Subcallosal Cingulate Research Articles

Noninvasive modulation of subcallosal cingulate and depression with focused ultrasonic waves

BackgroundSevere forms of depression have been linked to excessive subcallosal cingulate (SCC) activity. Stimulation of SCC with surgically implanted electrodes can alleviate depression, but current noninvasive techniques cannot directly and selectively modulate deep targets. We developed a new noninvasive neuromodulation approach that can deliver low-intensity focused ultrasonic waves to the SCC. Methods: Twenty-two subjects with treatment-resistant depression participated in a randomized, double-blind, sham-controlled study. Ultrasonic stimulation was delivered to bilateral SCC during concurrent functional MRI to quantify target engagement. Mood state was measured with the Sadness subscale of the Positive and Negative Affect Schedule before and after 40 minutes of real or sham SCC stimulation. Change in depression severity was measured with the 6-item Hamilton Depression Rating Scale (HDRS- 6) at 24 hours and 7 days. Results: Functional MRI demonstrated a target-specific decrease in SCC activity during stimulation (p=0.028, n=16). In 7 of 16 participants, SCC neuromodulation was detectable at the individual-subject level with a single 10-minute scan (p<0.05, small-volume-correction). Mood and depression scores improved more with real than with sham stimulation. In the per-protocol sample (n=19), real stimulation was superior to sham for HDRS-6 at 24 hours and for Sadness (both p<0.05, d>1). Non-significant trends were found in the intent-to-treat sample. Conclusions: This small pilot study indicates that ultrasonic stimulation modulates SCC activity and can rapidly reduce depressive symptoms. The capability to noninvasively and selectively target deep brain areas creates new possibilities for future development of circuit-directed therapeutics, and for the dissection of deep-brain circuit function in humans.

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

Structural connectivity modifications following deep brain stimulation of the subcallosal cingulate and nucleus accumbens in severe anorexia nervosa.

Anorexia nervosa (AN) is a mental health disorder characterized by significant weight loss and associated medical and psychological comorbidities. Conventional treatments for severe AN have shown limited effectiveness, leading to the exploration of novel interventional strategies, including deep brain stimulation (DBS). However, the neural mechanisms driving DBS interventions, particularly in psychiatric conditions, remain uncertain. This study aims to address this knowledge gap by examining changes in structural connectivity in patients with severe AN before and after DBS. Sixteen participants, including eight patients with AN and eight controls, underwent baseline T1-weigthed and diffusion tensor imaging (DTI) acquisitions. Patients received DBS targeting either the subcallosal cingulate (DBS-SCC, N = 4) or the nucleus accumbens (DBS-NAcc, N = 4) based on psychiatric comorbidities and AN subtype. Post-DBS neuroimaging evaluation was conducted in four patients. Data analyses were performed to compare structural connectivity between patients and controls and to assess connectivity changes after DBS intervention. Baseline findings revealed that structural connectivity is significantly reduced in patients with AN compared to controls, mainly regarding callosal and subcallosal white matter (WM) tracts. Furthermore, pre- vs. post-DBS analyses in AN identified a specific increase after the intervention in two WM tracts: the anterior thalamic radiation and the superior longitudinal fasciculus-parietal bundle. This study supports that structural connectivity is highly compromised in severe AN. Moreover, this investigation preliminarily reveals that after DBS of the SCC and NAcc in severe AN, there are WM modifications. These microstructural plasticity adaptations may signify a mechanistic underpinning of DBS in this psychiatric disorder.

268. Subcallosal Cingulate Deep Brain Stimulation for Depression: Long-Term Safety and Effectiveness Outcomes From a Pooled Analysis of 172 Patients

268. Subcallosal Cingulate Deep Brain Stimulation for Depression: Long-Term Safety and Effectiveness Outcomes From a Pooled Analysis of 172 Patients

267. Clinical and Functional Efficacy of Long-Term Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

267. Clinical and Functional Efficacy of Long-Term Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

Developing and Validating Marker of Treatment Response for Subcallosal Cingulate Deep Brain Stimulation

Developing and Validating Marker of Treatment Response for Subcallosal Cingulate Deep Brain Stimulation

Emerging Outlook on Personalized Neuromodulation for Depression: Insights From Tractography-Based Targeting

BackgroundDeep brain stimulation has shown promise in treating individual patients with treatment-resistant depression, but larger-scale trials have been less successful. Here, we created what is, to our knowledge, the largest meta-analysis with individual patient data to date to explore whether the use of tractography enhances the efficacy of deep brain stimulation for treatment-resistant depression. MethodsWe systematically reviewed 1823 articles, selecting 32 that contributed data from 366 patients. We stratified the individual patient data based on stimulation target and use of tractography. Using 2-way type III analysis of variance, Welch’s 2-sample t tests, and mixed-effects linear regression models, we evaluated changes in depression severity 1 year (9–15 months) postoperatively and at last follow-up (4 weeks to 8 years) as assessed by depression scales. ResultsTractography was used for medial forebrain bundle (MFB) (n = 17 tractography/32 total), subcallosal cingulate (SCC) (n = 39 tractography/241 total), and ventral capsule/ventral striatum (n = 3 tractography/41 total) targets; it was not used for bed nucleus of stria terminalis (n = 11), lateral habenula (n = 10), and inferior thalamic peduncle (n = 1). Across all patients, tractography significantly improved mean depression scores at 1 year (p < .001) and last follow-up (p = .009). Within the target cohorts, tractography improved depression scores at 1 year for both MFB and SCC, though significance was met only at the α = 0.1 level (SCC: β = 15.8%, p = .09; MFB: β = 52.4%, p = .10). Within the tractography cohort, patients with MFB tractography showed greater improvement than patients with SCC tractography (72.42 ± 7.17% vs. 54.78 ± 4.08%) at 1 year (p = .044). ConclusionsOur findings underscore the promise of tractography in deep brain stimulation for treatment-resistant depression as a method for personalization of therapy, supporting its inclusion in future trials.

Brain mechanisms underlying the emotion processing bias in treatment-resistant depression

Depression is associated with a cognitive bias towards negative information and away from positive information. This biased emotion processing may underlie core depression symptoms, including persistent feelings of sadness and a reduced capacity to experience pleasure. The neural mechanisms responsible for this biased emotion processing remain unknown. Here we had a unique opportunity to record stereotactic electroencephalography signals in the amygdala and prefrontal cortex (PFC) from 5 patients with treatment-resistant depression (TRD) and 12 patients with epilepsy (as control) while they participated in an affective bias task in which happy and sad faces were evaluated. First, compared with the control group, patients with TRD showed increased amygdala responses to sad faces in the early stage (around 300 ms) and decreased amygdala responses to happy faces in the late stage (around 600 ms) following the onset of faces. Furthermore, during the late stage of happy-face processing, alpha-band activity in the PFC as well as alpha-phase locking between the amygdala and the PFC were significantly greater in patients with TRD compared with the control group. The increased amygdala activation during the early stage of sad-face processing suggests an overactive bottom-up processing system in TRD. Meanwhile, the reduced amygdala response during the late stage of happy-face processing could be attributed to increased top-down inhibition by the PFC through alpha-band oscillation, which may be relieved following deep brain stimulation in the subcallosal cingulate and the ventral capsule/ventral striatum.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Multimodal imaging measures in the prediction of clinical response to deep brain stimulation for refractory depression: A machine learning approach

Objectives This study compared machine learning models using unimodal imaging measures and combined multi-modal imaging measures for deep brain stimulation (DBS) outcome prediction in treatment resistant depression (TRD). Methods Regional brain glucose metabolism (CMRGlu), cerebral blood flow (CBF), and grey matter volume (GMV) were measured at baseline using 18F-fluorodeoxy glucose (18F-FDG) positron emission tomography (PET), arterial spin labelling (ASL) magnetic resonance imaging (MRI), and T1-weighted MRI, respectively, in 19 patients with TRD receiving subcallosal cingulate (SCC)-DBS. Responders (n = 9) were defined by a 50% reduction in HAMD-17 at 6 months from the baseline. Using an atlas-based approach, values of each measure were determined for pre-selected brain regions. OneR feature selection algorithm and the naïve Bayes model was used for classification. Leave-out-one cross validation was used for classifier evaluation. Results The performance accuracy of the CMRGlu classification model (84%) was greater than CBF (74%) or GMV (74%) models. The classification model using the three image modalities together led to a similar accuracy (84%0 compared to the CMRGlu classification model. Conclusions CMRGlu imaging measures may be useful for the development of multivariate prediction models for SCC-DBS studies for TRD. The future of multivariate methods for multimodal imaging may rest on the selection of complementing features and the developing better models.Clinical Trial Registration: ClinicalTrials.gov (#NCT 01983904)

Prefrontal network engagement by deep brain stimulation in limbic hubs.

Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). We demonstrate a shared frontotemporal circuit consisting of the ventromedial prefrontal cortex, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found participant-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

Stereo-EEG-guided network modulation for psychiatric disorders: Interactive holographic planning

BackgroundConnectomic modeling studies are expanding understanding of the brain networks that are modulated by deep brain stimulation (DBS) therapies. However, explicit integration of these modeling results into prospective neurosurgical planning is only beginning to evolve. One challenge of employing connectomic models in patient-specific surgical planning is the inherent 3D nature of the results, which can make clinically useful data integration and visualization difficult. MethodsWe developed a holographic stereotactic neurosurgery research tool (HoloSNS) that integrates patient-specific brain models into a group-based visualization environment for interactive surgical planning using connectomic hypotheses. HoloSNS currently runs on the HoloLens 2 platform and it enables remote networking between headsets. This allowed us to perform surgical planning group meetings with study co-investigators distributed across the country. ResultsWe used HoloSNS to plan stereo-EEG and DBS electrode placements for each patient participating in a clinical trial (NCT03437928) that is targeting both the subcallosal cingulate and ventral capsule for the treatment of depression. Each patient model consisted of multiple components of scientific data and anatomical reconstructions of the head and brain (both patient-specific and atlas-based), which far exceed the data integration capabilities of traditional neurosurgical planning workstations. This allowed us to prospectively discuss and evaluate the positioning of the electrodes based on novel connectomic hypotheses. ConclusionsThe 3D nature of the surgical procedure, brain imaging data, and connectomic modeling results all highlighted the utility of employing holographic visualization to support the design of unique clinical experiments to explore brain network modulation with DBS.

Stereo-EEG-guided network modulation for psychiatric disorders: Surgical considerations

BackgroundDeep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. Objective/Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. MethodsWe implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. ResultsIntraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). ConclusionThis novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.

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.

Right inferior frontal gyrus theta-burst stimulation reduces smoking behaviors and strengthens fronto-striatal-limbic resting-state functional connectivity: a randomized crossover trial.

Functional and anatomical irregularities in the right inferior frontal gyrus (rIFG), a ventrolateral prefrontal region that mediates top-down inhibitory control over prepotent behavioral responding, are implicated in the ongoing maintenance of nicotine dependence (ND). However, there is little research on the effects of neuromodulation of the rIFG on smoking behavior, inhibitory control, and resting-state functional connectivity (rsFC) among individuals with ND. In this double-blind, crossover, theta-burst stimulation (TBS) study, adults with ND (N = 31; female: n = 15) completed a baseline session and were then randomized to two counterbalanced sessions of functionally neuronavigated TBS to the rIFG: continuous TBS (cTBS) on 1 day and intermittent TBS (iTBS) on another. Differences in cigarette cravings, smoking, and fronto-striatal-limbic rsFC were assessed. Relative to baseline, cTBS significantly reduced appetitive and withdrawal cravings immediately after treatment. The effects of cTBS on withdrawal craving persisted for 24 h, as well as produced a reduction in smoking. Furthermore, cTBS significantly strengthened rsFC between the rIFG pars opercularis and subcallosal cingulate (fronto-striatal circuit), and between the rIFG pars opercularis and the right posterior parahippocampal gyrus (fronto-limbic circuit). At post-24 h, cTBS-induced increase in fronto-striatal rsFC was significantly associated with less appetitive craving, while the increase in fronto-limbic rsFC was significantly associated with less withdrawal craving and smoking. These findings warrant further investigation into the potential value of rIFG cTBS to attenuate smoking behavior among individuals with ND.

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

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.

437. A Novel Subcallosal Cingulate Biomarker of Deep Brain Stimulation Mediated Stable Depression Recovery

437. A Novel Subcallosal Cingulate Biomarker of Deep Brain Stimulation Mediated Stable Depression Recovery

208 DBS-Induced Improvement in Cognitive Control is Mediated by Theta Oscillations in Human Intracranial Recordings

INTRODUCTION: Deficits in cognitive control, defined as the ability to adjust response or attention in the face of competing or changing demands, are thought to be responsible for inflexible behaviors in neuropsychiatric diseases. Here, we seek to understand frontotemporal networks underlying dysfunctional cognitive function using sEEG recordings and deep brain stimulation (DBS) in human subjects with treatment-resistant depression (TRD). METHODS: We employed a forced two-choice cognitive control task where the strength in the target and the distractor interference of a visual stimulus was parametrically and independently varied, resulting in granular variation in response congruence. This task was performed in 13 total subjects, 10 of whom underwent sEEG implants for epilepsy monitoring, whereas 3 subjects were participating in a clinical trial of DBS for TRD and were additionally implanted with DBS leads in the ventral capsule/ventral striatum and subcallosal cingulate. RESULTS: Reaction time (RT) and accuracy worsened with increasing levels of conflict across all subjects (Cohen’s d-accuracy = 0.7, Cohen’s d-RT = 0.2) prior to stimulation. Single-trial regression analyses revealed a parametric effect of task conflict with theta-band (4-7 Hz) power across the dorsolateral PFC (dlPFC), dorsal anterior cingulate cortex, orbitofrontal cortex (OFC) as well as the insula. DBS significantly improved behavioral performance, demonstrated by reduced RT (1080 土 10 ms to 840 土 50 ms), and improved accuracy(70 土 9.8% to 90 土 5%). While we observed an overall increase in theta power across the PFC and ACC in TRD participants following DBS, the effect of conflict in theta power was reversed (theta power decreased with increasing conflict in dlPFC and OFC). CONCLUSIONS: Leveraging this unique behavioral paradigm with concurrent distributed intracranial recordings and causal manipulation broadens our understanding of neural substrates of decision-making as well as the mechanisms of therapeutic action of DBS for TRD and other psychiatric disorders.