Subcallosal Cingulate Research Articles

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.

Avoiding monetary loss: A human habenula functional MRI ultra-high field study

A number of convergent human neuroimaging and animal studies suggest that habenula neurons fire in anticipation of non-rewarding outcomes, and suppress their firing in anticipation of rewarding outcomes. This normative function of the habenula appears disrupted in depression, and may be critical to the anti-depressant effects of ketamine. However, studying habenula functionality in humans using standard 3 T MRI is inherently limited by its small size. We employed ultra-high field (7 T) fMRI to investigate habenular activity in eighteen healthy volunteers during a Monetary Incentive Delay Task, focussing on loss avoidance, monetary loss and neutral events. We assessed neural activation in the field of view (FOV) in addition to ROI-based habenula-specific activity and generalized task-dependent functional connectivity. Whole FOV results indicated substantial neural differences between monetary loss and neutral outcomes, as well as between loss avoidance and neutral outcomes. Habenula-specific analyses showed bilateral deactivation during loss avoidance, compared to other outcomes. This first investigation into the habenula's role during loss avoidance revealed that the left habenula further differentiated between loss avoidance and monetary loss. Functional connectivity between the right habenula and the ipsilateral hippocampus and subcallosal cingulate (regions implicated in memory and depression pathophysiology) was enhanced when anticipating potential losses compared to anticipating neutral outcomes. Our findings suggest that the human habenula responds most strongly to outcomes of loss avoidance when compared to neutral and monetary losses, suggesting a role for the habenula in both reward and aversive processing. This has critical relevance to understanding the pathophysiology of habenula function in mood and other neuropsychiatric disorders, as well as the mechanism of action of habenula-targeting antidepressants such as ketamine.

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.

Functional Connectivity Profiles of Subcallosal Cingulate Cortex Deep Brain Stimulation for Treatment Resistant Depression

Subcallosal cingulate cortex (SCC) deep brain stimulation (DBS) is an experimental intervention for treatment-resistant depression (TRD). Little, however, is known about initial brain state patterns that might predict outcome. The objective of this study is to examine individual functional connectivity (FC) profiles of the SCC DBS target and test if the functional connectivity profile of effective SCC DBS can predict long-term response.

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.

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.

Left versus right subcallosal cingulate deep brain stimulation for treatment-resistant depression

Deep brain stimulation (DBS) of the subcallosal cingulate has emerged as a promising therapy for treatment-resistant depression (TRD). To date, all studies have employed bilateral stimulation; however, the physiology of affect and pathophysiology of depression are known to be asymmetric across hemispheres. Unilateral stimulation may provide efficacy while decreasing risk. Five patients were exposed to unilateral open-label DBS to the subcallosal cingulate for 12 weeks each to the left and then right hemispheres in a double-blind, crossover fashion. After 12 weeks of stimulation to each hemisphere, bilateral stimulation was initiated, and patients were followed for 12 additional weeks. Additionally, nine months of long-term follow up data were collected. Left, but not right, unilateral stimulation was associated with significant decrease in depression scores; with bilateral stimulation, all patients improved and one patient remitted. No serious adverse events were associated with surgery or acute or chronic stimulation. This small study suggests that unilateral DBS to the subcallosal cingulate may be an effective treatment for TRD. All patients improved with bilateral stimulation, though antidepressant effects following 12 weeks were modest. These findings contrast somewhat with prior open-label trials, though duration of bilateral stimulation was shorter in this trial. The current study continues to confirm safety of implantation and use of DBS to the subcallosal cingulate for patients with TRD and highlights the importance of personalization of therapy, for example by hemisphere, in future trials.

The prediction of resilience to alcohol consumption in youths: insular and subcallosal cingulate myeloarchitecture.

The prediction of alcohol consumption in youths and particularly biomarkers of resilience, is critical for early intervention to reduce the risk of subsequent harmful alcohol use. At baseline, the longitudinal relaxation rate (R1), indexing grey matter myelination (i.e. myeloarchitecture), was assessed in 86 adolescents/young adults (mean age = 21.76, range: 15.75-26.67 years). The Alcohol Use Disorder Identification Test (AUDIT) was assessed at baseline, 1- and 2-year follow-ups (12- and 24-months post-baseline). We used a whole brain data-driven approach controlled for age, gender, impulsivity and other substance and behavioural addiction measures, such as problematic cannabis use, drug use-related problems, internet gaming, pornography use, binge eating, and levels of externalization, to predict the change in AUDIT scores from R1. Greater baseline bilateral anterior insular and subcallosal cingulate R1 (cluster-corrected family-wise error p < 0.05) predict a lower risk for harmful alcohol use (measured as a reduction in AUDIT scores) at 2-year follow-up. Control analyses show that other grey matter measures (local volume or fractional anisotropy) did not reveal such an association. An atlas-based machine learning approach further confirms the findings. The insula is critically involved in predictive coding of autonomic function relevant to subjective alcohol cue/craving states and risky decision-making processes. The subcallosal cingulate is an essential node underlying emotion regulation and involved in negative emotionality addiction theories. Our findings highlight insular and cingulate myeloarchitecture as a potential protective biomarker that predicts resilience to alcohol misuse in youths, providing novel identifiers for early intervention.

A Decade of Progress in Deep Brain Stimulation of the Subcallosal Cingulate for the Treatment of Depression.

Major depression contributes significantly to the global disability burden. Since the first clinical study of deep brain stimulation (DBS), over 446 patients with depression have now undergone this neuromodulation therapy, and 29 animal studies have investigated the efficacy of subgenual cingulate DBS for depression. In this review, we aim to provide a comprehensive overview of the progress of DBS of the subcallosal cingulate in humans and the medial prefrontal cortex, its rodent homolog. For preclinical animal studies, we discuss the various antidepressant-like behaviors induced by medial prefrontal cortex DBS and examine the possible mechanisms including neuroplasticity-dependent/independent cellular and molecular changes. Interestingly, the response rate of subcallosal cingulate Deep brain stimulation marks a milestone in the treatment of depression. DBS achieved response and remission rates of 64–76% and 37–63%, respectively, from clinical studies monitoring patients from 6–24 months. Although some studies showed its stimulation efficacy was limited, it still holds great promise as a therapy for patients with treatment-resistant depression. Overall, further research is still needed, including more credible clinical research, preclinical mechanistic studies, precise selection of patients, and customized electrical stimulation paradigms.

Efficacy of Deep Brain Stimulation: Subcallosal Cingulate Cortex Activity Holds the Key

Depressed people show hyperactivity in the subgenual anterior cingulate cortex (Brodmann area 25), and those with less hyperactivity in this area have

Dorsolateral Prefrontal Cortex and Subcallosal Cingulate Connectivity Show Preferential Antidepressant Response in Major Depressive Disorder

BackgroundMajor depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. MethodsEMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, −1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. ResultsGreater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). ConclusionsThe level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.

Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression (TRD), but response rates in open-label studies were not replicated in a large multicenter trial. Identifying biomarkers of response could improve patient selection and outcomes. We examined SCC metabolic activity as both a predictor and marker of SCC DBS treatment response. Brain glucose metabolism (CMRGlu) was measured with [18F] FDG-PET at baseline and 6 months post DBS in 20 TRD patients in a double-blind randomized controlled trial where two stimulation types (long pulse width (LPW) n = 9 and short pulse width (SPW) n = 11) were used. Responders (n = 10) were defined by a ≥48% reduction in Hamilton Depression Rating Scale scores after 6 months. The response rates were similar with five responders in each stimulation group: LPW (55.6%) and SPW (44.5%). First, differences in SCC CMRGlu in responders and non-responders were compared at baseline. Then machine learning analysis was performed with a leave-one-out cross-validation using a Gaussian naive Bayes classifier to test whether baseline CMRGlu in SCC could categorize responders. Finally, we compared 6-month change in metabolic activity with change in depression severity. All analyses were controlled for age. Baseline SCC CMRGlu was significantly higher in responders than non-responders. The machine learning analysis predicted response with 80% accuracy. Furthermore, reduction in SCC CMRGlu 6 months post DBS correlated with symptom improvement (r(17) = 0.509; p = 0.031). This is the first evidence of an image-based treatment selection biomarker that predicts SCC DBS response. Future studies could utilize SCC metabolic activity for prospective patient selection.

A Randomized Trial of Deep Brain Stimulation to the Subcallosal Cingulate and Nucleus Accumbens in Patients with Treatment-Refractory, Chronic, and Severe Anorexia Nervosa: Initial Results at 6 Months of Follow Up

Background: The main objective of this study was to assess the safety and efficacy of deep brain stimulation (DBS) in patients with severe anorexia nervosa (AN). Methods: Eight participants received active DBS to the subcallosal cingulate (SCC) or nucleus accumbens (NAcc) depending on comorbidities (affective or anxiety disorders, respectively) and type of AN. The primary outcome measure was body mass index (BMI). Results: Overall, we found no significant difference (p = 0.84) between mean preoperative and postoperative (month 6) BMI. A BMI reference value (BMI-RV) was calculated. In patients that received preoperative inpatient care to raise the BMI, the BMI-RV was defined as the mean BMI value in the 12 months prior to surgery. In patients that did not require inpatient care, the BMI-RV was defined as the mean BMI in the 3-month period before surgery. This value was compared to the postoperative BMI (month 6), revealing a significant increase (p = 0.02). After 6 months of DBS, five participants showed an increase of ≥10% in the BMI-RV. Quality of life was improved (p = 0.03). Three cases presented cutaneous complications. Conclusion: DBS may be effective for some patients with severe AN. Cutaneous complications were observed. Longer term data are needed.

Subcallosal Cingulate Structural Connectivity Differs in Responders and Nonresponders to Electroconvulsive Therapy

BackgroundSubcallosal cingulate (SCC) activity is associated with treatment response in major depressive disorder (MDD). Using electroconvulsive therapy (ECT) as a treatment model in this exploratory study, we addressed whether pretreatment SCC structural connectivity with corticolimbic-striatal circuitry relates to therapeutic outcome and whether these connectivity patterns change with treatment. MethodsDiffusion magnetic resonance imaging scans were acquired in 43 patients with MDD (mean [SD] age = 41 [13] years; men/women: 18/25) before and within 1 week of completing an ECT index series and in 31 healthy control subjects scanned twice (mean [SD] age = 38 [11] years; men/women: 17/18). Probabilistic tractography from subject-specific anatomically defined SCC seed regions to the ventral striatum (VS), anterior cingulate cortex (ACC), and bilateral medial prefrontal cortex (mPFC) was used to estimate structural connectivity in the target network. ResultsSCC-mPFC connectivity was lower in responders (>50% symptom improvement) than nonresponders both before (p < .014) (difference 37%–96% left and right hemispheres) and after (p = .023) (difference 100% right hemisphere) treatment. SCC-mPFC connectivity in responders was also decreased compared with control subjects both at baseline (p = .012) and after ECT (p = .006), whereas nonresponders had SCC–right mPFC connectivity similar to that of control subjects. Subjects with MDD also showed decreased SCC-ACC connectivity compared with control subjects (baseline: p < .003, after ECT: p = .001), although SCC-ACC connectivity did not distinguish responders from nonresponders. Bilateral SCC-VS connectivity decreased (11%) with ECT (p = .021) regardless of treatment response. ConclusionsWhile SCC-ACC connectivity may be a hallmark of MDD compared with control subjects, lower pretreatment SCC-mPFC connectivity in ECT responders (compared with nonresponders and control subjects) suggests that connectivity in this pathway may serve as a potential biomarker of therapeutic outcome and be relevant for treatment selection.

S50. COGNITION AND EMOTION REGULATION IN SCHIZOPHRENIA PATIENTS WITH A HISTORY OF AGGRESSION

BackgroundStudies have shown a convergence of neural systems implicated in cognitive control and social emotional functions with mechanisms involved in emotion regulation, awareness, and impulsive aggression. In a sample of patients with a history of aggression, we examined the association of cognitive and social cognitive functions with emotion regulation capacity, emotional awareness, impulse control, and aggression.MethodsParticipants were 78 individuals with schizophrenia or schizoaffective disorder that participated in a cognitive training study. Emotion regulation capacity was indexed by obtaining participants’ heart rate variability (HRV), respiration, and skin conductance while participants viewed pictures selected from the International Affective Picture System (IAPS). Three blocks of pictures were presented—a neutral block depicting pictures of everyday objects preceded by audio recordings of their description; an emotionally-evocative block preceded by their description, and a reappraisal block of emotionally-evocative pictures preceded by reappraisal statements. A subset of participants (N=37) completed the emotion regulation task. The MATRICS Consensus Cognitive Battery (MCCB), the Reading the Mind in the Eyes Task (Eyes Task), and the Emotion Recognition-40 (ER-40) were administered to assess cognitive functioning, mentalizing, and facial affect recognition respectively. Negative affectivity was captured using the Positive and Negative Affect Schedule (PANAS) whereas aggression was measured with the Taylor Aggression Paradigm (TAP) and the Overt Aggression Scale Modified (OAS-M).In a smaller subsample of 12 individuals, we performed analyses of activation patterns during the performance of the emotion regulation task. Regions of interest (ROI) included the dACC, DLPFC, VLPFC, vmPFC, left and right amygdala, and the subcallosal cingulate. We created a regional mask of the cognitive control and emotional appraisal regions for event-related fMRI.ResultsThere were inverse associations between performance on the MCCB and the Eyes Task and indices of emotion regulation capacity—in particular, significant associations were obtained with Low Frequency/High Frequency HRV ratio (r=-0.324, p<0.05) and SCL (r=-0.331, p<0.05). Both HRV and respiration measures were inversely correlated with aggression measured with the TAP suggesting an association between reduced emotion regulation capacity and a risk for aggression.There were inverse associations between activation within the event-related regional mask and low frequency/high frequency heart rate variability ratio at rest (r=-0.504, p=0.095) and during the viewing of emotionally-evocative pictures (r = -0.264, p=0.36). Associations with HRV were especially remarkable for the dorsomedial, ventrolateral, and right amygdala regions.Remarkably, increased activation in the regional mask when reappraisal statements were provided with emotionally-evocative pictures was inversely correlated with the life history of aggression LHA (r=-0.32, p=0.28, n=14) and OAS (r=-0.284, p=0.34, n=14) aggression scores. This pattern was present when the dACC, right and left amygdala, DLPFC, VLPFC, and the subcallosal cingulate were set as the seed region.DiscussionThe results show an association between cognitive functions and emotion regulation capacity indexed by measuring physiological arousal during the performance of the picture viewing task. Emotion regulation capacity also showed significant association with aggression. Deficits in cognitive and social cognitive abilities may contribute to and be viable targets for improving emotion regulation capacity and decreasing aggression risk.

Perturbation-Based Mapping of Subcallosal Cingulate With Deep Brain Stimulation: Cortical Oscillatory Dynamics to Confirm Target for Electrical Neuromodulation

Perturbation-based mapping is an emerging approach to the study of circuit dynamics in the living human brain. Pulses of deep brain stimulation (DBS) to the subcallosal cingulate (SCC) evoke a coherent and reliable cortical response, recorded on the scalp surface with dense array EEG, that may reflect endogenous network dynamics. As precision targeting within the SCC region has been linked to DBS treatment efficacy, we examined features of the cortical perturbation map that change when stimulation is delivered to different locations within the surgical target region.

Subcallosal Cingulate Resting State Connectivity Responses to Cognitive Behavioral Therapy in Depression

Aberrant activity of the subcallosal cingulate cortex (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses on resting-state fMRI data (rsFC), collected before and after cognitive behavioral therapy in patients with major depressive disorder (MDD), using seeds from three subdivisions of the SCC.

Improved Rapid Effects of Deep Brain Stimulation in the Subcallosal Cingulate

Deep Brain Stimulation of the Subcallosal Cingulate (SCC-DBS) is a promising therapy for Treatment-Resistant Depression. In most studies, antidepressant effects were evidenced in clinical endpoints around 6 months. Intraoperative stimulation (IOS) effects have been reported, as well as rapid relief of depression in the days after the surgery. Understanding of the contributing factors to this rapid effect is essential to the future design and implementation of standardized surgical protocols.

Longitudinal Changes in Subcallosal Cingulate Local Field Potential Features in Patients Undergoing DBS for Treatment-Resistant Depression

Subcallosal cingulate deep brain stimulation (SCC DBS) has shown promising results in treatment-resistant depression (TRD). Understanding of the local effects of DBS in targeted region could advance effective stimulation strategies. We report changes in response to acute stimulation in six SCC DBS patients that may reflect adaptive processes that underly therapeutic effects of DBS.

Experts Debate What's Next for DBS for Depression

Experts Debate What's Next for DBS for Depression