Thomas E. Schlaepfer

Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans.

Major depression (MD) might be conceptualized as pathological under-arousal of positive affective systems as parts of a network of brain regions assessing, reconciling and storing emotional stimuli versus an over-arousal of parts of the same network promoting separation-distress/GRIEF. In this context depression can be explained as an emotional pain state that is the result of a disregulation of several sub-systems that under physiological conditions are concerned with bodily or emotional homeostasis of the human organism in a social context. Physiologically, homeostasis is maintained by influences of the SEEKING system represented - amongst others - by the medial forebrain bundle (MFB). Neuroimaging studies show that the MFB has a proven access to the GRIEF/Sadness system. A functional decoupling of these systems with a dysfunctional GRIEF pathway might result in MD. Therewith GRIEF and SEEKING/PLEASURE systems play important roles as opponents in maintenance of emotional homeostasis. Chronic electrical modulation of the reward SEEKING pathways with deep brain stimulation might show anti-depressive effects in humans suffering from MD by re-initiating an emotional equilibrium (of higher or lower activity) between these opposing systems.

A neuromodulation experience registry for deep brain stimulation studies in psychiatric research: Rationale and recommendations for implementation

be noted. We encourage other researchers, even those outside medical research settings, to measure and document side effects whenever feasible. accumulate beneficial effects aggregate adverse events collect long-term data collect data on ineffective DBS/failed trials give back the benefit of aggregated information to the patient identify side effects that might serve as therapeutic effects detect modifications of prespecified primary outcome measures coordination of research trials and research groups reduce idiosyncrasy in research and in IRB decision-making provide orientation for IRB review compensate for the short-comings of early psychosurgery attract industry funders Aviad A. Hadar, Stergios Makris, Kielan Yarrow Department of Psychology, Social Science Building Northampton Square, City University London London EC1V 0HB, United Kingdom E-mail address: abby191@city.ac.uk (A. A. Hadar)

The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder

Deep brain stimulation (DBS) is a promising putative modality for the treatment of refractory psychiatric disorders such as major depression and obsessive-compulsive disorder (OCD). Several targets have been posited; however, a clear consensus on differential efficacy and possible modes of action remain unclear. DBS to the supero-lateral branch of the medial forebrain bundle (slMFB) has recently been introduced for major depression (MD). Due to our experience with slMFB stimulation for MD, and because OCD might be related to similar dysfunctions of the reward system, treatment with slMFB DBS seams meaningful. Here we describe our first 2 cases together with a hypothetical mode of action. We describe diffusion tensor imaging (DTI) fiber tractographically (FT)-assisted implantation of the bilateral DBS systems in 2 male patients. In a selected literature overview, we discuss the possible mode of action. Both patients were successfully implanted and stimulated. The follow-up time was 12 months. One patient showed a significant response (Yale-Brown Obsessive-Compulsive Scale [YBOCS] reduction by 35%); the other patient reached remission criteria 3 months after surgery (YBOCS<14) and showed mild OCD just above the remission criterion at 12 months follow-up. While the hypermetabolism theory for OCD involves the cortico-striato-thalamo-cortical (CSTC) network, we think that there is clinical evidence that the reward system plays a crucial role. Our findings suggest an important role of this network in mechanisms of disease development and recovery. In this uncontrolled case series, continuous bilateral DBS to the slMFB led to clinically significant improvements of ratings of OCD severity. Ongoing research focuses on the role of the reward system in OCD, and its yet-underestimated role in this underlying neurobiology of the disease.

Brain stimulation treatments for depression

We read with some confusion and concern the recent WFSBP Guidelines for Biological Treatment of Unipolar Depressive Disorders published by the respective WFSBP Task Force. While the “ Update 2013 ” is generally true to the title and an important clinical summary for the fi eld, the sections regarding brain stimulation methods are in fact quite outdated and thereby likely to mislead readers. Their review and recommendations are in fact contradicted by the current recommendations of the WFSBP Taskforce on Brain Stimulation (Schlaepfer et al. 2010). For example, when discussing how to treat treatment-resistant patients, there is no mention of using transcranial magnetic stimulation (TMS) (see their Figure 3), which clearly has class I level of effi cacy according to accepted review criteria. When discussing electroconvulsive therapy (ECT), there is no mention of the important recent advance with ultra brief unilateral stimulation, which is now the default method of ECT in many practices because of the decreased cognitive side effects with similar effi cacy (Sackeim et al. 2008). The section on TMS appears particularly out of date. The authors reference one meta-analysis (Martin 2003) only and refer to it as “ recent ” . There have now been 13 meta-analyses, and new published study data in this fi eld have fundamentally changed in the last decade. There have been large randomized controlled trials showing clear acute effi cacy of TMS over sham and follow-up studies showing both reasonable size and durability of the effect (O ’ Reardon et al. 2007; George et al. 2010; McDonald et al. 2011; Carpenter et al. 2012; Mantovani et al. 2012). All of these larger RCTs have taken place since the 2003 cited meta-analysis. There are now two manufacturers with FDA approval of their devices, based on pivotal multisite trial data. As of 2010, there were 89 different peer-reviewed published randomized controlled trials of TMS for depression. For ease of access they are listed in a downloadable spreadsheet maintained on the servers of the journal Brain Stimulation (Polley et al. 2011). We urge the authors to actually update this section of the guidelines, or acknowledge and refer readers to the WFSBP Brain Stimulation taskforce guidelines in this area, where experts with these new technologies have reached different conclusions (Schlaepfer et al. 2010). For example, with respect to TMS and depression, the 2010 WFSBP guidelines recommend, For the acute management of patients with moderately treatment resistant depression: There is suffi cient class I evidence of acute effi cacy for TMS in depression in medication-free unipolar depressed patients. The large body of evidence from single site small sample trials suggests that it may also be useful clinically in moderately treatment resistant patients, either alone or used adjunctively with medications. We thus recommend that psychiatrists consider using TMS in non-psychotic adults with major depression. Typically patients will have tried and failed at least one attempt at medication therapy, although this is not required ... As rTMS effi cacy data is continuing to emerge, the choice of stimulation parameters including frequency, laterality, intensity and duration of treatment will need to be determined by a psychiatrist familiar with the relevant and recent rTMS literature.

Neuromodulation - ECT, rTMS, DBS

Neuromodulation techniques have been part of psychiatry since the introduction of electroconvulsive therapy over 60 years ago, but their applications remain controversial. In particular, they are disregarded for their invasiveness, risk of changing personal identity or resemblance to early psychosurgery. Here we show that stringent ethical analyses are hampered rather than facilitated by these concepts and issues. Instead, ethical implications of neuromodulation techniques are more productively analyzed by use of widely shared ethical criteria that, in addition, can easily be applied to empirical evidence and thus allow to turn from speculative, rhethoric to evidence-based ethics. This will be shown for each neuromodulation technique, namely electroconvulsive therapy (ECT), psychiatric repetitive transcranial magnetic stimulation (rTMS) and psychiatric deep-brain stimulation (DBS). We will argue that each neuromodulation technique has to be thoroughly assessed for its benefit, harm and respect of the patient’s will. However, not only the application per se needs special ethical attention, but also their perception and portrayal in the public. This analysis will prepare the ground for ethically justified, empirically comprehensive neuromodulation in the highly vulnerable population of psychiatric patients and allow stringent future societal discussions about its legitimation.

Deep brain stimulation for bipolar disorder-review and outlook.

Research on deep brain stimulation (DBS) for treatment-resistant psychiatric disorders has established preliminary efficacy signals for treatment-resistant depression. There are only few studies on DBS that included patients suffering from bipolar disorder. This article gives an overview of these studies concerning DBS targets, antidepressant efficacy, and the occurrence of manic/hypomanic symptoms under stimulation. First, promising results show that all patients experienced significant improvement in depressive symptomatology. In a single case, hypomanic symptoms occurred, but they could be resolved by adjusting stimulation parameters. Furthermore, this article highlights important clinical differences between unipolar and bipolar depression that have to be considered throughout the course of treatment.

Panksepp’s SEEKING System Concepts and Their Implications for the Treatment of Depression with Deep-Brain Stimulation

Panksepp, as the true founder of the field of affective neuroscience, has predicted that the understanding of the emotional systems of animals will lead to understanding on the nature of human feelings. The Target Article that we comment on most convincingly shows a careful analysis of impaired SEEKING function for the clinical entity of major depression. It becomes increasingly clear that certain affective imbalances of this and other disorders (e.g., addiction) converge on a common subcortical emotional system, the very SEEKING system that Wright & Panksepp discuss. We conclude our comment with the first report of actual medial forebrain bundle (SEEKING system) stimulation results in humans, treated for therapy refractory depression and performed by our group.