L-DLPFC - SGC Marker of Depression

Left-Dorsolateral Prefrontal Cortex (DLPFC) - Subgenual anterior Cingulate Cortex (SGC) circuit as a treatment resistant depression response marker in transcranial magnetic stimulation treatment

Neurophysiological Biomarkers for Neuromodulation in Treatment-Resistant Depression

As a neuroscientist driven by the challenge of unraveling depression’s neural circuits, my work has centered on developing circuit-specific biomarkers using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to guide and optimize neuromodulation therapies for treatment-resistant depression (TRD). This aligns seamlessly with my research interests in mechanistic neurophysiological markers and targeted interventions. From my postdoctoral at the Centre for Addiction and Mental Health (CAMH) to my role at UC San Diego, where I helped establish the Interventional Psychiatry Program, I have led and contributed to studies validating subgenual cingulate cortex (SGC) hyperactivity and dorsolateral prefrontal cortex (DLPFC)-SGC effective connectivity as pivotal features of TRD. These biomarkers not only illuminate depression’s pathophysiology but also inform personalized treatments with repetitive TMS (rTMS) and potentially other circuit spesific interventions Looking ahead, I envision extending this to accelerated intermittent theta-burst stimulation (aiTBS) protocols, integrating multimodal data for targeting, to advance clinical outcomes. A cornerstone of my research is the theoretical anticorrelation between the left DLPFC and SGC, where rTMS treatment directed to the DLPFC may modulate SGC activity transsynaptically, normalizing hyperactivity as measured by TMS-EEG and linked to depressive symptoms.

Centered image — Figure 1. Schematic of theoretical connectivity between the left dorsolateral prefrontal cortex (DLPFC) and subgenual cingulate cortex (SGC), illustrating potential transsynaptic modulation pathways targeted in neuromodulation therapies for TRD.

In an early study I led, we used TMS-EEG to probe SGC hyperactivity and DLPFC-SGC effective connectivity in TRD patients before and after high-frequency rTMS (Hadas et al., 2019). Quantifying SGC activity via significant current density (SCD) and connectivity via significant current scattering (SCS), we found elevated baseline measures in TRD versus controls, with SCD at the subgenual cortex classifying TRD at 77% accuracy. Active rTMS reduced these toward normal levels, correlating baseline SCD with Hamilton Rating Scale for Depression (HRSD-17) scores (ρ = 0.41, P = .03) and SCS changes with symptom relief (ρ = 0.58, P = .047). This was among the first demonstrations of TMS-EEG capturing causal connectivity shifts, positioning DLPFC-SGC dysregulation as a viable therapeutic target.

Extending this biomarker to Magnetic Seizure Therapy (MST), a seizure inducing neuromodultory intervention for TRD with reduced cognitive side effects when compared to Electroconvulsive Therapy (ECT), I spearheaded a study showing post-MST reductions in DLPFC-SGC effective connectivity (P < .036), correlating with HRSD-24 improvements (ρ = 0.46, P < .031). Hippocampal (Hipp) localized activation also decreased (P < .015), linking to Montreal Cognitive Assessment (MoCA) changes (ρ = -0.59, P < .026). This dissociated efficacy mechanisms (SGC-DLPFC connectivity) from cognitive impacts (Hipp activation), underscoring TMS-EEG’s value for treatment monitoring symptoms and side-effects spesific biomarkers production (Hadas et al., 2020).

Correlation between fMRI functional connectivity and source localized TMS-EEG activation at the DLPFC-SGC circuit

Building on these foundations, I contributed to a multimodal study integrating resting-state functional MRI (RSFC) with TMS-EEG in 42 TRD patients undergoing individualized aiTBS (Sun et al., 2025; Sun et al., 2025). We found that more negative baseline RSFC between the DLPFC target and SGC correlated with smaller (less negative) N100 amplitudes (Spearman’s ρ = -0.37, P = 0.02) and reduced cortical evoked activity (CEA) in the SGC (ρ = 0.29, P = 0.07). This suggests stronger DLPFC-SGC anticorrelation reflects enhanced inhibitory control, allowing DLPFC-targeted TMS to better suppress SGC activity. Reconciling prior findings—where higher SGC TMS-EEG activation signals worse depression, but negative RSFC predicts better outcomes—this work bridges modalities, supporting personalized targeting without invasive methods. The The manuscript is in progress!!

These projects, where I served as first author on the foundational TMS-EEG studies and collaborator on multimodal extensions, highlight my proficiency in biomarker pipelines—from data acquisition to analysis. They fuel my future directions for clinically applicable TMS-EEG biomarkers for depression. By translating these insights from bench to bedside, including my consulting at Deliberate.ai and Salma Health for AI-driven diagnostics, I aim to revolutionize TRD care through innovative, cross-disciplinary science.

References

2025

Relationship between TMS-EEG source activity in the subgenual cingulate following left dorsolateral prefrontal cortex stimulation and the resting state functional connectivity between the two regions

Yinming Sun, Mohsen Poorganji, Emma Boyd, and 5 more authors

Jan 2025

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Major depressive disorder (MDD) is a debilitating illness that affects nearly 20% of the US population. MDD has been associated with an overactivation of the subgenual cingulate (SGC), while effective treatments have been associated with a suppression of SGC activity. While treatments involving transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (LDLPFC) cannot directly activate the SGC, it has been postulated that part of the therapeutic effect is achieved via transsynaptic activation of the deeper SGC region. Support for this theory comes from both studies with fMRI-based resting-state functional connectivity (RSFC) and concurrent TMS and EEG (TMS-EEG) source activation. Indeed, it has been shown that stimulating the region of the LDLPFC that is most anticorrelated with the SGC based on individual pretreatment RSFC can lead to better treatment outcomes. At the same time, larger EEG based current density from the SGC following single TMS pulses before treatment has been shown to be correlated with better treatment outcomes. To reconcile the two supporting theories, baseline RSFC and TMS-EEG data from 50 MDD patients undergoing a course of accelerated intermittent theta burst (iTBS) treatment are analyzed. Single pulse TMS-EEG is assessed by stimulating the RSFC based treatment target, while the exact value of the RSFC between the SGC and LDLPFC are determined based on cortical regions activated above a certain electric field threshold. It is hypothesized that a stronger negative RSFC (i.e., anticorrelation) between the stimulation target and the SGC will result in a larger evoked current density in the region by single pulse TMS. If our hypothesis is correct, it would mean that the targeted region and the SGC are coupled through transsynaptic connections that rely on inhibitory synapses that suppress each other at rest while strengthening the transient neuronal synchronization resulting from an external stimulus (i.e., TMS pulse).
In progress: Subgenual cingulate TMS-EEG response from dorsolateral prefrontal transcranial magnetic stimulation relates to the functional connectivity between the two regions in patients with treatment resistant depression

Yinming Sun, Mohsen Poorganji, Emma Boyd, and 9 more authors

Jan 2025

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Introduction: Treatment resistant depression (TRD) is associated with an overactivation of the subgenual cingulate (SGC). Transcranial magnetic stimulation (TMS) delivered to the left dorsolateral prefrontal cortex (DLFPC) may achieve its antidepressant effect via transsynaptic activation of the SGC. While higher activation of the SGC by single pulse TMS -EEG assessed from the DLPFC is associated with worse depression, a more negative fMRI resting state functional connectivity (RSFC) between the DLPFC and SGC is associated with better TMS treatment outcomes. To reconcile previous findings, we wanted to determine how those two measures are related based on multimodal data from the same TRD patients. Methods: Baseline RSFC and TMS-EEG measures from 42 MDD patients enrolled in a course of individualized accelerated intermittent theta-burst stimulation (iTBS) treatment were analyzed. The RSFC was calculated between the individual treatment target and the SGC, while the cortical evoked activity (CEA) from 20 to 500 ms and the negative peak at 100 ms (N100) were calculated from the SGC source localized TMS evoked potential. Results: More negative RSFC between the DLPFC target and SGC was associated with a smaller N100 (i.e., less negative) (Spearman’s Rho = -0.37, Pval = 0.02) and a smaller CEA (Spearman’s Rho = 0.29, Pval = 0.07) at the SGC. Conclusion: A higher anticorrelation between the DLPFC and SGC may indicate a stronger inhibitory connection between the two that enables a TMS pulse delivered at the anticorrelated DLPFC region to better suppress excitatory and inhibitory activity at the SGC.

2020

Subgenual cingulate connectivity and hippocampal activation are related to MST therapeutic and adverse effects

Itay Hadas, Reza Zomorrodi, Aron T. Hill, and 4 more authors

Translational Psychiatry, Nov 2020

Number: 1 Publisher: Nature Publishing Group

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Aberrant connectivity between the dorsolateral prefrontal cortex (DLPFC) and the subgenual cingulate cortex (SGC) has been linked to the pathophysiology of depression. Indirect evidence also links hippocampal activation to the cognitive side effects of seizure treatments. Magnetic seizure therapy (MST) is a novel treatment for patients with treatment resistant depression (TRD). Here we combine transcranial magnetic stimulation with electroencephalography (TMS-EEG) to evaluate the effects of MST on connectivity and activation between the DLPFC, the SGC and hippocampus (Hipp) in patients with TRD. The TMS-EEG was collected from 31 TRD patients prior to and after an MST treatment trial. Through TMS-EEG methodology we evaluated significant current scattering (SCS) as an index of effective connectivity between the SGC and left DLPFC. Significant current density (SCD) was used to assess activity at the level of the Hipp. The SCS between the SGC and DLPFC was reduced after the course of MST (p \textless 0.036). The DLPFC-SGC effective connectivity reduction correlated with the changes in Hamilton depression score pre-to-post treatment (R = 0.46; p \textless 0.031). The SCD localized to the Hipp was reduced after the course of MST (p \textless 0.015), and the SCD change was correlated with montreal cognitive assessment (MOCA) scores pre-post the course of MST (R = −0.59; p \textless 0.026). Our findings suggest that MST treatment is associated with SGC-DLPFC connectivity reduction and that changes to cognition are associated with Hipp activation reduction. These findings demonstrate two distinct processes which drive efficacy and side effects separately, and might eventually aid in delineating physiological TRD targets in clinical settings.

2019

Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder: A Secondary Analysis of a Randomized Clinical Trial

Itay Hadas, Yinming Sun, Pantelis Lioumis, and 7 more authors

JAMA Network Open, Jun 2019

Number: 6 15 citations (Crossref) [2021-06-13]

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Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD. Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment. Design, Setting, and Participants In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018. Main Outcomes and Measures Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression. Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10−6 [1.41 × 10−6] μA/mm2 vs 3.8 × 10−7 [7.8 × 10−7] μA/mm2; z = –2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = –2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10−7 [3.67 × 10−7] μA/mm2 vs 7.00 × 10−7 [7.51 × 10−7] μA/mm2; z = −2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = −2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047). Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness. Trial Registration: ClinicalTrials.gov identifier: NCT01515215