About

Yvette I. Sheline, M.D., is the McLure Professor of Psychiatry and Behavioral Research at the University of Pennsylvania Perelman School of Medicine. She serves as the Director of the Center for Neuromodulation in Depression and Stress (CNDS) and is a member of the Radiation Safety Committee and the Advisory Board of the Penn Medicine Neuroscience Center. Her research focuses on identifying brain markers of depression and anxiety treatment response across disorders using structural and functional neuroimaging techniques, with the goal of improving brain neuromodulation strategies. She has been involved in numerous funded projects investigating treatments such as transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and vagus nerve stimulation (VNS), aiming to understand their mechanisms and optimize their efficacy. Her work also includes developing neuroimaging harmonization methods and exploring neural circuit biomarkers related to depression and resilience, particularly in late-life depression and Alzheimer’s disease. Dr. Sheline's contributions extend to understanding the neurobiological underpinnings of depression, treatment outcomes, and the effects of neuromodulatory therapies, making her a leading figure in psychiatric neuroimaging research.

Research topics

• Political Science
• Psychiatry
• Medicine

Selected publications

• Decreased within-default mode network connectivity with accelerated intermittent theta burst stimulation across unipolar and bipolar depression: Candidate transdiagnostic circuit marker for treatment response

  Transcranial magnetic stimulation . · 2026-01-29

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Translating the Role of Spreading Depolarization in Electroconvulsive Therapy in Mice and Humans

  Biological Psychiatry · 2026-04-25

  article
  PublisherDOI

• Decreased within-default mode network connectivity with accelerated intermittent theta burst stimulation across unipolar and bipolar depression: Candidate transdiagnostic circuit marker for treatment response

  medRxiv · 2026-01-01

  articleOpen access1st authorCorresponding

  ABSTRACT Background An accelerated schedule of intermittent theta burst stimulation (aiTBS) has been shown to improve clinical efficacy of transcranial magnetic stimulation for bipolar disorder (BD) and major depressive disorder (MDD). We investigated the functional connectivity changes underpinning clinical effects of aiTBS on transdiagnostic treatment-resistant depression (TRD). Methods Data were collected from two studies: an open-label active aiTBS study for MDD and a double-blind, randomized control aiTBS study for BD. Thirty-four participants (18 female/16 male) with transdiagnostic TRD currently experiencing moderate to severe depressive episodes (Montgomery-Åsberg Rating Scale [MADRS] score ≥ 20). Participants received active (22 total; 12 BD/10MDD) or sham (12 BD) aiTBS delivered to personalized left dorsolateral prefrontal cortical targets. Participants completed MRI scans before and after ten sessions of active or sham aiTBS per day for five days. Within each aiTBS group (active/sham), connectivity changes within the default mode network (DMN) following aiTBS and their correlations with MADRS scores were evaluated. Results Immediately following aiTBS, active group members had lower within-DMN connectivity ( p = .01, d = –0.62) and lower MADRS scores ( p < .0001) than at baseline; these changes were correlated ( r = .47, p = .03). They also reported decreased insomnia ( p < .0001) and suicidality ( p < .0001). These changes were not present in the sham BD group ( p s = .29– .92). Conclusions aiTBS was associated with decreased within-DMN connectivity among people with transdiagnostic TRD, which could underlie depression improvement. The study is registered on ClinicalTrials.gov (study identifier NCT05228457 ). https://clinicaltrials.gov/study/NCT05228457

  PublisherOA PDFDOI

• 39. White Matter Microstructural Changes Following Electroconvulsive Therapy in Treatment-Resistant Depression

  Biological Psychiatry · 2026-04-25

  article
  PublisherDOI

• Continuous theta burst stimulation to the intraparietal cortex among patients with posttraumatic stress disorder

  Brain stimulation · 2025-01-01

  articleOpen access

  Conclusion:Based on these considerations, we present specific candidate TMS-EEG markers correlating with the excitability of specific circuits relevant to the expression of anxiety.We expect that this result will support the development of future more effective personalized brain stimulation paradigms for the treatment of anxiety.

  PublisherOA PDFDOI

• A mechanistic trial of the neurobiology of extinction learning and intraparietal sulcus stimulation: Protocol

  Contemporary Clinical Trials Communications · 2025-12-23

  articleOpen access

  Post-traumatic stress disorder (PTSD) links to impaired extinction learning post-trauma. While treatments like prolonged exposure therapy improve this learning, they benefit only 40-60 % of patients. Optimal arousal supports extinction learning, but excessive arousal can hinder it. The intraparietal sulcus (IPS) is involved in arousal regulation but has not yet been targeted using continuous theta burst stimulation (cTBS) in PTSD. This study is the first to explore the effect of IPS cTBS on extinction learning in PTSD. This study aims to 1) evaluate the impact of IPS cTBS on anxiety potentiated startle (APS) among patients with PTSD compared to sham IPS cTBS, 2) examine whether IPS cTBS improves extinction learning relative to neutral learning, and 3) identify the ideal dose of cTBS. Adults with PTSD will participate in six visits, involving clinical assessments, functional MRI (fMRI), and IPS cTBS. Participants will undergo diagnostic interviews, generate trauma and neutral scripts, and complete script-driven imagery tasks. They will receive active or sham cTBS (counterbalanced) paired with trauma or neutral scripts during separate visits. Follow-up assessments occur at 24 h and 30 days post-intervention. IRB approval and preliminary preparations began in January 2024. Recruitment started in April 2024 and is projected to conclude by April 2028. Ethical procedures are approved by the University of Pennsylvania IRB (Protocol Number: 849571). This will be the first study to evaluate the synergistic effects of extinction training with IPS cTBS in individuals with PTSD. Our findings will strengthen the neurobiological basis of augmenting extinction training with IPS cTBS.

  PublisherDOI

• Durability of the Benefit of Vagus Nerve Stimulation in Markedly Treatment-Resistant Major Depression: A RECOVER Trial Report

  medRxiv · 2025-10-19

  preprintOpen access

  ABSTRACT Importance Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability). Objective Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression. Design Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. Setting Outpatient. Participants Adults with moderate-severe MDD with ≥4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (N=214). Interventions VNS and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, ketamine/esketamine) were characterized over the 12-month extension. Main Outcomes and Measures The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression–Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori . Results Most participants with substantial benefit maintained their benefit (18-month median=78.8%; 24-month median=79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median=83.1%; 24-month median=81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median=30.6%) and 24 (median=37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatry modalities. Conclusions and Relevance Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year. Significance Statement Patients with markedly treatment-resistant major depression have low likelihood of benefiting from antidepressant treatments and high likelihood of rapid relapse if benefit is obtained. In 214 participants randomized in the RECOVER trial to active treatment with adjunctive Vagus Nerve Stimulation (VNS) therapy, outcomes after a second year of stimulation were examined for depressive symptom severity, function, and quality of life. Participants with meaningful benefit at 12 months maintained this level of benefit or better at 24 months at high rates (median ≥80% across all measures). Durability was strong for symptoms, function, and quality of life regardless of the threshold used to define benefit and was not attributable to changes in concomitant treatments. Moreover, a substantial proportion of participants had meaningful improvement at 24 months who did not at 12 months. In a sample characterized by profound chronicity and treatment resistance, active VNS was associated with exceptionally strong durability of benefit.

  PublisherOA PDFDOI

• Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report

  The International Journal of Neuropsychopharmacology · 2025-12-20 · 4 citations

  articleOpen access

  IMPORTANCE: Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability). OBJECTIVE: Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression. DESIGN: Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. SETTING: Outpatient. PARTICIPANTS: Adults with moderate-severe MDD with ≥ 4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (n = 214). INTERVENTIONS: Vagus nerve stimulation and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, and ketamine/esketamine) were characterized over the 12-month extension. MAIN OUTCOMES AND MEASURES: The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression-Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite measures with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori. RESULTS: Most participants with substantial benefit maintained their benefit (18-month median = 78.8%; 24-month median = 79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median = 83.1%; 24-month median = 81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median = 30.6%) and 24 (median = 37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatric modalities. CONCLUSIONS AND RELEVANCE: Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year.

  PublisherDOI

• Evaluating Vagus Nerve Stimulation Therapy for Treatment-Resistant Bipolar Depression: An 18-Month Analysis of Symptom Severity and Suicidality

  Scholarly Commons (University of Pennsylvania) · 2025-09-15

  otherOpen access

  While Vagus Nerve Stimulation (VNS) is an FDA-approved therapy and already available on the market, it is not yet covered by Medicaid/Medicare services. Simultaneously, treatment-resistant depression (TRD) patients face limited treatment options and a significantly reduced quality of life. Hence by trialling Vagus Nerve stimulation’s effect on Bipolar treatment resistant Depression, we may determine if there are significant and satisfactory clinical outcomes to justify its coverage. This study aims to question if active VNS therapy, as an adjunct to treatment as usual, leads to a significant reduction in symptom severity and suicidality in patients with TRD over the first 18 months of treatment. This analysis focuses on the first 18 months of a mandated 5-year, double-blind, sham-controlled trial. Participants with bipolar TRD who had failed four or more antidepressant treatments were surgically implanted with a VNS generator. They were randomized to receive either active or sham stimulation for the first 12 months, after which all devices were activated. The study assessed changes in symptom severity (measured by the Clinical Global Impression – Improvement Scale, CGI-I) and suicidality (measured by the Sheehan Suicidality Tracking Scale) as an adjunct to treatment as usual. No statistically significant reduction in suicidality was observed over the 18-month period. However, analysis of the CGI-I scores indicated a significant reduction in overall symptom severity. This improvement was significantly greater following the activation of the VNS implant compared to pre-activation baselines. These preliminary 18-month data suggest that adjunctive VNS Therapy may yield significant benefits in reducing symptom severity, though not suicidality, in a highly treatment-resistant bipolar depression population. These findings are a critical step in evaluating the therapy's potential for providing clinically meaningful outcomes for Medicare beneficiaries.

  Publisher

• Electroconvulsive therapy generates a postictal wave of spreading depolarization in mice and humans

  Nature Communications · 2025-05-18 · 11 citations

  articleOpen access

  Electroconvulsive therapy (ECT) is a fast-acting, highly effective, and safe treatment for medication-resistant depression. Historically, the clinical benefits of ECT have been attributed to generating a controlled seizure; however, the underlying neurobiology is understudied and unresolved. Using optical neuroimaging of neural activity and hemodynamics in a mouse model of ECT, we demonstrated that a second brain event follows seizure: cortical spreading depolarization (CSD). We found that ECT pulse parameters and electrode configuration directly shaped the wave dynamics of seizure and subsequent CSD. To translate these findings to human patients, we used non-invasive diffuse optical monitoring of cerebral blood flow and oxygenation during routine ECT treatments. We observed that human brains reliably generate hyperemic waves after ECT seizure which are highly consistent with CSD. These results challenge a long-held assumption that seizure is the primary outcome of ECT and point to new opportunities for optimizing ECT stimulation parameters and treatment outcomes. The underlying mechanism of electroconvulsive therapy remains not fully understood. Here, the authors use optical neuroimaging in mice and humans to show that electroconvulsive therapy elicits a second brain event after seizure—spreading depolarization—a previously hidden phenomenon that may help to understand and optimize this treatment.

  PublisherOA PDFDOI

Recent grants

• STRESS AND INFLAMMATION IN THE PATHOPHYSIOLOGY OF LATE-LIFE DEPRESSION

  NIH · $2.4M · 2013–2020

• Integrative Training in the Neurocircuitry of Affective Disorders

  NIH · $1.1M · 2016–2021

• Citalopram Decreases CSF AB: A Randomized Dose Finding Trial

  NIH · $1.8M · 2014–2018

• NIH Grant K24MH079510

  NIH · $853k · 2013

• Dimensional connectomics of anxious misery

  NIH · $2.8M · 2016–2021

Frequent coauthors

• John C. Morris

  Washington University in St. Louis

  56 shared

• Mark A. Mintun

  54 shared

• John R. Cirrito

  Washington University in St. Louis

  36 shared

• Abraham Z. Snyder

  Mallinckrodt (United States)

  29 shared

• Joanne C. Beer

  29 shared

• Darsol Seok

  University of California, Los Angeles

  27 shared

• Desmond J. Oathes

  University of Pennsylvania

  26 shared

• Nicholas L. Balderston

  University of Pennsylvania

  25 shared