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. 2010 Sep 15;68(6):553-9.
doi: 10.1016/j.biopsych.2010.04.025. Epub 2010 Jun 19.

Smaller Cornu Ammonis 2-3/dentate Gyrus Volumes and Elevated Cortisol in Multiple Sclerosis Patients With Depressive Symptoms

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Smaller Cornu Ammonis 2-3/dentate Gyrus Volumes and Elevated Cortisol in Multiple Sclerosis Patients With Depressive Symptoms

Stefan M Gold et al. Biol Psychiatry. .
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Background: The hippocampus is likely involved in mood disorders, but in vivo evidence for the role of anatomically distinct hippocampal subregions is lacking. Multiple sclerosis, an inflammatory disease of the central nervous system, is linked to a high prevalence of depression as well as hippocampal damage and may thus provide important insight into the pathologic correlates of medical depression. We examined the role of subregional hippocampal volume for depression in relapsing-remitting multiple sclerosis.

Methods: Anatomically defined hippocampal subregional volumes (cornu ammonis 1-3 [CA1-CA3] and the dentate gyrus [CA23DG], subiculum, entorhinal cortex) were measured using a high-resolution T2-weighted magnetic resonance imaging sequence in 29 relapsing-remitting multiple sclerosis patients and 20 matched healthy control subjects. Diurnal salivary cortisol was assessed at awakening, 4 pm, and 9 pm on 2 consecutive days. Subjects also completed the Beck Depression Inventory.

Results: Multiple sclerosis patients showed smaller hippocampal volumes compared with control subjects, particularly in the CA1 and subiculum subregions. In addition, multiple sclerosis patients with depressive symptoms (Beck Depression Inventory score >13) also showed smaller CA23DG volumes and higher cortisol levels. Within the multiple sclerosis group, CA23DG volume was correlated with depressive symptoms and cortisol levels. There were no associations with number of previous steroid treatments, global atrophy, or disease duration.

Conclusions: This report provides in vivo evidence for selective association of smaller CA23DG subregional volumes in the hippocampus with cortisol hypersecretion and depressive symptoms in multiple sclerosis.

Conflict of interest statement

Financial disclosure

None of the authors has any conflicting financial interests to declare.


Figure 1
Figure 1. High-resolution MR scanning of the hippocampus
The sagittal T2-weighted scout image illustrates the superimposed slice prescription for 16 coronal structural images covering the hippocampal formation (A). High-resolution T2-weighted coronal image (B) indicating region shown in (C). Magnified images of the hippocampus (C) were segmented using color-coded masks of hippocampal subregions (D). MR scan resolution is not adequate to differentiate the dentate gyrus and CA2 and CA3 fields separately so they are considered as a single subregion (CA23DG). Red = Dentate gyrus and CA2&3 (CA23DG); yellow = CA1; green = Subiculum (Sub), blue = Entorhinal cortex (ERC).
Figure 2
Figure 2. Regional hippocampal atrophy in RRMS
Compared to healthy controls (n=20), MS patients (n=29) had significantly smaller volumes in Cornu Ammonis 1 (CA1) as well as Subiculum (Sub) but not CA2–CA3 and the Dentate Gyrus (CA23DG) or Entorhinal Cortex (ERC) (A). Consequently, MS patients showed significantly smaller total hippocampal volumes (B). MS patients also showed subtle elevations in evening cortisol levels (C) resulting in flatter cortisol slopes, which however fell short of statistical significance (D).
Figure 3
Figure 3. Selective regional hippocampal atrophy and HPA axis activity in MS patients with higher levels of depressive symptoms
MS patients were classified as non-depressed (BDI-II 0–13, n=21) or mild-to-moderately depressed (BDI-II>13, n=8) according to published cut-offs. Both MS groups showed smaller volumes in Cornu Ammonis 1 (CA1) as well as Subiculum (Sub) compared to healthy controls (n=20). However, only MS patients with elevated depressive symptoms also showed atrophy in CA2–CA3 and the Dentate Gyrus (CA23DG) (A). As a result, only MS patients with depressive symptoms exhibited smaller total hippocampal volumes (B). In addition, only MS with depressive symptoms had elevated evening cortisol levels (C) and thus significantly flatter cortisol slopes (D).
Figure 4
Figure 4. Selective and specific associations between depressive symptoms, subregional hippocampal volumes and cortisol levels in RRMS
Within the MS group (n=29), there was a significant inverse correlation between BDI-II depression scores and volumes in CA23DG (A). In addition, smaller volumes in the CA23DG region were associated with flatter cortisol slope (B).

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