Deep Brain Stimulation For Treatment-resistant Depression Research Articles

Presurgical structural imaging and clinical outcome in combined bed nucleus of the stria terminalis–nucleus accumbens deep brain stimulation for treatment-resistant depression

BackgroundStructural imaging holds great potential for precise targeting and stimulation for deep brain stimulation (DBS). The anatomical information it provides may serve as potential biomarkers for predicting the efficacy of...

Adverse Effects of Deep Brain Stimulation for Treatment-Resistant Depression: A Scoping Review.

Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD). Although adverse effects have been reported in early-phase and a few randomized clinical trials, little is known about its overall safety profile, which has been assumed to be similar to that of DBS for movement disorders. The objective of this study was to pool existing safety data on DBS for TRD. Following PRISMA guidelines, PubMed was searched for English articles describing adverse outcomes after DBS for TRD. Studies were included if they reported at least 5 patients with a minimal follow-up of 6 months. After abstract (n = 607) and full-article review (n = 127), 28 articles reporting on 353 patients met criteria for final inclusion. Follow-up of the studies retrieved ranged from 12 to 96 months. Hemorrhages occurred in 0.8% of patients and infections in 10.2%. The rate of completed suicide was 2.5%. Development or worsening of depressive symptoms, anxiety, and mania occurred in 18.4%, 9.1%, and 5.1%, respectively. There were some differences between targets, but between-study heterogeneity precluded statistical comparisons. In conclusion, DBS for TRD is associated with surgical and psychiatric adverse events. Hemorrhage and infection occur at rates within an accepted range for other DBS applications. The risk of suicide after DBS for TRD is 2.5% but may not represent a significant deviation from the natural history of TRD. Finally, risks of worsening depression, anxiety, and the incidence of mania should be acknowledged when considering DBS for TRD.

Effects of deep brain stimulation on cognitive functioning in treatment-resistant depression: a systematic review and meta-analysis.

Deep brain stimulation (DBS) is a promising intervention for treatment-resistant depression (TRD). Effects on cognitive functioning are unclear since they have been studied in small samples. We aim to estimate the impact of DBS on cognitive functioning in TRD with a systematic review and meta-analyses. After systematically searching PubMed we included 10 studies which compared standardized neuropsychological tests before and after DBS or between active and sham DBS in TRD. Different random-effects meta-analyses were done for different cognitive (sub-)domains and for different follow-up time windows (<6 months, 6-18 months, and >18 months). We found no significant differences in cognitive functioning up to 6 months of DBS. After 6-18 months of DBS small to moderate improvements were found in verbal memory (Hedge's g = 0.22, 95% CI = [0.01-0.43], p = 0.04), visual memory (Hedge's g = 0.37, 95% CI = [0.03-0.71], p = 0.04), attention/psychomotor speed (Hedge's g = 0.26, 95% CI = [0.02-0.50], p = 0.04) and executive functioning (Hedge's g = 0.37, 95% CI = [0.15-0.59], p = 0.001). Not enough studies could be retrieved for a meta-analysis of effects after >18 months of DBS or for the comparison of active and sham DBS. Qualitatively, generally no differences in cognitive functioning between active and sham DBS were found. No cognitive decline was found in this meta-analysis up to 18 months of DBS in patients with TRD. Results even suggest small positive effects of DBS on cognitive functioning in TRD, although this should be interpreted with caution due to lack of controlled data.

ID: 221667 Lessons in BROADEN and Since BROADEN: The Long and Winding Path to FDA Breakthrough Designation

Treatment-resistant depression (TRD) is characterized by a failure to achieve remission or respond to multiple antidepressant trials of adequate dose and duration in the current episode. Up to a third of patients with Major Depressive Disorder fail to achieve remission after four established treatments, denoting TRD. After each sequential treatment, there is a decreased probability of achieving remission, with a relapse rate of 83% after the fourth treatment. Deep brain stimulation (DBS) has been explored clinically using various targets, although several large randomized controlled trials did not show a difference between stimulation and sham control. BROADEN, the pivotal RCT investigating subcallosal cingulate (SCC) DBS for TRD, was halted early after 6-months by the sponsor due low likelihood of success. However, long-term follow-up (LTFU) data revealed continued, sustained improvement in depressive symptom severity, prompting a further look into the possibility of DBS as a therapeutic option for TRD.

Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

Neuromodulation for treatment-resistant depression: Functional network targets contributing to antidepressive outcomes.

Non-invasive brain stimulation is designed to target accessible brain regions that underlie many psychiatric disorders. One such method, transcranial magnetic stimulation (TMS), is commonly used in patients with treatment-resistant depression (TRD). However, for non-responders, the choice of an alternative therapy is unclear and often decided empirically without detailed knowledge of precise circuit dysfunction. This is also true of invasive therapies, such as deep brain stimulation (DBS), in which responses in TRD patients are linked to circuit activity that varies in each individual. If the functional networks affected by these approaches were better understood, a theoretical basis for selection of interventions could be developed to guide psychiatric treatment pathways. The mechanistic understanding of TMS is that it promotes long-term potentiation of cortical targets, such as dorsolateral prefrontal cortex (DLPFC), which are attenuated in depression. DLPFC is highly interconnected with other networks related to mood and cognition, thus TMS likely alters activity remote from DLPFC, such as in the central executive, salience and default mode networks. When deeper structures such as subcallosal cingulate cortex (SCC) are targeted using DBS for TRD, response efficacy has depended on proximity to white matter pathways that similarly engage emotion regulation and reward. Many have begun to question whether these networks, targeted by different modalities, overlap or are, in fact, the same. A major goal of current functional and structural imaging in patients with TRD is to elucidate neuromodulatory effects on the aforementioned networks so that treatment of intractable psychiatric conditions may become more predictable and targeted using the optimal technique with fewer iterations. Here, we describe several therapeutic approaches to TRD and review clinical studies of functional imaging and tractography that identify the diverse loci of modulation. We discuss differentiating factors associated with responders and non-responders to these stimulation modalities, with a focus on mechanisms of action for non-invasive and intracranial stimulation modalities. We advance the hypothesis that non-invasive and invasive neuromodulation approaches for TRD are likely impacting shared networks and critical nodes important for alleviating symptoms associated with this disorder. We close by describing a therapeutic framework that leverages personalized connectome-guided target identification for a stepwise neuromodulation paradigm.

White Matter Microstructure Associated with the Antidepressant Effects of Deep Brain Stimulation in Treatment-Resistant Depression: A Review of Diffusion Tensor Imaging Studies

Treatment-resistant depression (TRD) is a severe disorder characterized by high relapse rates and decreased quality of life. An effective strategy in the management of TRD is deep brain stimulation (DBS), a technique consisting of the implantation of electrodes that receive a stimulation via a pacemaker-like stimulator into specific brain areas, detected through neuroimaging investigations, which include the subgenual cingulate cortex (sgCC), basal ganglia, and forebrain bundles. In this context, to improve our understanding of the mechanism underlying the antidepressant effects of DBS in TRD, we collected the results of diffusion tensor imaging (DTI) studies exploring how WM microstructure is associated with the therapeutic effects of DBS in TRD. A search on PubMed, Web of Science, and Scopus identified 11 investigations assessing WM microstructure in responders and non-responders to DBS. Altered WM microstructure, particularly in the sgCC, medial forebrain bundle, cingulum bundle, forceps minor, and uncinate fasciculus, was associated with the antidepressant effect of DBS in TRD. Overall, the results show that DBS targeting selective brain regions, including the sgCC, forebrain bundle, cingulum bundle, rectus gyrus, anterior limb of the internal capsule, forceps minor, and uncinate fasciculus, seem to be effective for the treatment of TRD.

Deep Brain Stimulation for Depression Informed by Intracranial Recordings

The success of deep brain stimulation (DBS) for treating Parkinson’s disease has led to its application to several other disorders, including treatment-resistant depression. Results with DBS for treatment-resistant depression have been heterogeneous, with inconsistencies largely driven by incomplete understanding of the brain networks regulating mood, especially on an individual basis. We report results from the first subject treated with DBS for treatment-resistant depression using an approach that incorporates intracranial recordings to personalize understanding of network behavior and its response to stimulation. These recordings enabled calculation of individually optimized DBS stimulation parameters using a novel inverse solution approach. In the ensuing double-blind, randomized phase incorporating these bespoke parameter sets, DBS led to remission of symptoms and dramatic improvement in quality of life. Results from this initial case demonstrate the feasibility of this personalized platform, which may be used to improve surgical neuromodulation for a vast array of neurologic and psychiatric disorders.

Personality changes with subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression.

Background:Deep brain stimulation (DBS) is a promising investigational approach for treatment-resistant depression. However, reports suggesting changes in personality with DBS for movement disorders have raised clinical and ethical concerns. We prospectively examined changes in personality dimensions and antidepressant response to subcallosal cingulate (SCC)-DBS for treatment-resistant depression.Methods:Twenty-two patients with treatment-resistant depression underwent SCC-DBS. We used the NEO Five-Factor Inventory for personality assessment at baseline and every 3 months until 15 months post-DBS. We assessed depression severity monthly using the Hamilton Depression Rating Scale.Results:We found a significant decrease in neuroticism (p = 0.002) and an increase in extraversion (p = 0.001) over time, showing a change toward normative data. Improvement on the Hamilton Depression Rating Scale was correlated with decreases in neuroticism at 6 months (p = 0.001) and 12 months (p < 0.001), and with an increase in extraversion at 12 months (p = 0.01). Changes on the Hamilton Depression Rating Scale over time had a significant covariate effect on neuroticism (p < 0.001) and extraversion (p = 0.001). Baseline openness and agreeableness predicted response to DBS at 6 (p = 0.006) and 12 months (p = 0.004), respectively.Limitations:Limitations included a small sample size, a lack of sham control and the use of subjective personality evaluation.Conclusion:We observed positive personality changes following SCC-DBS, with reduced neuroticism and increased extraversion related to clinical improvement in depression, suggesting a state effect. As well, pretreatment levels of openness and agreeableness may have predicted subsequent response to DBS. The NEO Five-Factor Inventory assessment may have a role in clinical decision-making and prognostic evaluation in patients with treatment-resistant depression who undergo SCC-DBS.

Deep Brain Stimulation for Treatment-Resistant Depression: Towards a More Personalized Treatment Approach.

Major depressive disorder (MDD) affects approximately 4.4% of the world’s population. One third of MDD patients do not respond to routine psychotherapeutic and pharmacotherapeutic treatment and are said to suffer from treatment-resistant depression (TRD). Deep brain stimulation (DBS) is increasingly being investigated as a treatment modality for TRD. Although early case studies showed promising results of DBS, open-label trials and placebo-controlled studies have reported inconsistent outcomes. This has raised discussion about the correct interpretation of trial results as well as the criteria for patient selection, the choice of stimulation target, and the optimal stimulation parameters. In this narrative review, we summarize recent studies of the effectiveness of DBS in TRD and address the relation between the targeted brain structures and clinical outcomes. Elaborating upon that, we hypothesize that the effectiveness of DBS in TRD can be increased by a more personalized and symptom-based approach. This may be achieved by using resting-state connectivity mapping for neurophysiological subtyping of TRD, by using individualized tractography to help decisions about stimulation target and electrode placement, and by using a more detailed registration of symptomatic improvements during DBS, for instance by using ‘experience sampling’ methods.

Deep Brain Stimulation for Major Depression and Obsessive-Compulsive Disorder—Discontinuation of Ongoing Stimulation

Deep brain stimulation (DBS) is currently under research for the treatment of psychiatric disorders, e.g., obsessive-compulsive disorder (OCD) and treatment-resistant depression (TRD). Since the application of DBS in psychiatry has been in use for about 20 years, it is necessary to evaluate its long-term use now. A main issue in the long-term treatment of DBS concerns the effects of a discontinuation of stimulation due to intended as well as unintended reasons. In this contribution, the literature describing discontinuation effects following DBS in OCD and TRD is reviewed. Furthermore, a patient is reported in depth who experienced an unintended discontinuation of supero-lateral medial forebrain bundle (slMFB) DBS for TRD. In this case, the battery was fully depleted without the patient noticing. DBS had led to a sustained response for seven years before discontinuation of stimulation for just several weeks caused a progressive worsening of depression. Altogether, the rapid occurrence of symptom worsening, the absence of a notification about the stimulation status and the difficulties to recapture antidepressant response represent important safety aspects. For a further understanding of the described effects, time courses until worsening of depression as well as biological mechanisms need to be investigated in double-blind controlled trials.

Tactics: an open-source platform for planning, simulating and validating stereotactic surgery

Frame-based stereotaxy is widely used for planning and implanting deep-brain electrodes. In 2013, as part of a clinical study on deep-brain stimulation for treatment-resistant depression, our group identified a need for software to simulate and plan stereotactic procedures. Shortcomings in extant commercial systems encouraged us to develop Tactics. Tactics is purpose-designed for frame-based stereotactic placement of electrodes. The workflow is far simpler than commercial systems. By simulating specific electrode placement, immediate in-context view of each electrode contact, and the cortical entry site are available within seconds. Post implantation, electrode placement is verified by linearly registering post-operative images. Tactics has been particularly helpful for invasive electroencephalography electrodes where as many as 20 electrodes are planned and placed within minutes. Currently, no commercial system has a workflow supporting the efficient placement of this many electrodes. Tactics includes a novel implementation of automated frame localization and a user-extensible mechanism for importing electrode specifications for visualization of individual electrode contacts. The system was systematically validated, through comparison against gold-standard techniques and quantitative analysis of targeting accuracy using a purpose-built imaging phantom mountable by a stereotactic frame. Internal to our research group, Tactics has been used to plan over 300 depth-electrode targets and trajectories in over 50 surgical cases, and to plan dozens of stereotactic biopsies. Source code and pre-built binaries for Tactics are public and open-source, enabling use and contribution by the extended community.

Deep Brain Stimulation for the Treatment of Resistant Depression: Systematic Review of the Literature

AbstractDepression is the leading cause of disability worldwide, and it is related to high suicide rates. Furthermore, a great number of patients do not respond to any of the available treatments. Deep brain stimulation (DBS), a versatile technology with expanding indications, is considered a potential treatment for resistant depression. However, in over 10 years of clinical research, its efficacy has not been completely proven. Although new trials using DBS for treatment-resistant depression keep emerging, two of the three Level I evidence-based studies recently conducted have not provided conclusive data. Methodological limitations and major biases have compromised the obtention of clearer results. In this systematic review of the literature, we intend to critically assess the clinical trials performed in this field.

Deep Brain Stimulation for Depression: An Update

Depression is an often debilitating disorder affecting a person’s ability to work and function. Treatment-resistant depression (TRD) leads to many interventions and significant health care costs. Deep brain stimulation (DBS) is an emerging potential intervention for those with TRD who have undergone adequate medication, therapy, and rTMS/ECT trials, but who continue to suffer from unremitting depressive symptoms. The latest clinical safety and efficacy data of DBS for TRD is presented in this review. Since the origin of DBS is rooted in specific neuroanatomical targets, the discussion is organized according to target brain region. Relevant neuroimaging and animal studies are discussed, when available, as to how they shed light on possible mechanisms of action. Lastly, critical ethical issues related to informed consent and decision-making capacity are considered.

Commentary: Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation.

Commentary: Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation.

Deep Brain Stimulation Modulates Gamma Oscillations and Theta-Gamma Coupling in Treatment Resistant Depression.

Deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG) is becoming an effective therapeutic option for treatment resistant depression (TRD). Identifying the neurophysiological mechanisms altered by DBS may lead to more tailored treatment parameters and enhanced efficacy. Twenty TRD patients with implanted DBS in the SCG were recruited. Patients participated in three EEG recording sessions, one with DBS ON, one with DBS randomized to ON or OFF, and one with DBS OFF. During each session, subjects performed N-back working memory tasks, namely the 0-back and 3-back. Fourteen subjects with valid EEG were included in the analysis. Changes in frontal gamma oscillations (30-50 Hz) and coupling between theta (4-7 Hz) and gamma oscillations as a result of DBS stimulation were quantified and correlated with depressive symptoms. DBS stimulation resulted in suppression of frontal oscillations in the ON state relative to the OFF state during the N-back tasks. Greatest suppression was demonstrated in beta and gamma oscillations and most pronounced during the 3-back. Suppression of gamma oscillations in the 3-back correlated with a reduction in depressive symptoms. DBS ON relative to OFF in the 3-back also resulted in an increase in theta-gamma coupling that correlated with a reduction in depressive symptoms. Suppression of gamma oscillations and increased theta-gamma coupling through DBS is likely mediated by both SCG activation of inhibitory circuits and an enhancement of plasticity in the frontal cortex. Activation of both pathways may explain the therapeutic properties of DBS in TRD.

Rapid Communications

The mood regulatory mechanisms of deep brain stimulation (DBS)therapy are yet to be fully understood. DBS is shown to have antidepressant actions in severe, treatment-resistant depression (TRD).Interestingly, DBS of mesoaccumbens neurologic targets, includingthe nucleus accumbens (NAc), have also been shown to induce mania in vulnerable individuals. The nucleus accumbens (NAc) is a critical node in the mesocorticolimbic system and plays a major role in mediating antidepressant behavioral responses in the forced swim test (FST), a preclinical screen for antidepressant efficacy. This study investigates the antidepressant effects of NAc DBS in an established animal model of TRD. Wistar rats were divided into 4 groups: TRD-DBS (n = 9), TRD-Sham (n = 8), TRD (n = 10), and Control (n = 10). Bilateral stimulating electrodes were implanted into the NAc of TRD-Sham and TRD-DBS animals. Antidepressant-resistance and depression behaviors were induced through adrenocorticotropic-hormone (ACTH-(1–24); 100 lg/day; 2nd and 3rd weeks) administration and concurrent social isolation (all 3 weeks) respectively. DBS was administered throughout the 2nd week of ACTH treatment via a back mounted rodent DBS system. 24-hour locomotor activity counts were obtained using infrareddetectors and weekly sucrose preference tests were performedthroughout the 3 week protocol. Open field and FST were completedat the end of the 3 weeks. Brains were then removed and stored at 80°C. NAc tissue levels of brain-derived and glialderived neurotrophic factors (BDNF and GDNF, respectively) were quantified using western blot. Results demonstrate significant increases in locomotor activity for TRD-DBS animals (DBS-Vs-Sham: p = 0.0248). Lowered immobility was observed during FST for TRD-DBS animals (DBS-Vs-Sham: p = 0.0188). ACTHinduced BDNF expression increased in the outer region substructure NAc-shell (p = 0.0487) and decreased in the inner region substructure NAc-core (p = 0.0275) compared to controls. These datasupport antidepressant actions of NAc DBS in TRD. Local changes in neurotrophic factors may contribute to these mechanisms. Importantly, observed increases in locomotor activity over the 3 weeks highlight the potential for mesoaccumbens DBS to impact behaviors such as locomotor activity which may contribute to risk for induction of mania. Preliminary analysis of concurrent effects of daily dopamine reuptake inhibitor GBR12909 (16 mg/kg) administration coupled with NAc DBS demonstrates dopamine-mediated augmentation of these mania-like behaviors.

Deep Brain Stimulation of the Human Reward System for Major Depression—Rationale, Outcomes and Outlook

Deep brain stimulation (DBS) as a putative approach for treatment-resistant depression (TRD) has now been researched for about a decade. Several uncontrolled studies--all in relatively small patient populations and different target regions-have shown clinically relevant antidepressant effects in about half of the patients and very recently, DBS to a key structure of the reward system, the medial forebrain bundle, has yielded promising results within few days of stimulation and at much lower stimulation intensities. On the downside, DBS procedures in regions are associated with surgical risks (eg, hemorrhage) and psychiatric complications (suicidal attenuation, hypomania) as well as high costs. This overview summarizes research on the mechanisms of brain networks with respect to psychiatric diseases and--as a novelty--extrapolates to the role of the reward system in DBS for patients with treatment-resistant depression. It further evaluates relevant methodological aspects of today's research in DBS for TRD. On the scientific side, the reward system has an important yet clearly under-recognized role in both neurobiology and treatment of depression. On the methodological side of DBS research in TRD, better animal models are clearly needed to explain clinical effects of DBS in TRD. Larger sample sizes, long-term follow-up and designs including blinded sham control are required to draw final conclusions on efficacy and side effects. Practical research issues cover study design, patient tracking, and the discussion of meaningful secondary outcome measures.

Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS

The field of non-pharmacological therapies for treatment resistant depression (TRD) is rapidly evolving and new somatic therapies are valuable options for patients who have failed numerous other treatments. A major challenge for clinicians (and patients alike) is how to integrate the results from published clinical trials in the clinical decision-making process.We reviewed the literature for articles reporting results for clinical trials in particular efficacy data, contraindications and side effects of somatic therapies including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagal nerve stimulation (VNS) and deep brain stimulation (DBS). Each of these devices has an indication for patients with different level of treatment resistance, based on acuteness of illness, likelihood of response, costs and associated risks. ECT is widely available and its effects are relatively rapid in severe TRD, but its cognitive adverse effects may be cumbersome. TMS is safe and well tolerated, and it has been approved by FDA for adults who have failed to respond to one antidepressant, but its use in TRD is still controversial as it is not supported by rigorous double-blind randomized clinical trials. The options requiring surgical approach are VNS and DBS. VNS has been FDA-approved for TRD, however it is not indicated for management of acute illness. DBS for TRD is still an experimental area of investigation and double-blind clinical trials are underway.

Update on Deep Brain Stimulation for Treatment-Resistant Depression

Major depression is one of the leading causes of disability worldwide since it is often accompanied by high rates of resistance to treatment. Up to 40% of patients do not remit after two adequate pharmacological tryouts (as indicated by STAR*D study). Poor efficacy of drugs for treatment-resistant depression (TRD) has prompted investigation of alternative treatment strategies. Deep Brain Stimulation (DBS) involves the high-frequency electrical stimulation of stereotaxically implanted electrodes in certain brain regions. Various target areas have been examined for DBS to modulate cortico-limbic circuits, including the anterior limb in the internal capsule, the ventral capsule / ventral striatum (VC/VS), the nucleus accumbens (NAc), and the subgenual cingulate gyrus (SCG, Cg25). DBS for treatment-resistant depression is showing promising results in the few studies published to date, and could potentially open new therapeutic opportunities as an effective long-term treatment strategy with low adverse effects for such a chronic, refractory population.