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The role of the dentate gyrus in stress-related disorders

Molecular Psychiatry volume 25, pages 1361–1363 (2020)Cite this article

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In this journal, the effects of 5-week electroconvulsive therapy (ECT) on hippocampal subfield volumes in patients with major depressive disorder (MDD) were recently reported [1]. Using high-resolution structural MRI scans at 7T, Nuninga and colleagues showed that ECT in MDD patients resulted in increased bilateral dentate gyrus (DG) volumes, which was positively associated with clinical improvement. The authors suggested that increased DG volumes after ECT may reflect adult neurogenesis. In line with this suggestion, animal chronic stress models of depression and anxiety show impaired neurogenesis, which improves after ECT and antidepressant medication (see ref. [2] for a review). This led to the neurogenic theory of depression and anxiety, postulating that stress-related disorders result from impaired neurogenesis, and that restoring neurogenesis leads to recovery [2, 3]. Human studies provide indirect evidence for this theory: smaller DG volumes are observed in patients with stress-related disorders, including depression [4, 5], anxiety and posttraumatic stress disorder (PTSD) [6]. Furthermore, medicated MDD patients show larger DG volumes compared to unmedicated MDD patients [7]. The longitudinal study of Nuninga and colleagues is the first to show increased DG volumes after ECT in depressed patients, thereby providing important insights into neural mechanisms underlying treatment efficacy in stress-related disorders. However, the current report also raises several interpretational issues, and more importantly, opens the way for improving future research into the role of the DG in stress-related disorders.

Although the findings of Nuninga and colleagues are promising, several interpretational issues remain. The first question is whether there is a baseline (pre-treatment) difference in DG volumes between MDD patients and control participants (DG volume patients: 792.59 mm3 vs controls: 869.77 mm3). Unfortunately, no statistical tests were reported for this group comparison. However, we note that the magnitude of this group difference (77.18 mm3) is comparable to that of the significant DG volume difference between baseline and exit in patients (75.44 mm3). Furthermore, DG volumes in MDD patients seem to be normalized to the same level as healthy controls after ECT (DG volume controls at baseline: 869.77 mm3 vs patients post-treatment: 868.03 mm3, no statistical tests are reported). Given this potential group difference, as well as the possible normalization of this difference, statistically demonstrating group differences before and after treatment would have greatly facilitated the interpretation of ECT effects. However, we acknowledge that statistical testing of group differences in DG volumes is hampered by the small sample size of the control group (n = 8). The second question is whether baseline DG volumes are associated with pre-treatment symptom severity. The authors did not report this, nor did they correct for baseline symptom severity in the linear regression analysis showing that baseline DG volumes predict clinical treatment response. Therefore, the question remains whether this observation of baseline DG volumes predicting clinical treatment response can be (partly) explained by an association between DG volume and symptom severity at baseline. A third question arises from the fact that the linear regression analysis shows opposite effects for left and right DG volumes: whereas left DG volume at baseline is negatively associated with change in depression symptom severity, right DG volume at baseline shows a positive relationship. Again, interpretation of these abovementioned finings is complicated by the small sample size (23 patients and 8 controls), which is acknowledged by the authors. The effect size that was detected for pre vs post treatment comparison in the control group was 0.521. Our power calculation shows that to achieve 80% power, a sample size of 31 is required. Alternatively, with the sample size of 8 the study only achieves 25% power. Taken together, these interpretational issues call for well-powered prospective longitudinal studies to investigate whether smaller DG volumes represent a cause or consequence of stress-related disorders, thereby improving insights into neural mechanisms underlying stress vulnerability, resilience and treatment efficacy.

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Authors and Affiliations

  1. Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, Netherlands

    Saskia B. J. Koch & Karin Roelofs

  2. Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, Netherlands

    Saskia B. J. Koch & Karin Roelofs

  3. Brain Imaging and Analysis Center, Duke University School of Medicine, Durham, NC, USA

    Rajendra A. Morey

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Correspondence to Saskia B. J. Koch.

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Koch, S.B.J., Morey, R.A. & Roelofs, K. The role of the dentate gyrus in stress-related disorders. Mol Psychiatry 25, 1361–1363 (2020). https://doi.org/10.1038/s41380-019-0572-4

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