Abstract
Mental disorders are a major cause of long-term disability and are a direct cause of mortality, with approximately 800.000 individuals dying from suicide every year worldwide - a high proportion of them related to major depressive disorder (MDD)^1^. Healthy relatives of patients with major depressive disorder (MDD) are at risk to develop the disease. This higher vulnerability is associated with structural^2-4^ and functional brain changes^5^. However, we found using high angular resolution diffusion imaging (HARDI) with 61 diffusion directions that neuron tracts between frontal cortices and limbic as well as temporal and parietal brain regions are characterized by better diffusion coefficients in unaffected relatives (UHR), who managed to stay healthy, compared to healthy volunteers without any family history for a psychiatric disease (HC). Moreover, those UHR with stronger fibre connections better managed incidences of adversity in early life without later developing depression, while in HC axonal connections were found to be decreased when they had early-life adversity. Altogether these findings indicate the presence of stronger neural fibre connections in UHR, which seem to be associated with resilience against environmental stressors, which we suggest occur through epigenetic mechanisms.
Highlights
Stress led to depressive-like states accompanied by atrophy and loss of neurons in the adult hippocampus in experimental studies 6
Sub threshold depression scores were significantly higher in unaffected healthy relatives (UHR) compared to healthy subjects (HC) reflecting the familial risk for developing major depressive disorder (MDD), whereby all values were still within the normal range (Supplementary Table 1)
No differences were seen in depression severity between UHR with and without early life adversity, there was a positive correlation between depression severity and fractional anisotropy (FA) values in the whole group of subjects reflecting the fact that UHR had significant higher FA values and higher depression scores compared to HC
Summary
Stress led to depressive-like states accompanied by atrophy and loss of neurons in the adult hippocampus in experimental studies 6. These effects of stress seem to depend on individual characteristics since initial vulnerability of a mouse to social defeat stress seems to be determined by its basal concentration of transcription factors (ΔFosB (Fos family transcription factor). The aim of the present study was to investigate microstructural changes in white matter tracts in a sample of unaffected healthy relatives (UHR) of patients with MDD at familial risk to develop the disease, but who managed to stay well, compared to healthy subjects (HC) without any familial risk for psychiatric diseases. The second objective was to investigate whether early-life adversity interacts with group differences and whether this might add to findings from experimental studies showing the importance of epigenetic mechanisms
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