Treatment resistant depression as a failure of brain homeostatic mechanisms: Implications for deep brain stimulation

Given the profound negative public health effects of major depressive disorder (MDD), and data suggesting only modest effectiveness of existing psychological and pharmacological treatments for this condition, there has been increasing interest in exploring the antidepressant potential of non-pharmacological, brain-based interventions, such as deep brain stimulation (DBS). The use of the DBS for psychiatric indications follows a decade of data suggesting that DBS is an effective, evidence-based strategy for the treatment of movement disorders such as Parkinson's disease. At the present time there is open-label case series data to suggest that DBS in the subgenual cingulate gyrus, ventral caudate/ventral striatum, and the nucleus accumbens, is associated with antidepressant effects in individuals who fail to respond to conventional treatments for MDD. However a number of unresolved issues about the optimal use of DBS for MDD remain, such as the optimal anatomical placement of the electrodes and the mechanisms of its antidepressant effects. This review summarizes the clinical experience of DBS for treatment resistant depression (TRD). The rationale for the use of DBS for TRD is reviewed in the context of the growing neuroimaging literatures exploring the biomarkers of antidepressant response, and the neural substrates of emotional regulation in both normal and pathological states.     

Deep brain stimulation in the treatment of depression

Blomstedt P, Sjöberg RL, Hansson M, Bodlund O, Hariz MI. Deep brain stimulation in the treatment of depression. Objective: To present the technique of deep brain stimulation (DBS) and to evaluate the studies conducted on DBS in the treatment of therapy‐refractory major depressive disorder (MDD). Method: A review of the literature on DBS in the treatment of MDD was conducted. Results: The results of DBS in MDD have been presented in 2 case reports and 3 studies of 47 patients operated upon in 5 different target areas. Positive effects have been presented in all studies and side effects have been minor. DBS in the nucleus accumbens resulted in a mean reduction of Hamilton depression rating scale (HDRS) of 36% after 1 year and 30% of the 10 patients achieved remission. DBS in the internal capsule/ventral striatum resulted in a reduction of 44% after 1 year, and at the last evaluation after in mean 2 years, 40% of the 15 patients were in remission. The 20 patients with subcallosal cingulated gyrus DBS had a reduction of HDRS of 52% after 1 year, and 35% were within 1 point from remission or in remission. Conclusion: DBS is a promising treatment for therapy‐refractory MDD. The published experience is, however, limited, and the method is at present an experimental therapy.     

Current Status of Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Clinical Review of Different Targets

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Despite optimal cognitive-behavioral and pharmacologic therapy, approximately 10% of patients remain treatment resistant. Currently, deep brain stimulation (DBS) is being investigated as an experimental therapy for treatment-refractory OCD. This review focuses on the efficacy and adverse events of all published DBS targets for OCD: anterior limb of the internal capsule, ventral striatum/ventral capsule, nucleus accumbens, nucleus subthalamicus, and inferior thalamic peduncle. Small studies with various designs indicate an overall average Yale-Brown Obsessive Compulsive Scale score decrease ranging from 6.8 to 31 points. The average overall responder rate is ±50%. The frequency of adverse events seems to be limited. Larger prospective studies including neuroimaging are needed to estimate adequately the true potential of DBS in treatment of OCD and to elucidate its underlying mechanism of action and optimal brain target. We conclude that DBS may be a promising and safe therapy for treatment-resistant OCD.     

The application of vagus nerve stimulation and deep brain stimulation in depression

Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment-resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6-12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and the nucleus accumbens. Antidepressant effects of DBS were examined in case series with a total number of 50 TRD patients. Stimulation of different brain regions resulted in a reduction of depressive symptoms. The clinical data on the use of VNS and DBS in TRD are encouraging. The major contribution of the methods is a novel approach that allows for precise targeting of the specific brain areas, nuclei and circuits implicated in the etiopathogenesis of neuropsychiatric disorders. For clinical practice, it is necessary to identify patients who may best benefit from VNS or DBS.     

Resting state brain network function in major depression – Depression symptomatology,antidepressant treatment effects,future research

The alterations of functional connectivity brain networks in major depressive disorder (MDD) have been subject of a large number of studies. Using different methodologies and focusing on diverse aspects of the disease, research shows heterogeneous results lacking integration. Disrupted network connectivity has been found in core MDD networks like the default mode network (DMN), the central executive network (CEN), and the salience network, but also in cerebellar and thalamic circuitries. Here we review literature published on resting state brain network function in MDD focusing on methodology, and clinical characteristics including symptomatology and antidepressant treatment related findings. There are relatively few investigations concerning the qualitative aspects of symptomatology of MDD, whereas most studies associate quantitative aspects with distinct resting state functional connectivity alterations. Such depression severity associated alterations are found in the DMN, frontal, cerebellar and thalamic brain regions as well as the insula and the subgenual anterior cingulate cortex. Similarly, different therapeutical options in MDD and their effects on brain function showed patchy results. Herein, pharmaceutical treatments reveal functional connectivity alterations throughout multiple brain regions notably the DMN, fronto-limbic, and parieto-temporal regions. Psychotherapeutical interventions show significant functional connectivity alterations in fronto-limbic networks, whereas electroconvulsive therapy and repetitive transcranial magnetic stimulation result in alterations of the subgenual anterior cingulate cortex, the DMN, the CEN and the dorsal lateral prefrontal cortex. While it appears clear that functional connectivity alterations are associated with the pathophysiology and treatment of MDD, future research should also generate a common strategy for data acquisition and analysis, as a least common denominator, to set the basis for comparability across studies and implementation of functional connectivity as a scientifically and clinically useful biomarker.     

Deep brain stimulation in addiction: a review of potential brain targets

Deep brain stimulation (DBS) is an adjustable, reversible, non-destructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS is currently investigated in psychiatry for the treatment of refractory obsessive-compulsive disorder, Tourette syndrome and depressive disorder. Although recent research in both animals and humans has indicated that DBS may be an effective intervention for patients with treatment-refractory addiction, it is not yet entirely clear which brain areas should be targeted. The objective of this review is to provide a systematic overview of the published literature on DBS and addiction and outline the most promising target areas using efficacy and adverse event data from both preclinical and clinical studies. We found 7 animal studies targeting six different brain areas: nucleus accumbens (NAc), subthalamic nucleus (STN), dorsal striatum, lateral habenula, medial prefrontal cortex (mPFC) and hypothalamus, and 11 human studies targeting two different target areas: NAc and STN. Our analysis of the literature suggests that the NAc is currently the most promising DBS target area for patients with treatment-refractory addiction. The mPFC is another promising target, but needs further exploration to establish its suitability for clinical purposes. We conclude the review with a discussion on translational issues in DBS research, medical ethical considerations and recommendations for clinical trials with DBS in patients with addiction.     

Deep brain stimulation for autism spectrum disorder

Deep brain stimulation (DBS) is a medical treatment that aims to obtain therapeutic effects by applying chronic electrical impulses in specific brain structures and neurological circuits. Over the years, DBS has been studied for the treatment of many psychiatric disorders. Scientific research on the use of DBS in people with autism has focused this interest mainly on treatment-resistant obsessive-compulsive disorder, drug-resistant epilepsy, self-injurious behaviors (SIB), and aggressive behaviors toward the self. Autism spectrum disorder (ASD) includes a group of developmental disabilities characterized by patterns of delay and deviance in the development of social, communicative, and cognitive skills and the presence of repetitive and stereotyped behaviors as well as restricted interests. People with autism often have numerous medical and psychiatric comorbidities that worsen the quality of life of patients and their caregivers. Obsessive-compulsive symptoms can be found in up to 81.3% of people with autism. They are often severe, refractory to treatment, and particularly difficult to treat. SIB has a high prevalence in severely retarded individuals and is often associated with autism. Drug treatment of both autism and SIB presents a therapeutic challenge. To describe the current state of the art regarding the efficacy of DBS in people with ASD, a literature search was conducted for relevant studies using the PubMed database. Thirteen studies have been considered in this paper. Up to date, DBS has been used for the stimulation of the nucleus accumbens, globus pallidus internus, anterior limb of the internal capsule, ventral anterior limb of the internal capsule, basolateral amygdala, ventral capsule and ventral striatum, medial forebrain bundle, and posterior hypothalamus. In the total sample of 16 patients, 4 were adolescents, and 12 were adults. All patients had symptoms resistant to multiple drug therapy. Many patients taken into consideration by the studies showed clinical improvements as evidenced by the scores of the psychopathological scales used. In some cases, clinical improvements have varied over time, which may require further investigation. Among the new therapeutic perspectives, DBS could be a valid option. However, further, and more in-depth research is needed in this field.     

Surgical targets in Psychiatric disorders. From movement to emotions

Deep brain stimulation (DBS) for psychiatric disorders refractory to conventional treatments are currently been performed based on the knowledge obtained in the motor disorder surgery and mainly in Parkinson's disease. Depression, obsessive-compulsive disorder (OCD) and Tourette syndrome, all of them are cortico-striato-thalamo-cortical pathological process involved in the limbic loop of the basal ganglia. This review describes the different targets in these pathological neuro-psychiatric disorders. For OCD there are currently two targets, ventral striatum (VS) Accumbens nucleus (Nacc) and the subthalamic nucleus (STN). In refractory depression the subgenual area (25 Brodmann area) and VS/Nacc. For Tourette syndrome the ventralis oralis internus and centromedianum/parafascicularis of the thalamus (Voi and CM/Pf) and the internal part of the globus pallidus (GPi). Currently there are no specific surgical target for each pathological disorder because clinical results reported are very similar after stimulation surgery. In other point, a selected surgical target also may improve different pathologies.     

Detecting consciousness in a total locked-in syndrome: An active event-related paradigm

Abstract

Objective: To descirbe smiling and euphoria induced by deep brain stimulation (DBS). Background and Significance: The brain systems inducing emotional experiences and displays are not entirely known, but the ventral striatum including the nucleus accumbens have been posited to play a critical role in mediating emotions with positive valence. DBS has been successfully employed for the treatment of movement disorders, and most recently obsessive compulsive disorder (OCD). The purpose of this report is to describe the emotional changes associated with stimulation of the ventral striatum. Methods: A single patient with intractable OCD had electrode arrays placed in the right and left anterior limbs of the internal capsule and region of the nucleus accumbens. Changes in facial movement during stimulation were quantified by video recording. Ten video segments, time locked to the onset of stimulation, were digitized and changes in pixel intensity that occurred over both sides of the lower face, on a frame by frame basis, following stimulation onset were computed. These summed changes in pixel intensity represented the dependent variable of “entropy” and directly corresponded to changes in light reflectance that occur during facial movement. Results: During stimulation on both the right and left side, the patient consistently developed a half smile on the side of the face contralateral to the stimulating electrode, and also became euphoric. The effect ceased when DBS was discontinued. Conclusions: DBS in the region of the nucleus accumbens produced smile and euphoria suggesting that alterations in the ventral striatum may result in emotional experience and displays. We hypothesize the existence of a limbic-motor network responsible for such changes. This observation suggests that DBS may be useful as a therapy for mood disorders.     

Deep Brain Stimulation of the Subgenual Cingulate Cortex for the Treatment of Chronic Low Back Pain

ObjectivesDespite converging basic scientific and clinical evidence of the link between chronic pain and depression, existing therapies do not often take advantage of this overlap. Here, we provide a critical review of the literature that highlights the intersection in brain networks between chronic low back pain (CLBP) and depression and discuss findings from previous deep brain stimulation (DBS) studies for pain. Based on a multidimensional model of pain processing and the connectivity of the subgenual cingulate cortex (SCC) with areas that are implicated in both CLBP and depression, we propose a novel approach to the treatment of CLBP using DBS of the SCC.Materials and MethodsA narrative review with literature assessment.ResultsCLBP is associated with a shift away from somatosensory representation toward brain regions that mediate emotional processes. There is a high degree of overlap between these regions and those involved in depression, including the anterior cingulate cortex, medial prefrontal cortex, nucleus accumbens, and amygdala. Whereas target sites from previous DBS trials for pain were not anatomically positioned to engage these areas and their associated networks, the SCC is structurally connected to all of these regions as well as others involved in mediating sensory, cognitive, and affective processing in CLBP.ConclusionsCLBP and depression share a common underlying brain network interconnected by the SCC. Current data and novel technology provide an optimal opportunity to develop clinically effective trials of SCC DBS for CLBP.     

Increased neural response to peer rejection associated with adolescent depression and pubertal development

Sensitivity to social evaluation has been proposed as a potential marker or risk factor for depression, and has also been theorized to increase with pubertal maturation. This study utilized an ecologically valid paradigm to test the hypothesis that adolescents with major depressive disorder (MDD) would show altered reactivity to peer rejection and acceptance relative to healthy controls in a network of ventral brain regions implicated in affective processing of social information. A total of 48 adolescents (ages 11–17), including 21 with a current diagnosis of MDD and 27 age- and gender-matched controls, received rigged acceptance and rejection feedback from fictitious peers during a simulated online peer interaction during functional neuroimaging. MDD youth showed increased activation to rejection relative to controls in the bilateral amygdala, subgenual anterior cingulate, left anterior insula and left nucleus accumbens. MDD and healthy youth did not differ in response to acceptance. Youth more advanced in pubertal maturation also showed increased reactivity to rejection in the bilateral amygdala/parahippocampal gyrus and the caudate/subgenual anterior cingulate, and these effects remained significant when controlling for chronological age. Findings suggest that increased reactivity to peer rejection is a normative developmental process associated with pubertal development, but is particularly enhanced among youth with depression.     

Alterations in amplitude of low frequency fluctuation in treatment‐naïve major depressive disorder measured with resting‐state fMRI

There are limited resting‐state functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD). Of these studies, functional connectivity analyses are mostly used. However, a new method based on the magnitude of low frequency fluctuation (LFF) during resting‐state fMRI may provide important insight into MDD. In this study, we examined the amplitude of LFF (ALFF) within the whole brain during resting‐state fMRI in 30 treatment‐naïve MDD subjects and 30 healthy control (HC) subjects. When compared with HC, MDD subjects showed increased ALFF in the frontal cortex (including the bilateral ventral/dorsal anterior cingulate cortex, orbitofrontal cortex, premotor cortex, ventral prefrontal cortex, left dorsal lateral frontal cortex, left superior frontal cortex), basal ganglia (including the right putamen and left caudate nucleus), left insular cortex, right anterior entorhinal cortex and left inferior parietal cortex, together with decreased ALFF in the bilateral occipital cortex, cerebellum hemisphere, and right superior temporal cortex. These findings may relate to characteristics of MDD, such as excessive self‐referential processing and deficits in cognitive control of emotional processing, which may contribute to the persistent and recurrent nature of the disorder. Hum Brain Mapp 35:4979–4988, 2014. © 2014 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Variability of white matter anatomy in the subcallosal cingulate area

The subcallosal cingulate (SCC) area is a putative hub in the brain network underlying depression. Deep brain stimulation (DBS) targeting a particular subregion of SCC, identified as the intersection of forceps minor (FM), uncinate fasciculus (UCF), cingulum and fronto‐striatal fiber bundles, may be critical to a therapeutic response in patients with severe, treatment‐resistant forms of major depressive disorder (MDD). The pattern and variability of the white matter anatomy and organization within SCC has not been extensively characterized across individuals. The goal of this study is to investigate the variability of white matter bundles within the SCC that structurally connect this region with critical nodes in the depression network. Structural and diffusion data from 100 healthy subjects from the Human Connectome Project database were analyzed. Anatomically defined SCC regions were used as seeds to perform probabilistic tractography and to estimate the connectivity from the SCC to subject‐specific target areas believed to be involved in the pathology of MDD including ventral striatum (VS), UCF, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC). Four distinct areas of connectivity were identified within SCC across subjects: (a) postero‐lateral SCC connectivity to medial temporal regions via UCF, (b) postero‐medial connectivity to VS, (c) superior‐medial connectivity to ACC via cingulum bundle, and (d) antero‐lateral connectivity to mPFC regions via forceps minor. Assuming white matter connectivity is critical to therapeutic response, the improved anatomic understanding of SCC as well as an appreciation of the intersubject variability are critical to developing optimized therapeutic targeting for SCC DBS.     

A Randomized Trial Directly Comparing Ventral Capsule and Anteromedial Subthalamic Nucleus Stimulation in Obsessive-Compulsive Disorder: Clinical and Imaging Evidence for Dissociable Effects

Background

Deep brain stimulation (DBS) is an emerging treatment for severe obsessive-compulsive disorder (OCD). We compared the efficacy of ventral capsule/ventral striatal (VC/VS) and anteromedial subthalamic nucleus (amSTN) DBS in the same patients and tested for mechanistic differences on mood and cognitive flexibility and associated neural circuitry. The possible synergistic benefit of DBS at both sites and cognitive behavioral therapy was explored.

Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia

Decreases in glial cell density and in GFAP mRNA in the anterior cingulate cortex have been reported in schizophrenia, bipolar disorder and major depressive disorder. Our study examines astrocyte and oligodendrocyte density in the white and grey matter of the subgenual cingulate cortex, and at the midline of the genu of the corpus callosum, in schizophrenia, bipolar disorder, depression and normal control cases. Serial coronal sections were stained with H and E for anatomical guidance, cresyl haematoxylin for oligodendrocyte identification and GFAP immunohistochemistry for astrocyte identification. Oligodendrocyte and astrocyte density was measured using systematic anatomical distinctions and randomised counting methods. A significant decrease in astrocyte density was observed in schizophrenia compared with normal controls in the cingulate grey matter, cingulate white matter and the midline of the corpus callosum (p = 0.025). Bipolar disorder and depression cases showed no significant changes in astrocyte density. Oligodendrocytes did not show any changes between diagnostic groups. In subgenual cingulate cortex, the ratio of oligodendrocytes to astrocytes was decreased between the controls and the three disease groups, suggesting a specific glial cell type specific change in schizophrenia.     

Neuropathic Pain and Deep Brain Stimulation

Deep brain stimulation (DBS) is a neurosurgical intervention the efficacy, safety, and utility of which are established in the treatment of Parkinson’s disease. For the treatment of chronic, neuropathic pain refractory to medical therapies, many prospective case series have been reported, but few have published findings from patients treated with current standards of neuroimaging and stimulator technology over the last decade . We summarize the history, science, selection, assessment, surgery, programming, and personal clinical experience of DBS of the ventral posterior thalamus, periventricular/periaqueductal gray matter, and latterly rostral anterior cingulate cortex (Cg24) in 113 patients treated at 2 centers (John Radcliffe, Oxford, UK, and Hospital de São João, Porto, Portugal) over 13 years. Several experienced centers continue DBS for chronic pain, with success in selected patients, in particular those with pain after amputation, brachial plexus injury, stroke, and cephalalgias including anesthesia dolorosa. Other successes include pain after multiple sclerosis and spine injury. Somatotopic coverage during awake surgery is important in our technique, with cingulate DBS under general anesthesia considered for whole or hemibody pain, or after unsuccessful DBS of other targets. Findings discussed from neuroimaging modalities, invasive neurophysiological insights from local field potential recording, and autonomic assessments may translate into improved patient selection and enhanced efficacy, encouraging larger clinical trials.     

Depression,rumination and the default network

Major depressive disorder (MDD) has been characterized by excessive default-network activation and connectivity with the subgenual cingulate. These hyper-connectivities are often interpreted as reflecting rumination, where MDDs perseverate on negative, self-referential thoughts. However, the relationship between connectivity and rumination has not been established. Furthermore, previous research has not examined how connectivity with the subgenual cingulate differs when individuals are engaged in a task or not. The purpose of the present study was to examine connectivity of the default network specifically in the subgenual cingulate both on- and off-task, and to examine the relationship between connectivity and rumination. Analyses using a seed-based connectivity approach revealed that MDDs show more neural functional connectivity between the posterior-cingulate cortex and the subgenual-cingulate cortex than healthy individuals during rest periods, but not during task engagement. Importantly, these rest-period connectivities correlated with behavioral measures of rumination and brooding, but not reflection.     

Long-term Habituation of the Smile Response with Deep Brain Stimulation

Human and animal research has shown that the ventral striatum, including the nucleus accumbens, may play a critical role in mediating positive emotions. Recently we described a subject with obsessive-compulsive disorder who intra-operatively exhibited the acute onset of an asymmetric smile and acute positive emotional change with contralateral deep brain stimulation (DBS) in either the right or left nucleus accumbens and anterior limb of the internal capsule region. The purpose of the present study was to examine the stability of the stimulation-induced smile(s) over a 12-month period. Custom computer software objectively quantified left and right facial movement during DBS. Although stimulation-induced smiles were elicited at one and two months post-surgery, they were no longer present from 3–12 months following chronic high frequency DBS. The smiles could not be elicited even with long washout periods. These findings imply potential long-term habituation and changes in the neural chemistry (possibly neuroplasticity) induced by chronic DBS.     

Long-term habituation of the smile response with deep brain stimulation

Human and animal research has shown that the ventral striatum, including the nucleus accumbens, may play a critical role in mediating positive emotions. Recently we described a subject with obsessive-compulsive disorder who intra-operatively exhibited the acute onset of an asymmetric smile and acute positive emotional change with contralateral deep brain stimulation (DBS) in either the right or left nucleus accumbens and anterior limb of the internal capsule region. The purpose of the present study was to examine the stability of the stimulation-induced smile(s) over a 12-month period. Custom computer software objectively quantified left and right facial movement during DBS. Although stimulation-induced smiles were elicited at one and two months post-surgery, they were no longer present from 3-12 months following chronic high frequency DBS. The smiles could not be elicited even with long washout periods. These findings imply potential long-term habituation and changes in the neural chemistry (possibly neuroplasticity) induced by chronic DBS.