Subcallosal Cingulate Gyrus Research Articles

ID: 332414 A Characterization of the Subcallosal Cingulate Gyrus as a Target for DBS in Treatment-Resistant Depression

ID: 332414 A Characterization of the Subcallosal Cingulate Gyrus as a Target for DBS in Treatment-Resistant Depression

Effective connectivity between deep brain stimulation targets in individuals with treatment-resistant depression.

The therapeutic effect of deep brain stimulation on patients with treatment-resistant depression is strongly dependent on the connectivity of the stimulation region with other regions associated with depression. The aims of this study are to characterize the effective connectivity between the brain regions playing important roles in depression and further investigate the underlying pathophysiological mechanisms of treatment-resistant depression and the mechanisms involving deep brain stimulation. Thirty-three individuals with treatment-resistant depression and 29 healthy control subjects were examined. All subjects underwent resting-state functional MRI scanning. The coupling parameters reflecting the causal interactions among deep brain stimulation targets and medial prefrontal cortex were estimated using spectral dynamic causal modelling. Our results showed that compared to the healthy control subjects, in the left hemisphere of treatment-resistant depression patients, the nucleus accumbens was inhibited by the inferior thalamic peduncle and excited the ventral caudate and the subcallosal cingulate gyrus, which in turn excited the lateral habenula. In the right hemisphere, the lateral habenula inhibited the ventral caudate and the nucleus accumbens, both of which inhibited the inferior thalamic peduncle, which in turn inhibited the cingulate gyrus. The ventral caudate excited the lateral habenula and the cingulate gyrus, which excited the medial prefrontal cortex. Furthermore, these effective connectivity links varied between males and females, and the left and right hemispheres. Our findings suggest that intrinsic excitatory/inhibitory connections between deep brain stimulation targets are impaired in treatment-resistant depression patients, and that these connections are sex dependent and hemispherically lateralized. This knowledge can help to better understand the underlying mechanisms of treatment-resistant depression, and along with tractography, structural imaging, and other relevant clinical information, may assist to determine the appropriate region for deep brain stimulation therapy in each treatment-resistant depression patient.

Functional brain network features specify DBS outcome for patients with treatment resistant depression.

Deep brain stimulation (DBS) has shown therapeutic benefits for treatment resistant depression (TRD). Stimulation of the subcallosal cingulate gyrus (SCG) aims to alter dysregulation between subcortical and cortex. However, the 50% response rates for SCG-DBS indicates that selection of appropriate patients is challenging. Since stimulation influences large-scale network function, we hypothesized that network features can be used as biomarkers to inform outcome. In this pilot project, we used resting-state EEG recorded longitudinally from 10 TRD patients with SCG-DBS (11 at baseline). EEGs were recorded before DBS-surgery, 1-3 months, and 6 months post surgery. We used graph theoretical analysis to calculate clustering coefficient, global efficiency, eigenvector centrality, energy, and entropy of source-localized EEG networks to determine their topological/dynamical features. Patients were classified as responders based on achieving a 50% or greater reduction in Hamilton Depression (HAM-D) scores from baseline to 12 months post surgery. In the delta band, false discovery rate analysis revealed that global brain network features (segregation, integration, synchronization, and complexity) were significantly lower and centrality of subgenual anterior cingulate cortex (ACC) was higher in responders than in non-responders. Accordingly, longitudinal analysis showed SCG-DBS increased global network features and decreased centrality of subgenual ACC. Similarly, a clustering method separated two groups by network features and significant correlations were identified longitudinally between network changes and depression symptoms. Despite recent speculation that certain subtypes of TRD are more likely to respond to DBS, in the SCG it seems that underlying brain network features are associated with ability to respond to DBS. SCG-DBS increased segregation, integration, and synchronizability of brain networks, suggesting that information processing became faster and more efficient, in those patients in whom it was lower at baseline. Centrality results suggest these changes may occur via altered connectivity in specific brain regions especially ACC. We highlight potential mechanisms of therapeutic effect for SCG-DBS.

Response and Safety Outcomes in Treatment-Resistant Depression After Subcallosal Cingulate Gyrus Deep Brain Stimulation

Response and Safety Outcomes in Treatment-Resistant Depression After Subcallosal Cingulate Gyrus Deep Brain Stimulation

Individualized targeting is warranted in subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression: A tractography analysis.

Subcallosal cingulate gyrus (SCG) is a target of deep brain stimulation (DBS) for treatment-resistant depression. However, previous randomized controlled trials report that approximately 42% of patients are responders to this therapy of last resort, and suboptimal targeting of SCG is a potential underlying factor to this unsatisfactory efficacy. Tractography has been proposed as a supplementary method to enhance targeting strategy. We performed a connectivity-based segmentation in the SCG region via probabilistic tractography in 100 healthy volunteers from the Human Connectome Project. The SCG voxels with maximum connectivity to brain regions implicated in depression, including Brodmann Area 10 (BA10), cingulate cortex, thalamus, and nucleus accumbens were identified, and the conjunctions were deemed as tractography-based targets. We then performed deterministic tractography using these targets in additional 100 volunteers to calculate streamline counts compassing to relevant brain regions and fibers. We also evaluated the intra- and inter-subject variance using test-retest dataset. Two tractography-based targets were identified. Tractography-based target-1 had the highest streamline counts to right BA10 and bilateral cingulate cortex, while tractography-based target-2 had the highest streamline counts to bilateral nucleus accumbens and uncinate fasciculus. The mean linear distance from individual tractography-based target to anatomy-based target was 3.2 ± 1.8 mm and 2.5 ± 1.4 mm in left and right hemispheres. The mean ± SD of targets between intra- and inter-subjects were 2.2 ± 1.2 and 2.9 ± 1.4 in left hemisphere, and 2.3 ± 1.4 and 3.1 ± 1.7 in right hemisphere, respectively. Individual heterogeneity as well as inherent variability from diffusion imaging should be taken into account during SCG-DBS target planning procedure.

Weekly community-based dance training over eight months reduces depression and BOLD signals in subcallosal cingulate gyrus (SCG) for people with Parkinson’s Disease: An observational study. (Preprint)

Weekly community-based dance training over eight months reduces depression and BOLD signals in subcallosal cingulate gyrus (SCG) for people with Parkinson’s Disease: An observational study. (Preprint)

PO077 / #815 CONNECTIVITY-BASED ANALYSIS OF SUBCALLOSAL CINGULATE GYRUS TARGET IN DEEP BRAIN STIMULATION FOR TREATMENT-RESISTANT DEPRESSION: E-POSTER VIEWING

Subcallosal cingulate gyrus (SCG) is established as a potential deep brain stimulation (DBS) target for treatment-resistant depression (TRD) for decades. The optimal target positioning within SCG region is still in vague. Recently, connectivity-based target analysis is proposed as a potential method to help target positioning.

A cognitive neurogenetic approach to uncovering the structure of executive functions

One central mission of cognitive neuroscience is to understand the ontology of complex cognitive functions. We addressed this question with a cognitive neurogenetic approach using a large-scale dataset of executive functions (EFs), whole-brain resting-state functional connectivity, and genetic polymorphisms. We found that the bifactor model with common and shifting-specific components not only was parsimonious but also showed maximal dissociations among the EF components at behavioral, neural, and genetic levels. In particular, the genes with enhanced expression in the middle frontal gyrus (MFG) and the subcallosal cingulate gyrus (SCG) showed enrichment for the common and shifting-specific component, respectively. Finally, High-dimensional mediation models further revealed that the functional connectivity patterns significantly mediated the genetic effect on the common EF component. Our study not only reveals insights into the ontology of EFs and their neurogenetic basis, but also provides useful tools to uncover the structure of complex constructs of human cognition.

A narrative review on invasive brain stimulation for treatment-resistant depression.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Effects of lateral habenula and ventral medial prefrontal cortex deep brain stimulation in rats

Deep brain stimulation (DBS) has promising outcomes in treatment-resistant depression (TRD). Several regions, including the subcallosal cingulate gyrus (SCG), nucleus accumbens, ventral capsule/ ventral striatum, and lateral habenula (LHb), can be targeted for TRD treatment. However, which target provides the best results remains controversial. We evaluated the antidepressant and antianxiety effects of DBS of the ventral medial prefrontal cortex (vmPFC) and LHb in stressed rats using the forced swimming test (FST) and open field test (OFT). Bilateral high-frequency DBS of the vmPFC and LHb induced a significant decrease of the immobility time compared with that of controls ( p < 0.05) in the FST. In the OFT, rats receiving vmPFC and LHb DBS showed no difference in the number of entries and time spent in the center area compared with those of control rats. However, vmPFC DBS provoked a significant decrease of these parameters compared with those of rats receiving LHb DBS ( p < 0.05). These results suggested that vmPFC and LHb DBS had similar antidepressant effects, whereas LHb DBS was more effective in reducing anxiety-like behaviors. The results provide a reference for high-frequency DSB of SCG and LHb in TRD.

Current use of deep brain stimulation for treatment-resistant depression in different geographic regions of the world

Deep brain stimulation (DBS) has emerged as a promising neurosurgical intervention for managing treatment-resistant depression (TRD). In this study, we conducted a literature review to evaluate the geographic distribution of published and ongoing clinical studies of DBS for TRD, along with documenting the anatomical sites used for electric stimulation in studies worldwide. The results showed large variation in the number of studies of DBS for TRD across different geographic regions and countries in the world, with research groups from North America and Europe contributing to 91% (n = 71) of all publications (N = 78) and 97% (n = 837) of all ongoing clinical trials (N = 867). Variation across countries also existed in the anatomical site used for stimulation, although the subcallosal cingulate gyrus was utilized most frequently overall (in 45 out of the 78 published studies), followed by the medial forebrain bundle and ventral capsule/ventral striatum including the nucleus accumbens. We conclude that DBS is increasingly being recognized worldwide as a promising intervention for TRD. To date, however, relatively few studies of DBS for TRD have been conducted by research groups from countries in Asia and Australasia. Clinical studies of DBS for TRD have come so far mainly from research groups located in North America and Europe, which poses a threat to the external validity of many reported study results, as well as representing a major challenge for future research.

Characterization of brain functional connectivity in treatment-resistant depression

ObjectiveTo characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. MethodsThirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal ‘degree’, a major feature of the graph theory. ResultsThe degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. ConclusionOur findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

Cholinergics contribute to the cellular mechanisms of deep brain stimulation applied in rat infralimbic cortex but not white matter

Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is a promising therapy for treatment-resistant depression. Pre-clinical models have been widely used to investigate the neural mechanisms underlying its antidepressant benefit. The ventral division of the medial prefrontal cortex (vmPFC), particularly the infralimbic cortex (IL), is the homologous region in rat and DBS applied to vmPFC shows antidepressant-like effects in the forced swim test. Therefore we investigated the cellular mechanisms of simulated DBS (sDBS) in layer 5 IL neurons, using in vitro whole-cell patch clamp recordings. sDBS in IL layer 5 induced a prolonged after-depolarization (ADP) in both pyramidal and fast spiking neurons, which was dependent on current amplitude and pulse width. In contrast, sDBS applied in the forebrain white matter fibers, although delivered at a higher intensity, failed to induce any persistent depolarization in layer 5 IL pyramidal neurons. Cholinergic blockade (atropine, 2.0 µM) decreased both the ADP amplitude and duration in pyramidal neurons, but left those in fast spiking neurons unchanged. These data suggest that: (i) sDBS in IL gray and white matter produced different cellular effects on pyramidal neurons; (ii) sDBS-induced ADP in pyramidal, but not fast spiking neurons, was mediated by acetylcholine; and (iii) different neuromodulators may contribute to sDBS-induced ADP in IL. In summary, cholinergic mediated ADP in pyramidal neurons may contribute to the antidepressant effects of DBS in IL.

Experts Debate What's Next for DBS for Depression

Experts Debate What's Next for DBS for Depression

Neuroanatomical predictors of response to subcallosal cingulate deep brain stimulation for treatment-resistant depression

Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a >50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Normalization by intracranial volume nullified some between-group differences in volumetric measures. There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

Resting-State Functional Connectivity in Popular Targets for Deep Brain Stimulation in the Treatment of Major Depression: An Application of a Graph Theory.

We examined the functional connectivity of subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), and ventral caudate (VCa), the main target areas for the treatment of major depression disorder (MDD), using deep brain stimulation (DBS). MDD is one of the most common diseases in the world, and approximately 30% of MDD patients do not respond to common therapies, including psychotherapy and antidepressant medications. Alternatively, DBS has been recently used to treat MDD. Resting state fMRI was obtained from seventeen healthy subjects and seven MDD patients. The functional connectivity network of the brain was constructed for all subjects and measured by the `degree' value for each SCG, NAc, and VCa regions using the graph theory analysis. The results show that the degree values of VCa and the left SCG are higher in the MDD group than the healthy group. Furthermore, the patterns of the degree values were different for the right and left hemispheres in MDD patients. Our findings suggest that degree values and their patterns have a potential to be used as diagnosis tools to detect the brain areas with abnormal functional connectivity.

Evaluation of brain volume alterations in HCV-infected patients after interferon-free therapy: A pilot study

The study was performed to evaluate cerebral volume changes in HCV-infected subjects before and after interferon-free therapy with direct-acting antiviral agents (DAA). We aimed also to estimate the impact of successful DAA therapy on the neuropsychological state of patients. Eleven HCV genotype 1 (GT1) patients treated with ombitasvir/paritaprevir (boosted with ritonavir) and dasabuvir, with or without ribavirin underwent brain magnetic resonance (MR) before and 24 weeks after completion of therapy. All patients achieved sustained viral response. Precise automatic parcellation was made using the fully-available software FreeSurfer 6.0. Statistically significant volume deceleration six months after treatment was found in the subcallosal cingulate gyrus, transverse frontopolar gyri and sulci, anterior segment of the circular sulcus of the insula and horizontal ramus of the anterior segment of the lateral sulcus. After DAA therapy we found statistically significant improvement in the performance of all three tasks of the Rey Complex Figure Test that permits the evaluation of different functions (attention, planning, working,memory). Additionally, significant amelioration in Percentage Conceptual Level Responses in The Wisconsin Card Sorting Test (a neurocognitive test for assessing intellectual functioning) was also discovered. Successful interferon-free therapy may lead to transient cerebral atrophy, probably by reducing neuroinflammation and oedema. This is the first pilot study of the alterations in brain volume after successful interferon-free therapy in chronic HCV patients. Longitudinal follow-up study is needed to observe further effects of therapy on cerebral structures volume changes.

Stereotactic ablative surgery versus deep brain stimulation for treatment-resistant depression: a review of clinical efficacy

Introduction: For the most severe cases of treatment-resistant depression (TRD), stereotactic lesions may be placed in the anterior cingulum bundle and/ or internal capsule to ameliorate symptoms of depression. Deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG) or in the ventral capsule/ ventral striatum (VS/VS) has been proposed as a reversible, titratable alternative to lesioning. The aim of this review is to summarize findings from stereotactic ablative surgery and DBS trials for TRD.

Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications.

Although deep brain stimulation (DBS) is an established treatment choice for Parkinson's disease (PD), essential tremor and movement disorders, its effectiveness for the management of treatment-resistant depression (TRD) remains unclear. Herein, we conducted an integrative review on major neuroanatomical targets of DBS pursued for the treatment of intractable TRD. The aim of this review article is to provide a critical discussion of possible underlying mechanisms for DBS-generated antidepressant effects identified in preclinical studies and clinical trials, and to determine which brain target(s) elicited the most promising outcomes considering acute and maintenance treatment of TRD. Major electronic databases were searched to identify preclinical and clinical studies that have investigated the effects of DBS on depression-related outcomes. Overall, 92 references met inclusion criteria, and have evaluated six unique DBS targets namely the subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), ventral capsule/ventral striatum or anterior limb of internal capsule (ALIC), medial forebrain bundle (MFB), lateral habenula (LHb) and inferior thalamic peduncle for the treatment of unrelenting TRD. Electrical stimulation of these pertinent brain regions displayed differential effects on mood transition in patients with TRD. In addition, 47 unique references provided preclinical evidence for putative neurobiological mechanisms underlying antidepressant effects of DBS applied to the ventromedial prefrontal cortex, NAc, MFB, LHb and subthalamic nucleus. Preclinical studies suggest that stimulation parameters and neuroanatomical locations could influence DBS-related antidepressant effects, and also pointed that modulatory effects on monoamine neurotransmitters in target regions or interconnected brain networks following DBS could have a role in the antidepressant effects of DBS. Among several neuromodulatory targets that have been investigated, DBS in the neuroanatomical framework of the SCG, ALIC and MFB yielded more consistent antidepressant response rates in samples with TRD. Nevertheless, more well-designed randomized double-blind, controlled trials are warranted to further assess the efficacy, safety and tolerability of these more promising DBS targets for the management of TRD as therapeutic effects have been inconsistent across some controlled studies.

A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression

BackgroundDeep brain stimulation (DBS) has been applied in treatment-resistant depression (TRD) as a putative intervention targeting different brain regions. However, the antidepressant effects of DBS for TRD in recent clinical trials remain controversial. MethodsWe searched Scopus, EMBASE, the Cochrane Library, PubMed, and PsycINFO for all published studies investigating the efficacy of DBS in TRD up to Feb 2017. Hamilton depression rating scale (HDRS) scores and Montgomery–Asberg depression rating scale (MARDS) scores were compared between baseline levels and those after DBS using the standardized mean difference (SMD) with 95% confidence intervals (CIs). The pooled response and remission rates were described using Risk Difference with 95% CIs. ResultsWe identified 14 studies of DBS in TRD targeting the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), medial forebrain bundle (MFB), and nucleus accumbens (NAcc). The overall effect sizes showed a significant reduction in HDRS after DBS stimulation in these four regions, with a standardized mean difference of −3.02 (95% CI=−4.28 to −1.77, p<0.00001) for SCG, −1.64 (95% CI=−2.80 to −0.49, p=0.005) for VC/VS, −2.43 (95% CI=−3.66 to −1.19, p=0.0001) for MFB, and −1.30 (95% CI=−2.16 to −0.44, p=0.003) for NAcc. DBS was effective, with high response rates at 1, 3, 6, and 12months. Some adverse events (AEs), especially some specific AEs related to targeting regions, occurred during the DBS treatment. ConclusionsDBS significantly alleviates depressive symptoms in TRD patients by targeting the SCG, VC/VS, MFB, and NAcc. Several adverse events might occur during DBS therapy, although it is uncertain whether some AEs can be linked to DBS treatment. Further confirmatory trials are required involving larger sample sizes.