Psychiatric Deep Brain Stimulation Research Articles

Closing the loop in psychiatric deep brain stimulation: physiology, psychometrics, and plasticity.

Deep brain stimulation (DBS) is an invasive approach to precise modulation of psychiatrically relevant circuits. Although it has impressive results in open-label psychiatric trials, DBS has also struggled to scale to and pass through multi-center randomized trials. This contrasts with Parkinson disease, where DBS is an established therapy treating thousands of patients annually. The core difference between these clinical applications is the difficulty of proving target engagement, and of leveraging the wide range of possible settings (parameters) that can be programmed in a given patient's DBS. In Parkinson's, patients' symptoms change rapidly and visibly when the stimulator is tuned to the correct parameters. In psychiatry, those same changes take days to weeks, limiting a clinician's ability to explore parameter space and identify patient-specific optimal settings. I review new approaches to psychiatric target engagement, with an emphasis on major depressive disorder (MDD). Specifically, I argue that better engagement may come by focusing on the root causes of psychiatric illness: dysfunction in specific, measurable cognitive functions and in the connectivity and synchrony of distributed brain circuits. I overview recent progress in both those domains, and how it may relate to other technologies discussed in companion articles in this issue.

The Role of Family Members in Psychiatric Deep Brain Stimulation Trials: More Than Psychosocial Support

Family members can provide crucial support to individuals participating in clinical trials. In research on the “newest frontier” of Deep Brain Stimulation (DBS)—the use of DBS for psychiatric conditions—family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and their family members as interview participants. Using dyadic thematic analysis—an approach that takes both the individuals and the relationship as units of analyses—this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions.

Patient feedback and psychosocial outcomes of deep brain stimulation in people with obsessive–compulsive disorder

Severe and refractory psychiatric patients can experience complex and profound changes in symptomology, functioning and well-being from deep brain stimulation (DBS) therapy. Currently, the efficacy of DBS is assessed by clinician rated scales of primary symptoms, yet this does not capture the multitude of DBS mediated changes or represent the patient perspective. We aimed to elucidate the patient perspective in psychiatric DBS application by investigating 1) symptomatic, and 2) psychosocial changes, 3) therapeutic expectations and satisfaction, 4) decision-making capacity, and 5) clinical care recommendations from treatment refractory obsessive–compulsive disorder (OCD) DBS patients. Participants enrolled in an open label clinical trial of DBS therapy for OCD who had reached clinical response were invited to participate in a follow up survey. Participants completed a 1) feedback survey relating to goals, expectations, and satisfaction of therapy, and 2) self-report questionnaires on psychosocial functioning including quality of life, cognitive insight, locus of control, rumination, cognitive flexibility, impulsivity, affect, and well-being. Greatest change was reported for quality of life, rumination, affect and cognitive flexibility. Participants reported realistic expectations, high satisfaction, adequate pre-operative education and decision-making capacity; and advocated for greater access to DBS care and more widespread support services. This is the first identified investigation on psychiatric patient perspectives of functioning and therapeutic outcomes following DBS. Insights from the study have implications for informing psychoeducation, clinical practices, and neuroethical debates. We encourage a greater patient-centred and biopsychosocial approach in evaluating and managing OCD DBS patients, by considering personally meaningful goals and addressing symptomatic and psychosocial recovery.

Recharge PSYCH: A Study on Rechargeable Implantable Pulse Generators in Deep Brain Stimulation for Psychiatric Disorders

Rechargeable implantable pulse generators (r-IPGs) for deep brain stimulation (DBS) promise longer battery life and fewer replacement surgeries versus non-rechargeable systems. Long-term data on the effects of recharging in patients who received DBS for psychiatric indications is limited. The Recharge PSYCH trial is the first study that included DBS patients with psychiatric disorders treated with different r-IPG models. Standardized questionnaires were sent to all psychiatric DBS patients with an r-IPG implanted at the time of the study. The primary endpoint was convenience of recharging. Secondary endpoints were rate of user confidence and rate of usage-related complications, as well as charge burden (defined as minutes per week needed to recharge). Data sets of n= 21 patients were eligible for data analysis. At the time of the survey patients were implanted with the r-IPG for a mean 31.8±22.4months. Prior to being implanted with an r-IPG, patients had undergone a median of 3 IPG replacements. The overall convenience of the charging process was rated as "easy" with a median of 8.0 out of 10.0 points. 33.3% of patients experienced situations in which the device could not be successfully recharged. In 38.1% of patients, therapy with the r-IPG was interrupted unintentionally. The average charge burden was 286±22.4minutes per week. Patients with psychiatric disorders rated the recharging process as "easy", but with a significantly higher charge burden and usage-related complication rates compared to published data on movement disorder DBS patients.

A human rights approach to low data reporting in clinical trials of psychiatric deep brain stimulation.

The reporting of clinical trial data is necessary not only for doctors to determine treatment efficacy, but also to explore new questions without unnecessarily repeating trials, and to protect patients and the public from dangers when data are withheld. This issue is particularly salient in those trials involving invasive neurosurgical interventions, such as deep brain stimulation (DBS), for 'treatment refractory' psychiatric disorders. Using the federal database ClinicalTrials.gov, it was discovered that out of the completed or unknown-status trials related to psychiatric DBS up to November 2018, only two had submitted results to ClinicalTrials.gov. These results suggest that, despite federal requirements to report clinical trial data, reporting on psychiatric DBS trials is problematically minimal. It is argued that a human rights approach to this problem establishes a legal and ethical foundation for the need to report clinical trial results in this area.

Deep brain stimulation of the internal capsule enhances human cognitive control and prefrontal cortex function

Deep brain stimulation (DBS) is a circuit-oriented treatment for mental disorders. Unfortunately, even well-conducted psychiatric DBS clinical trials have yielded inconsistent symptom relief, in part because DBS’ mechanism(s) of action are unclear. One clue to those mechanisms may lie in the efficacy of ventral internal capsule/ventral striatum (VCVS) DBS in both major depression (MDD) and obsessive-compulsive disorder (OCD). MDD and OCD both involve deficits in cognitive control. Cognitive control depends on prefrontal cortex (PFC) regions that project into the VCVS. Here, we show that VCVS DBS’ effect is explained in part by enhancement of PFC-driven cognitive control. DBS improves human subjects’ performance on a cognitive control task and increases theta (5–8Hz) oscillations in both medial and lateral PFC. The theta increase predicts subjects’ clinical outcomes. Our results suggest a possible mechanistic approach to DBS therapy, based on tuning stimulation to optimize these neurophysiologic phenomena.

How Deep Brain Stimulation of the Nucleus Accumbens Affects the Cingulate Gyrus and Vice Versa.

The nucleus accumbens (NA) and the cingulate gyrus (CG) are two vital limbic brain structures. They have attracted attention as deep brain stimulation (DBS) targets in the treatment of common refractory psychiatric illness. The primary purpose of this article was to review the current knowledge regarding the way that NA DBS affects the CG and vice versa. Methodologically, a thorough literature review was performed. According to the current literature, NA DBS modulates the function of several brain areas including the CG cortex. It specifically causes activation in the ipsilateral CG cortex and voltage-dependent reduction of its blood oxygenation. It also reverses anterior mid-CG cortex dysfunction and decreases metabolism in the subgenual CG. Moreover, NA DBS that induces mirth inhibits the function of the anterior CG cortex and enhances effective connectivity from anterior CG to the ventral striatum. On the other hand, although it is highly probable that CG DBS affects the NA, the exact nature of its effects remains unclear. Despite the increasing interest in psychiatric DBS, the available data on how NA DBS affects the CG and vice versa are restricted. This conclusion probably reflects the high complexity of the limbic circuits and necessitates further research.

Expression of the ectodomain of the rabies virus glycoprotein G in insect cells for diagnostic purposes in vaccinated llamas

This narrative review summarizes the recent literature on deep brain stimulation for treatment resistant obsessive-compulsive disorder highlighting both progress and challenges of this novel treatment. Common targets of psychiatric deep brain stimulation involve both white matter trajectories (anterior limb of the internal capsule, inferior thalamic peduncle, and medial forebrain bundle) and grey matter subcortical nuclei (nucleus accumbens, nucleus subthalamicus, and bed nucleus of the stria terminalis) each of which have been reported with a relevant beneficial effect on obsessive-compulsive symptoms. The mechanisms of action are only partially understood but increasing evidence points towards network effects involving the prefrontal cortex, the striatum and possibly anxiety-related anatomical structures. Deep brain stimulation is a promising therapeutical technique for otherwise treatment refractory patients, but many major issues are unresolved and thorough investigations are needed. Relevant topics for future investigations include treatment predictors and therapeutical augmentation. An international registry of patients treated with deep brain stimulation could improve our understanding of adverse events and target specific effects. In order to step forward, researchers must face inconvenient questions and outperform the status quo of clinical research in this field.

Rechargeable Stimulators in Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Prospective Interventional Cohort Study

From 1999 onwards, deep brain stimulation (DBS) has been proposed as an alternative to capsulotomy in refractory cases of obsessive-compulsive disorder (OCD). Although rechargeable implantable pulse generators (rIPGs) have been used extensively in DBS for movement disorders, there are no reports on rIPGs in patients with a psychiatric DBS indication, and even possible objections to their use. We aim to evaluate rIPGs in OCD in terms of effectiveness, applicability, safety, and need for IPG replacement. In this prospective before-after study recruiting from 2007 until 2012, OCD patients requiring at least one IPG replacement per 18 months were proposed to have a rIPG implanted at the next IPG depletion. OCD severity was the primary outcome. Ten patients were analyzed. Psychiatric symptoms and global functioning remained stable in the two years after as compared to the two years before rIPG implantation. Over the same period, the prescribed OCD medication doses did not increase and the DBS stimulation parameters were largely unaltered. Until the end of the follow-up (mean 4¾ years; maximum seven years), the DBS-related surgery frequency decreased and there were no rIPG replacements. During the first few weeks after implantation, two patients obsessively checked the rIPG, but afterwards there were no signs of compulsively checking or recharging the rIPG. Two patients experienced rIPG overdischarges (five occurrences in total). This is the first report on rIPGs in DBS for OCD patients. The use of rIPGs in this population appears to be effective, applicable, and safe and diminishes the need for IPG replacements.

Progress and challenges in deep brain stimulation for obsessive-compulsive disorder.

This narrative review summarizes the recent literature on deep brain stimulation for treatment resistant obsessive-compulsive disorder highlighting both progress and challenges of this novel treatment. Common targets of psychiatric deep brain stimulation involve both white matter trajectories (anterior limb of the internal capsule, inferior thalamic peduncle, and medial forebrain bundle) and grey matter subcortical nuclei (nucleus accumbens, nucleus subthalamicus, and bed nucleus of the stria terminalis) each of which have been reported with a relevant beneficial effect on obsessive-compulsive symptoms. The mechanisms of action are only partially understood but increasing evidence points towards network effects involving the prefrontal cortex, the striatum and possibly anxiety-related anatomical structures. Deep brain stimulation is a promising therapeutical technique for otherwise treatment refractory patients, but many major issues are unresolved and thorough investigations are needed. Relevant topics for future investigations include treatment predictors and therapeutical augmentation. An international registry of patients treated with deep brain stimulation could improve our understanding of adverse events and target specific effects. In order to step forward, researchers must face inconvenient questions and outperform the status quo of clinical research in this field.

Should DBS for Psychiatric Disorders be Considered a Form of Psychosurgery? Ethical and Legal Considerations.

Deep brain stimulation (DBS), a surgical procedure involving the implantation of electrodes in the brain, has rekindled the medical community's interest in psychosurgery. Whereas many researchers argue DBS is substantially different from psychosurgery, we argue psychiatric DBS-though a much more precise and refined treatment than its predecessors-is nevertheless a form of psychosurgery, which raises both old and new ethical and legal concerns that have not been given proper attention. Learning from the ethical and regulatory failures of older forms of psychosurgery can help shed light on how to address the regulatory gaps that exist currently in DBS research. To show why it is important to address the current regulatory gaps within psychiatric DBS, we draw on the motivations underlying the regulation of earlier forms of psychosurgery in the US. We begin by providing a brief history of psychosurgery and electrical brain stimulation in the US. Against this backdrop, we introduce psychiatric DBS, exploring current research and ongoing clinical trials. We then draw out the ethical and regulatory similarities between earlier forms of psychosurgery and psychiatric DBS. As we will show, the factors that motivated strict regulation of earlier psychosurgical procedures mirror concerns with psychiatric DBS today. We offer three recommendations for psychiatric DBS regulation, which echo earlier motivations for regulating psychosurgery, along with new considerations that reflect the novel technologies used in DBS.

Letter: Commentary: Deep Brain Stimulation as Clinical Innovation: An Ethical and Organizational Framework to Sustain Deliberations about Psychiatric Deep Brain Stimulation

Letter: Commentary: Deep Brain Stimulation as Clinical Innovation: An Ethical and Organizational Framework to Sustain Deliberations about Psychiatric Deep Brain Stimulation

In Reply: Commentary: Deep Brain Stimulation as Clinical Innovation: An Ethical and Organizational Framework to Sustain Deliberations About Psychiatric Deep Brain Stimulation.

In Reply: Commentary: Deep Brain Stimulation as Clinical Innovation: An Ethical and Organizational Framework to Sustain Deliberations About Psychiatric Deep Brain Stimulation.

Deep Brain Stimulation in Anorexia Nervosa: Hope for the Hopeless or Exploitation of the Vulnerable? The Oxford Neuroethics Gold Standard Framework.

Neurosurgical interventions for psychiatric disorders have a long and troubled history (1, 2) but have become much more refined in the last few decades due to the rapid development of neuroimaging and robotic technologies (2). These advances have enabled the design of less invasive techniques, which are more focused, such as deep brain stimulation (DBS) (3). DBS involves electrode insertion into specific neural targets implicated in pathological behavior, which are then repeatedly stimulated at adjustable frequencies. DBS has been used for Parkinson’s disease and movement disorders since the 1960s (4–6) and over the last decade has been applied to treatment-refractory psychiatric disorders, with some evidence of benefit in obsessive–compulsive disorder (OCD), major depressive disorder, and addictions (7). Recent consensus guidelines on best practice in psychiatric neurosurgery (8) stress, however, that DBS for psychiatric disorders remains at an experimental and exploratory stage. The ethics of DBS—in particular for psychiatric conditions—is debated (1, 8–10). Much of this discourse surrounds the philosophical implications of competence, authenticity, personality, or identity change following neurosurgical interventions, but there is a paucity of applied guidance on neuroethical best practice in psychiatric DBS, and health-care professionals have expressed that they require more (11). This paper aims to redress this balance by providing a practical, applied neuroethical gold standard framework to guide research ethics committees, researchers, and institutional sponsors. We will describe this as applied to our protocol for a particular research trial of DBS in severe and enduring anorexia nervosa (SE-AN) (https://clinicaltrials.gov/ct2/show/NCT01924598, unique identifier NCT01924598), but believe it may have wider application to DBS in other psychiatric disorders.

Deep Brain Stimulation as Clinical Innovation: An Ethical and Organizational Framework to Sustain Deliberations About Psychiatric Deep Brain Stimulation.

Deep brain stimulation (DBS) for psychiatric disorders needs to be investigated in proper research trials. However, there are rare circumstances in which DBS could be offered to psychiatric patients as a form of surgical innovation, therefore potentially blurring the lines between these research trials and health care. In this article, we discuss the conditions under which surgical innovation may be accepted as a practice falling at the frontiers of standard clinical care and research per se. However, recognizing this distinction does not settle all ethical issues. Our article offers ethical guideposts to allow clinicians, surgical teams, institutions, and institutional review boards to deliberate about some of the fundamental issues that should be considered before surgical innovation with psychiatric DBS is undertaken. We provide key guiding questions to sustain this deliberation. Then we review the normative and empirical literature that exists to guide reflection about the ethics of surgical innovation and psychiatric DBS with respect to general ethical questions pertinent to psychiatric DBS, multidisciplinary team perspectives in psychiatric DBS, mechanisms for oversight in psychiatric DBS, and capacity and consent in psychiatric DBS. The considerations presented here are to recognize the very specific nature of surgical innovation and to ensure that surgical innovation in the context of psychiatric DBS remains a limited, special category of activity that does not replace appropriate surgical research or become the standard of care based on limited evidence. DBS, deep brain stimulationIRB, institutional review boardOCD, obsessive-compulsive disorder.

Deep Brain Stimulation for Treatment-Refractory Mood and Obsessive-Compulsive Disorders

Deep brain stimulation (DBS) is an invasive therapy in which electrodes are surgically placed into the brain and deliver continuous electrical stimulation. It was originally developed for Parkinson’s disease and other movement disorders. As evidence emerged that certain mental disorders involved abnormal function of specific brain nuclei, multiple investigators launched trials of DBS for mental disorders, particularly major depression (MDD) and obsessive-compulsive disorder (OCD). While open-label results were promising, recent large well-designed clinical trials in MDD have failed. We review the result of major DBS studies to date in psychiatry and what they have taught us about DBS’ safety and efficacy. We further review a variety of animal and human neuroscience studies that have started to shed light on DBS’ mechanisms of action at multiple brain targets. From these, we identify major trends that are likely to drive psychiatric DBS development in the coming decade, including “closed-loop” responsive stimulation, biomarker-based patient selection, and a better modeling of phenotypic heterogeneity within mental disorders. We conclude that on balance, DBS remains promising as a psychiatric treatment, but recent evidence highlights a clear need for further development and a better understanding of mechanisms.

An Ethical Framework for Outcome Assessment in Psychiatric DBS

Deep brain stimulation (DBS) is an up-and-coming therapeutic approach in psychiatry. Although recent studies have demonstrated that DBS is relatively safe, little is known about its impact on a patient's life. A comprehensive outcome assessment is required so as to ensure valid scientific findings for the proper counseling of future patients; a thorough benefit–harm assessment plays an important role in planning of the therapeutic process. Starting from a basic anthropological and ethical premise, disorder-specific and intervention-related parameters concerning a wide range of data relating to the individual person would need to be amassed. These data can be collected by means of a combination of quantitative tests and qualitative interviews, including the perspective of the patient and of a closely related person. They can be presented using codes from the WHO International Classification of Functioning, Disability and Health (ICF). An international consensus group on outcome assessment and coding according to the ICF could be established in psychiatric DBS.

Responding Ethically to Patient and Public Expectations About Psychiatric DBS

In the last years, TV documentaries, articles in popular magazines, and Internet content have increased the public visibility of deep brain stimulation (DBS). The media may have also provoked significant clinical and public interest in potential future applications for treating psychiatric disorders beyond the current use of DBS in neurological disorders. In this article, we review and discuss the topic of patient and public understanding of DBS, focusing on both the clinical consequences of patient understanding as well as the broader social consequences of public understanding. The literature and the experience of clinicians suggest that strongly optimistic media reports of DBS have had detrimental consequences for informed consent and the management of patient expectations before and after surgery. Likewise, this context has created complex issues for trust between clinicians, patients, and their families and may have hard-to-predict social impacts including on the relationships between public understanding of neuroscience, biological therapies, stigma, and mental illness. We propose an approach to tackle the clinical and social consequences of media messages on public understanding within a broad and interdisciplinary effort with concrete actions. This approach includes actions by all key players, including not only providers but also patients and their family members, as well as journalists. To further address issues at the intersection of informed consent and patient expectation, there should be more discussion on and actual testing and measurement of these recommendations or similarly minded practice changes.

Axonal pathways linked to therapeutic and nontherapeutic outcomes during psychiatric deep brain stimulation

The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS. Our approach combined clinical data, diffusion tensor tractography, and computer models of patient-specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment-resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS). Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders. Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices.

The Ethical Differences Between Psychiatric and Neurologic DBS: Smaller Than We Think?

Dunn and colleagues argue that deep brain stimulation (DBS) for treatment-resistant depression (TRD) does not require any different or additional safeguards than other innovative, higher risk thera...