ECT - Associated Dentate Gyrus Plasticity Tracks Improvement in Core Depressive Symptoms
ISEN Research Committee • November 6, 2026

Takamiya et al. Study 

Hippocampal Dentate Gyrus Plasticity and Its Association With Dimensional Clinical Improvement Across Four Depression Treatment Interventions 

Akihiro Takamiya et al. 

American Journal of Psychiatry. Published online August 26, 2026.
DOI: 10.1176/appi.ajp.20251330 


Research Question 

Do cognitive-behavioral therapy (CBT), pharmacotherapy, repetitive transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT) produce measurable changes in hippocampal dentate gyrus volume, and are those changes associated with improvement in particular depressive symptom dimensions or cognitive function? 


Brief Background 

The dentate gyrus is a hippocampal subregion involved in learning, memory, emotional regulation, and multiple forms of neuroplasticity. Preclinical studies have identified increased dentate gyrus neurogenesis, synaptic remodeling, and related plasticity following antidepressant medications and electroconvulsive stimulation. 


Human MRI studies have reported increases in hippocampal or dentate gyrus volume following pharmacotherapy, repetitive transcranial magnetic stimulation, and ECT, although findings have varied across treatments and studies. 


It remains unclear whether dentate gyrus plasticity represents a final common pathway shared by effective depression treatments or a biological effect that is more specific to particular interventions. 


Study Location 

This was a prospective, multisite observational study conducted at four sites in Japan. MRI data were acquired using six 3-Tesla scanners. 


Study Sponsor 

The study was supported by the Japan Agency for Medical Research and Development through grant JP19dm0307102h0001. 


Inclusion Criteria 

Patients were eligible if they: 

  • Were 20-85 years old 
  • Met DSM-IV criteria for major depressive disorder 
  • Had a baseline 17-item Hamilton Depression Rating Scale score of at least 8 
  • Were scheduled in routine clinical care to receive cognitive-behavioral therapy, a pharmacologic treatment change, TMS, or ECT 


In addition to patients, healthy controls were also recruited.


Exclusion Criteria 

Key exclusions were: 

  • Bipolar disorder 
  • Dementia 
  • Current significant suicidal ideation or recurrent suicide attempts considered incompatible with safe participation in the longitudinal study 


How Many Participants 

450 participants: 181 healthy controls and 269 patients with major depressive disorder.


Study Intervention 

This was a nonrandomized observational study. Treatment was selected by the attending physician before enrollment, and all interventions were delivered in routine clinical settings rather than assigned or modified by the study team. 

Cognitive-behavioral therapy: N = 106; Sixteen weekly sessions 

Pharmacotherapy: N = 83; A clinically indicated medication initiation, switch, or augmentation after baseline assessment 

TMS: N = 39; 10-Hz stimulation; 3,000 pulses per day; Five treatment days per week for 4-6 weeks 

ECT: N = 41; pulse width of 0.5 ms; Treatments administered two or three times per week; Electrode placement and number of sessions were selected by treating physicians; Mean number of ECT sessions was 10.5, with a range of 4-19 


Follow-Up 

MRI and clinical assessments were conducted at three time points: 

  • TP1: Within two weeks before treatment 
  • TP2: Within two weeks after the treatment course 
  • TP3: Six months after treatment 


Endpoints 


Primary imaging outcome 

  • Bilateral CA4/dentate gyrus volume measured using the longitudinal FreeSurfer hippocampal subfield segmentation pipeline 


Primary clinical association 

  • Relationship between CA4/dentate gyrus volume and the HAM-D-17 core depressive symptom dimension, comprising psychomotor retardation, depressed mood, suicidality, work and interests, and guilt 


Results

 

Baseline Findings 

Patients with major depressive disorder had lower CA4/dentate gyrus volume than healthy controls. Within the MDD group, baseline CA4/dentate gyrus volume was not associated with baseline core depressive symptom severity.


The ECT group differed substantially from the other treatment groups at baseline. Participants receiving ECT were older, had more severe depressive symptoms, had a later age at illness onset, and were less likely to be experiencing a first depressive episode. 


Treatment-Associated CA4/Dentate Gyrus Changes 

Across all patients, CA4/dentate gyrus volume increased significantly over time. Post hoc analysis showed that only the ECT group experienced a statistically significant increase in CA4/dentate gyrus volume. No significant CA4/dentate gyrus volume increase was detected following CBT, pharmacotherapy, or TMS. 

At baseline, CA4/dentate gyrus volume in the ECT group was lower than in healthy controls. Following ECT, the difference was smaller and was no longer statistically significant: 


Relationship to Depressive Symptoms 

Changes in CA4/dentate gyrus volume were associated with changes in core depressive symptoms. In post hoc treatment-specific analyses, this relationship was found only in the ECT group. Volume changes were not significantly associated with the anxiety, somatic, or insomnia dimensions after correction for multiple comparisons. 


Six-Month Findings 

Across the three time points, CA4/dentate gyrus volume followed a nonlinear trajectory. This pattern was again driven by the ECT group: 

  • Significant increase from baseline to immediately after ECT 
  • Significant decrease from the post-treatment assessment to six months 
  • No significant longitudinal changes in the CBT, medication, or TMS groups 

Changes in CA4/dentate gyrus volume across the three assessments remained associated with changes in core depressive symptoms. 


Limitations 

  • CA4 and the dentate gyrus cannot be completely separated using the FreeSurfer atlas employed in this study. The reported region should therefore be understood as a combined CA4/dentate gyrus MRI segmentation rather than a purely dentate gyrus measurement.
  • Treatment assignment was not randomized. Patients received interventions selected through routine clinical decision-making, creating a substantial risk of confounding by indication. 
  • The treatment groups differed at baseline. The ECT group was older, had more severe depression, and had lower baseline CA4/dentate gyrus volume than several other groups. 
  • Nearly all ECT participants received bilateral treatment. The findings may not generalize to a predominantly right-unilateral ECT course or to specific pulse widths and dosing strategies. 
  • The association between volume change and core depressive symptom improvement was strong in the ECT mixed-effects analysis but modest in the complementary change-score analysis. This difference underscores that the estimated relationship depends partly on the statistical model. 


Summary and Implications 

This large, multisite longitudinal study found a robust increase in MRI-measured CA4/dentate gyrus volume following ECT but not following CBT, pharmacotherapy, or TMS. The ECT-associated volume increase tracked improvement in core depressive symptoms and was not associated with changes in measured cognitive performance. At six months, the initial enlargement had partially receded, producing an increase-decrease trajectory that paralleled changes in core depressive symptoms. 

The results argue against MRI-detectable dentate gyrus enlargement as a universal structural response to depression treatment. Instead, this imaging phenotype appears particularly associated with ECT under the conditions studied. The clinical correlation is noteworthy because it was specific to the core depressive symptom dimension rather than anxiety, somatic symptoms, insomnia, or cognitive outcomes.


Comments 

This study addresses an important mechanistic question by directly comparing longitudinal hippocampal subfield measurements across four commonly used depression treatments. Its principal strength is not simply the relatively large sample, but the combination of repeated imaging, multisite harmonization, dimensional symptom analyses, and six-month follow-up. 

The findings suggest that ECT produces a particularly large biological perturbation within the hippocampus. This may relate to the combination of electrical stimulation, generalized seizure activity, repeated treatment exposure, neurotrophic signaling, synaptic remodeling, glial responses, and changes in local tissue water or vasculature. Structural MRI alone cannot determine which of these processes is responsible. 

An important analytic choice was the emphasis on core depressive symptoms rather than reliance exclusively on the total HAM-D-17 score. Depression rating scales combine symptoms with potentially different biological substrates, and a treatment-related brain change may track one domain while having little relationship to others. The specificity of the observed association supports dimensional clinical analyses in future ECT biomarker studies. 

At the same time, the nonrandomized design substantially limits causal interpretation. The ECT participants were older, more severely depressed, and had lower baseline CA4/dentate gyrus volume. These differences are inherent to naturalistic treatment selection and make it difficult to determine whether the observed specificity reflects ECT itself, the characteristics of patients selected for ECT, the intensity of treatment exposure, or an interaction among these factors. 


Ultimately, the study provides compelling evidence that ECT is associated with a distinctive, clinically relevant, and partly reversible structural MRI signal in the CA4/dentate gyrus. It does not yet establish what microscopic process produces that signal or whether the structural change is causal, compensatory, or simply a marker of treatment exposure. 


AI Use Disclaimer 

Generative artificial intelligence was used as a supplemental editorial tool to assist with organizing and summarizing the source article in the established ISEN blog format. All study details, numerical results, and statistical estimates were restricted to information reported in the cited article. The final content has been reviewed and edited by the author, who retains responsibility for its accuracy and interpretation.


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