the offenders conduct appears to result from volitionally controlled behaviour that is seemingly incompatible with a neurological cause. Moreover, the article explores how responsibility can be compromised when offenders with acquired paedophilia have (partially) preserved moral knowledge despite their sexual disorder. The article then examines the option of offering mandatory treatment as an alternative to imprisonment for offenders with acquired paedophilia. Furthermore, the article addresses the ethical issues related to offering any form of quasi-coercive treatment as a condition of release. This study concludes that decisions to fully or partially excuse an individual who fulfil the diagnosis of acquired paedophilia should take all relevant information into account, both neurobiological and other environmental evidence, and should proceed on a careful case by case analysis before sentencing or offering treatment.