Previous investigations have documented lower hippocampal volume in depressed than in nondepressed persons9,10
; the present study is the first to report smaller hippocampal volume in healthy girls at high familial risk for depression but who have not yet experienced the disorder. Few studies have examined neuroanatomical anomalies in children at high risk for psychopathology. Recently, Ladouceur and colleagues48
reported increased hippocampal and parahippocampal volume in individuals at high risk for bipolar disorder. These results both underscore the potential importance of the hippocampal formation in affecting risk for psychopathology and highlight a possible biological differentiation between risk for bipolar versus unipolar depressive disorders. While the present data do not preclude an association between hippocampal volume reduction and episode duration in currently depressed individuals, they do raise the possibility that the depressed participants characterized in previous studies had reduced hippocampal volumes prior to the onset of their depressive episode.
While we do not know the cause of the reduced hippocampal volume in individuals at risk for depression, it is likely that genetics plays a significant role49
. Given their family history, the high-risk daughters in this study are likely to have a genetic predisposition for developing depression, which may also contribute to the reduction in hippocampal volume documented here. Several studies have reported associations between specific genes and reductions in hippocampal volume: the long variant of the serotonin transporter promoter region polymorphism in depressed patients50
; the met
allele of the brain-derived neurotrophic factor val66met
polymorphism in depressed patients and controls51
; and single nucleotide polymorphisms (SNPs) within the disrupted-in-schizophrenia 1 gene in schizophrenics52
. It is becoming increasingly clear, therefore, that the functional impact of genetic factors, including SNPs, on a complicated endophenotype such as neuroanatomical structure warrants further investigation53
Importantly, experiential variables have also been found to influence brain morphometry, especially in the context of depression. For example, a large number of studies have reported that childhood trauma, such as physical or sexual abuse, predicts reduced hippocampal volume in individuals who subsequently develop depression in adulthood54,55,56
, but a recent study by Lenze et al.57
found no association between childhood adversity and hippocampal volume. It is unlikely that a single gene or environmental stressor is responsible for the decreased hippocampal volume found in girls at risk for depression; it will be important to consider a combination of inherited characteristics and life experiences in understanding the results of the present study58
As we noted earlier, depressed individuals have been characterized by HPA-axis dysfunction and reductions in hippocampal volume4,5,9,10
. While the precise reasons for this decreased hippocampal volume are not clear from histopathological studies59
, it is well documented that glucocorticoids increase vulnerability of hippocampal neurons to excitotoxic insults8
. Consistent with its role in the negative feedback regulation of the HPA-axis that controls cortisol production, smaller hippocampal volume has been found to be associated with increased cortisol secretion in response to a stressor60
, increased adrenocorticotropic hormone release and inhibited feedback regulation in response to a stressor61
, as well as with vulnerability to post-traumatic stress disorder62
. Increased cortisol levels, in turn, could further impair hippocampal regulation and lead to increased cortisol production. Notably, early experiences, such as childhood abuse, can affect epigenetic regulation of the glucocorticoid system in the hippocampus well into adulthood63
. Indeed, a combination of genetic, epigenetic, and environmental factors may affect hippocampal regulation of the HPA-axis. Thus, high-risk individuals with reduced hippocampal volume may be especially vulnerable to HPA-axis dysregulation and hippocampal damage, especially in the context of the development of MDD.
Given the connection of the hippocampus with other limbic and cortical circuits involved in the regulation of mood and cognition, it is not surprising that reduced hippocampal volume has been associated with executive dysfunction in depressed individuals64
. The present finding of decreased hippocampal volume in a sample of never-depressed young girls at high risk for the development of this disorder may help to explain why people who have recovered from MDD continue to show deficits in psychological and neurocognitive functioning65
. In addition, reduced hippocampal volume has been found to predict poorer outcome in depressed individuals21
; thus, reduced hippocampal volume may reflect a vulnerability for recurrent depressive episodes. Finally, given evidence that reduction in hippocampal volume in depression may be associated with specific subtypes of depression, such as psychotic depression66
, it will be important to follow these participants to examine the association between reduced hippocampal volume and the probability of developing specific depressive disorders.
Despite the strengths of the present study, there are also a number of limitations. For example, we did not administer measures of neuropsychological functioning or obtain information about school performance in the sample and, therefore, do not know whether reduced hippocampal volume is associated with specific cognitive deficits, such as difficulties in memory67
. We also do not have data concerning antenatal and early life experiences of these participants aside from major psychopathology, such as PTSD, that might have resulted from these experiences. Obtaining a detailed assessment of early life experiences in future studies may help to elucidate the differential contribution of genetic and experiential factors to hippocampal volume. Finally, while the VBM analysis indicated that there were gray matter density reductions in the high-risk girls in bilateral hippocampus, manual tracing yielded significant volume reductions in high-risk participants only in the left hippocampus. Given that the manual segmentation also yielded reductions, though not statistically significant, in right hippocampal volume in the high-risk girls, VBM may be more sensitive than manual tracing to regional changes. In any case, however, the role of potentially asymmetric volume change in the hippocampi in young girls is an important direction for further study68
Identifying the factors that contribute to reduced hippocampal volume in individuals at high risk for MDD will be critical in helping to understand the mechanisms of inheritance of risk for this disorder. In this context, it will be important in future research to integrate brain imaging techniques with assessments of specific genetic risk factors and neuroendocrinological and psychosocial functioning. Given that the behavioral effects of many antidepressants depend on neurogenesis in the hippocampus69
, as well as the observation that antidepressant treatment prevents stress-related hippocampal volume loss70
and may reverse hippocampal volume reduction in depression22
, promoting neurogenesis through antidepressants or other interventions in individuals at high risk for depression may prevent or reverse neuronal or glial atrophy and, ultimately, delay or prevent the onset of the disorder.