RRMS patients and healthy controls were well matched for age and gender (see ). As expected, patients had significantly lower brain parenchymal fraction (BPF) indicating global atrophy on MRI. In addition, patients also had significantly higher levels of depressive symptoms and anxiety.
Demographic and clinical characteristics of patients with relapsing-remitting multiple sclerosis (RRMS) and healthy control subjects.
MS patients showed significantly lower volumes (corrected for head size) in the CA1 subregion (p<.001) and – to a lesser extent – the Subiculum (p=.002, ), resulting in significantly smaller total hippocampal volumes (p=.01, ). In contrast, no significant differences were observed in CA23DG or the ERC (). Group differences were identical after statistically controlling for global atrophy (CA1 p<.001; CA23DG p=.27; Subiculum p=.001; ERC p=.12; total hippocampus p=.01).
Regional hippocampal atrophy in RRMS
MS patients also showed subtle alterations in cortisol profiles with unchanged morning levels but slightly elevated evening levels (), resulting in a flatter cortisol slope (), although this fell short of statistical significance (p=.08).
Since MS patients had higher levels of depressive symptoms, and exhibited smaller hippocampal volumes as well as subtle alterations in the HPA axis, we further explored the possibility that hippocampal volume and cortisol slopes are related to severity of depressive symptoms. Based on published cut-off scores for the BDI-II (Beck et al 1996
), MS patients were classified as non-depressed (BDI-II score 0–13, n=21) or as having depressive symptoms indicative of mild to moderate depression (BDI-II score 14 or higher, n=8). No healthy control subject had BDI-II scores above the cut-off. As expected, BDI grouping showed highly significant differences in depressive symptoms and anxiety but no differences in age or gender distribution between the depressed and non-depressed MS patients. Importantly, there were also no differences in global atrophy, lesion load, or number of steroid treatments received previously (see ).
Demographic and clinical characteristics of patients with relapsing-remitting multiple sclerosis (RRMS) below and above the clinical cut-off for likely depression.
Both depressed and non-depressed MS groups showed smaller volumes in CA1 and Subiculum compared to healthy controls (). Importantly, MS patients above the BDI-II cut-off also showed smaller volumes in the CA23DG region. Neither of the groups differed from healthy controls in ERC volumes. Driven by the significantly smaller CA23DG volumes in depressed patients, only MS patients above the BDI-II cut-off showed significantly smaller total hippocampus volumes compared to controls (). Group differences yielded a very similar pattern when analyzing subregions of the left and right hippocampus separately (see Supplementary Table 1
Selective regional hippocampal atrophy and HPA axis activity in MS patients with higher levels of depressive symptoms
In addition, MS patients above the BDI-II cut-off also showed marked flattening of cortisol profiles. This was characterized by elevated evening levels but unchanged cortisol levels in the morning (), resulting in significantly flatter slopes () compared to non-depressed MS patients. In contrast, cortisol profiles and slope were not different between non-depressed MS patients and controls (). This indicates that diurnal cortisol flattening due to elevated evening cortisol (i.e. failure to decrease cortisol responses throughout the day) is associated with depression in MS, and not MS patients as a whole.
In addition to group comparisons, we next examined if there were direct correlations between depressive symptoms, subregional hippocampal volumes, and cortisol levels within the MS group. Spearman rank correlations revealed a significant inverse correlation between BDI-II scores and volume of the CA23DG region (r=−.38, p=.04, ) but no other region of the hippocampus. Cortisol slope was significantly associated with CA23DG volumes (r=−.46, p=.01, ) but no other region of the hippocampus. A stepwise linear regression model (R=.39, Adjusted R2=.12, p=.04) revealed that cortisol slope (β=−.39, p=.04) was the only significant predictor of CA23DG volume while global atrophy (β=.17, p=.36), total gray matter volume (β=.15, p=.42), age (β=.07, p=.72), disease duration (β=−.13, p=.50), and previous steroid treatments (β=−.04, p=.85) were not predictive. When disability (EDSS) was also entered, it added significantly to the explained variance (R=.56, Adjusted R2=.26, p=.008), however, cortisol slope remained the strongest predictor (cortisol β=−.43, p=.014; EDSS β=−.40, p=.02).
Selective and specific associations between depressive symptoms, subregional hippocampal volumes and cortisol levels in RRMS
Interestingly, while cortisol slope equally correlated with the left (r=−.41, p=.027) and the right (r=−.40, p=.03) CA23DG, correlations between CA23DG and depressive symptoms as measured by the BDI-II showed somewhat lateralized associations (left CA23DG-BDI r=−.34, p=.07; right CA23DG-BDI r=−.26, p=.16). This is in line with some previous studies in MDD suggesting a stronger association of the left hippocampus with depression (Bremner et al 2000
; Mervaala et al 2000
Lastly, we examined the role of antidepressant treatment on hippocampal volumes and cortisol levels. A total of six patients received selective serotonin reuptake inhibitors (SSRIs). Only one subject had BDI levels above the cut-off despite anti-depressive medication while the other five had BDI scores below the cut-off, indicative of effective anti-depressive therapy. We compared hippocampal volumes and cortisol slopes between four groups: Normal controls (n=20), non-depressed MS patients (based on the BDI cut-off) who did not take SSRIs (n=16), MS patients who were taking SSRIs and had BDI scores below the cut-off (indicative of well-controlled depression, n=5) and MS patients with unmedicated depression (n=7). Analyses revealed that only MS patients with unmedicated depression had significantly smaller volumes in CA23DG (supplementary Figure 1A
), and total hippocampus (supplementary Figure 1B
) as well as flatter cortisol slopes (supplementary Figure 1C
) compared to healthy controls. In contrast, MS patients with ‘well-controlled depression’ showed values similar to non-depressed MS patients and healthy controls.