Deep Brain Stimulation in Anorexia Nervosa: Hope for the Hopeless or Exploitation of the Vulnerable? The Oxford Neuroethics Gold Standard Framework.
ABSTRACT: 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.
Project description:Therapeutic benefits of deep brain stimulation (DBS), a neurosurgical treatment for certain movement disorders and other neurologic conditions, are well documented, but DBS mechanisms remain largely unexplained. DBS is thought to modulate pathological neural activity. However, although astrocytes, the most numerous cell type in the brain, play a significant role in neurotransmission, chemical homeostasis and synaptic plasticity, their role in DBS has not been fully examined. To investigate astrocytic function in DBS, we applied DBS-like high frequency electrical stimulation for 24 h to human astrocytes in vitro and analyzed single cell transcriptome mRNA profile. We found that DBS-like high frequency stimulation negatively impacts astrocyte metabolism and promotes the release of extracellular matrix (matricellular) proteins, including IGFBP3, GREM1, IGFBP5, THBS1, and PAPPA. Our results suggest that astrocytes are involved in the long-term modulation of extra cellular matrix environments and that they may influence persistent cell-to-cell interaction and help maintain neuromodulation over time.
Project description:The role of neuroimaging in psychiatric neurosurgery has evolved significantly throughout the field's history. Psychiatric neurosurgery initially developed without the benefit of information provided by modern imaging modalities, and thus lesion targets were selected based on contemporary theories of frontal lobe dysfunction in psychiatric disease. However, by the end of the 20th century, the availability of structural and functional magnetic resonance imaging (fMRI) allowed for the development of mechanistic theories attempting to explain the anatamofunctional basis of these disorders, as well as the efficacy of stereotactic neuromodulatory treatments. Neuroimaging now plays a central and ever-expanding role in the neurosurgical management of psychiatric disorders, by influencing the determination of surgical candidates, allowing individualized surgical targeting and planning, and identifying network-level changes in the brain following surgery. In this review, we aim to describe the coevolution of psychiatric neurosurgery and neuroimaging, including ways in which neuroimaging has proved useful in elucidating the therapeutic mechanisms of neuromodulatory procedures. We focus on ablative over stimulation-based procedures given their historical precedence and the greater opportunity they afford for post-operative re-imaging, but also discuss important contributions from the deep brain stimulation (DBS) literature. We conclude with a discussion of how neuroimaging will transition the field of psychiatric neurosurgery into the era of precision medicine.
Project description:<h4>Objective</h4>Stereotactic ablation (cingulotomy) and subcallosal cingulate deep brain stimulation (SCC DBS) of different regions of the cingulum bundle (CB) have been successfully used to treat psychiatric disorders, such as depression and bipolar disorder. They are hypothesized to work by disrupting white matter pathways involved in the clinical manifestation of these disorders. This study aims to compare the connectivity of different CB subregions using tractography to evaluate stereotactic targets for the treatment of mood disorders.<h4>Methods</h4>Fourteen healthy volunteers underwent 3T-MR imaging followed by connectivity analysis using probabilistic tractography. Twenty-one anatomic regions of interest were defined for each subject: 10 CB subregions (including the classical cingulotomy and SCC DBS targets) and 11 cortical/subcortical structures implicated in mood disorders. Connectivity results were compared using Friedman and Bonferroni-corrected post-hoc Wilcoxon tests.<h4>Results</h4>CB connectivity showed a high degree of regional specificity. Both of the traditional stereotactic targets had widespread connectivity with discrete topology. The cingulotomy target connected primarily to the dorsomedial frontal, dorsal anterior cingulate, and posterior cingulate cortices, whereas the SCC DBS target connected mostly to the subgenual anterior cingulate and medial/central orbitofrontal cortices. However, a region of the rostral dorsal CB, lying between these surgical targets, encompassed statistically equivalent connections to all five cortical regions.<h4>Conclusions</h4>The CB is associated with brain structures involved in affective disorders, and the rostral dorsal CB demonstrates connectivity that is comparable to the combined connectivity of cingulotomy and SCC DBS neurosurgical interventions. The rostral dorsal CB represents a surgical target worthy of clinical exploration for mood disorders.
Project description:Background:Research suggests that altered eating and the pursuit of thinness in anorexia nervosa (AN) are, in part, a consequence of aberrant reward circuitry. The neural circuits involved in reward processing and compulsivity overlap significantly, and this has been suggested as a transdiagnostic factor underpinning obsessive compulsive disorder, addictions and eating disorders. The nucleus accumbens (NAcc) is central to both reward processing and compulsivity. In previous studies, deep-brain stimulation (DBS) to the NAcc has been shown to result in neural and symptomatic improvement in both obsessive compulsive disorder and addictions. Moreover, in rats, DBS to the NAcc medial shell increases food intake. We hypothesise that this treatment may be of benefit in severe and enduring anorexia nervosa (SE-AN), but first, feasibility and ethical standards need to be established. The aims of this study are as follows: (1) to provide feasibility and preliminary efficacy data on DBS to the NAcc as a treatment for SE-AN; (2) to assess any subsequent neural changes and (3) to develop a neuroethical gold standard to guide applications of this treatment. Method:This is a longitudinal study of six individuals with SE-AN of >7?years. It includes an integrated neuroethical sub-study. DBS will be applied to the NAcc and we will track the mechanisms underpinning AN using magnetoelectroencephalography, neuropsychological and behavioural measures. Serial measures will be taken on each intensively studied patient, pre- and post-DBS system insertion. This will allow elucidation of the processes involved in symptomatic change over a 15-month period, which includes a double-blind crossover phase of stimulator on/off. Discussion:Novel, empirical treatments for SE-AN are urgently required due to high morbidity and mortality costs. If feasible and effective, DBS to the NAcc could be game-changing in the management of this condition. A neuroethical gold standard is crucial to optimally underpin such treatment development. Clinical Trial Registration:The study is ongoing and registered with www.ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01924598, 22 July, 2013. It has full ethical and HRA approval (Project ID 128658).
Project description:In neurosurgical literature, findings such as deep brain stimulation (DBS) electrode positions are conventionally reported in relation to the anterior and posterior commissures of the individual patient (AC/PC coordinates). However, the neuroimaging literature including neuroanatomical atlases, activation patterns, and brain connectivity maps has converged on a different population-based standard (MNI coordinates). Ideally, one could relate these two literatures by directly transforming MRIs from neurosurgical patients into MNI space. However obtaining these patient MRIs can prove difficult or impossible, especially for older studies or those with hundreds of patients. Here, we introduce a methodology for mapping an AC/PC coordinate (such as a DBS electrode position) to MNI space without the need for MRI scans from the patients themselves. We validate our approach using a cohort of DBS patients in which MRIs are available, and test whether several variations on our approach provide added benefit. We then use our approach to convert previously reported DBS electrode coordinates from eight different neurological and psychiatric diseases into MNI space. Finally, we demonstrate the value of such a conversion using the DBS target for essential tremor as an example, relating the site of the active DBS contact to different MNI atlases as well as anatomical and functional connectomes in MNI space.
Project description:Deep brain stimulation (DBS) has been offered to patients suffering of severe and resistant neuropsychiatric disorders like Obsessive Compulsive Disorder (OCD), Gilles de la Tourette Syndrome (TS) and Major Depression (MDD). Modulation of several targets within the cortico-striato-thalamo-cortical circuits can lead to a decrease of symptom severity in those patients. This review focuses on the recent clinical outcomes in DBS in psychiatric disorders. Studies on OCD and TS are now focusing on the long-term effects of DBS, with encouraging results regarding not only the decrease of symptoms, but also quality of life. They also highlighted efficient adjuvant techniques, like cognitive and behavioural therapy and support programs, to enhance an often-partial response to DBS. The application of DBS for MDD is more recent and, despite encouraging initial open-label studies, two large randomised studies have failed to demonstrate an efficacy of DBS in MDD according to evidence-based medicine criteria. Last years, DBS was also tested in other resistant psychiatric disorders, as anorexia nervosa and addiction, with encouraging preliminary results. However, today, no target - whatever the disease - can meet the criteria for clinical efficacy as recently defined by an international committee for neurosurgery for psychiatric disorders. Consequently, DBS in psychiatric disorders still needs to proceed within the frame of clinical trials.
Project description:The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.
Project description:Deep brain stimulation (DBS) has proven remarkably safe and effective in the treatment of movement disorders. As a result, it is being increasingly applied to a range of neurologic and psychiatric disorders, including medically refractory epilepsy. This review will examine the use of DBS in epilepsy, including known targets, mechanisms of neuromodulation and seizure control, published clinical evidence, and novel technologies. Cortical and deep neuromodulation for epilepsy has a long experimental history, but only recently have better understanding of epileptogenic networks, precise stereotactic techniques, and rigorous trial design combined to improve the quality of available evidence and make DBS a viable treatment option. Nonetheless, underlying mechanisms, anatomical targets, and stimulation parameters remain areas of active investigation.
Project description:Deep brain stimulation (DBS) for refractory psychiatric disorders shows promising effects on symptom-reduction, however, little is known regarding the effects of DBS on social outcome.A PubMed search based on original studies of DBS for psychiatric disorders [treatment resistant depression (TRD), Gilles de la Tourette's syndrome (GTS), and obsessive compulsive disorder (OCD)] was conducted. Data on social outcome following surgery were extracted and analyzed.Social functioning was not a primary outcome measure in the reviewed article. The literature is incomplete and inconclusive on this variable, however from the reported data, there is some evidence that DBS has the potential to improve social functioning.More systematic and detailed data gathering and reporting on social outcome with longer follow-ups are needed to evaluate more exhaustively the role of DBS in refractory psychiatric disorders.
Project description:The implantation of deep brain stimulation (DBS) electrodes into the human brain is a neurosurgical treatment for, e.g., movement disorders. We describe a novel approach to collecting brain tissue from DBS surgery-guiding instruments for liquid chromatography-mass spectrometry and RNA sequencing analyses. Proteomics and transcriptomics showed that the approach is useful for obtaining disease-specific expression data. A comparison between our improved and the previous approaches and related datasets was performed. BioStudies:https://www.ebi.ac.uk/biostudies/studies/S-BSST667 and Publication: https://www.biorxiv.org/content/10.1101/2021.06.18.448926v1