We found significant bilateral hippocampal atrophy in medication-free patients with major depression of a moderate severity. Morphological analysis localised the atrophy to distinct subregions within the hippocampi. Marked deformations were evident in the subiculum and CA1 subfield extending into the CA2-3 subfields largely in the tail regions of both hippocampi in depressed patients relative to healthy controls. The findings indicate that subregional hippocampal deficits are not confined to late-life depression (Ballmaier et al., 2008
), but are evident early in the illness.
The hippocampal deformations observed from MRI scans are supported by neuropathological findings (Rosoklija et al., 2000
). Neumister et al. (2004) reported decreased hippocampal volume in its whole and more pronounced in the posterior region, and Maller et al. (2007)
found localised volume reductions in the most posterior region of the tail of the hippocampus in patients with treatment-resistant depression. Posener et al. (2003)
noted specific abnormalities in the subiculum in patients with similar demographic features to those in the present study, but half the patient group was receiving psychiatric medications. In the present study, all patients were medication-free, right-handed, and had 2 or fewer episodes of depression. In late-life depression, Ballmaier et al. (2008)
observed extensive morphological abnormalities in the subiculum and CA1 subregions which extended into the CA2-3 subfields. In the late-life depression group, those patients with a comparable age of onset to our sample had an average of 5 previous episodes of depression at the time of their scan (Ballmaier et al., 2008
). Our findings revealed that the main hippocampal body was relatively intact while deformations were evident particularly in the tail region within the subiculum and CA1 subfield but as well in the CA2-3 subfields. Together, these data suggest that the subregional hippocampal abnormalities present at early stages in the illness may become more extensive with recurrent episodes, contributing to the hippocampal atrophy that is particularly evident in recurrent and treatment-resistant depression (reviewed in: Campbell et al., 2004
; Videbech and Ravnkilde, 2004
; McKinnon et al., 2009
The posterior portion of the hippocampus is engaged by memory retrieval (Lepage et al., 1998
), and the subiculum has been specifically implicated in the retrieval of episodic memories (Gabrieli et al., 1997
; Zeineh et al., 2003
; Eldridge et al., 2005
). Memory impairments are associated with hippocampal atrophy in depression (Hickie et al., 2005
). In particular, deficits in episodic memory are a commonly reported feature (Golinkoff and Sweeney, 1989
; Ilsley et al., 2005), which may be greater in the retrieval, as opposed to the encoding, aspects of the memory trace (Fossati et al., 2002
). These deficits are not evident in the first episode of depression, but become more prominent in recurrent depression (Fossati et al., 2004
). A main component of autobiographical memory is the recall of episodes in one’s life (Brewer, 1986
). It is widely recognised that individuals with depression have difficulty in recalling specific autobiographical events (Williams and Broadbent, 1986
; Williams and Scott, 1988
), instead they tend to produce an overgeneralised memory, which may be more pronounced with negative incidents (Williams and Scott, 1988
Although we observed a right lateralised deficit in hippocampal volume in first-episode patients, bilateral hippocampal atrophy has been reported in medication-naïve, first-episode patients with depression (Zhou et al.. 2010
), in medication-free patients with recurrent depression (Neumister et al., 2004), and a recent meta-analysis indicates a 4% aggregate loss in hippocampal volume in depression with no significant lateralisation effects (McKinnon et al., 2009
). A left lateralised reduction in hippocampal volume has been noted in first-episode male patients (Frodl et al., 2002
) and in late-life depression of a mean age of onset of 35 years (Ballmaier et al., 2008
). The reason for the right lateralised effect that we have observed is unclear, but we did not find any significant correlations with right or left hippocampal volume and the number of previous episodes, duration of illness, or severity of illness.
However, hippocampal atrophy is not specific to depression as it has been observed in other psychiatric disorders, such as schizophrenia (Sumich et al., 2002
), obsessive-compulsive disorder (Atmaca et al., 2008
), and borderline personality disorder (Driessen et al., 2000
). The present study may help to distinguish between hippocampal abnormalities found in depression and other psychiatric disorders. For example, both depression and schizophrenia have been associated with global hippocampal volume reductions (Sumich et al., 2002
). Morphological analysis revealed localised deformations in the anterior regions in schizophrenia (Narr et al., 2004
), while we found greater alterations in posterior tail regions. Furthermore, in schizophrenia the deficits were generally bilateral, more extensive, and clearly evident in patients in their first-episode (Narr et al., 2004
). In depression, the hippocampal deformations were more circumscribed in mid-life depression and volumetric atrophy was only found in the right hippocampus in first-episode depression. This dissociation between psychiatric disorders may have important aetiological and diagnostic implications, and the specificity of the morphological changes will require further investigation.
A caveat to the interpretation of morphological analysis though is limited anatomical accuracy. Hence, local deficits identified with shape mapping and MRI would be characterized with greater precision by neuropathological examination. Furthermore, the present study did not address possible causative mechanisms, such as hippocampal apoptosis and decreased neurogenesis, which may be driven by hypercortisolemia or diminished neurotrophin levels (Czeh and Lucassen, 2007
). Posener et al. (2003)
examined hippocampal morphology by delineating the boundaries of the hippocampus based on specific landmarks, reporting no difference in hippocampal volume but deficits in the subiculum region. The method though consisted of a limited number of anatomical landmarks to define hippocampal morphology which may have minimised gross and local irregularities. Moreover, we did not observe a correlation between hippocampal volume and the number of depressive episodes. The present group though consisted of patients with none or few previous episodes of depression, which may have limited the observation of any correlations as they may become evident in a larger sample with a greater range of episodes.
In summary, hippocampal deformations localised to the subiculum and CA1 subregion extending into the CA2-3 subregions were observed in patients with major depression. Subregional hippocampal deformations may distinguish depression from other psychiatric disorders.