Results Importance of religion or spirituality, but not frequency of attendance, was associated with thicker cortices in the left and right parietal and occipital regions, the mesial frontal lobe of the right hemisphere, and the cuneus and precuneus in the left hemisphere, independent of familial risk. In addition, the effects of importance on cortical thickness were significantly stronger in the high-risk than in the low-risk group, particularly along the mesial wall of the left hemisphere, in the same region where we previously reported a significant thinner cortex associated with a familial risk of developing depressive illness. We note that these findings are correlational and therefore do not prove a causal association between importance and cortical thickness.Conclusions and Relevance A thicker cortex associated with a high importance of religion or spirituality may confer resilience to the development of depressive illness in individuals at high familial risk for major depression, possibly by expanding a cortical reserve that counters to some extent the vulnerability that cortical thinning poses for developing familial depressive illness.We previously reported a 90% decreased risk, assessed prospectively for 10 years, of developing major depressive disorder (MDD) in adult offspring of depressed probands (high familial risk ) who said that religion or spirituality was highly important to them.1 Attendance at religious services and religious denomination did not decrease the risk of MDD. Among the same participants in our 25-year, longitudinal, multigenerational study of MDD who underwent magnetic resonance imaging (MRI), we identified large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere and mesial wall of the left hemisphere in adult offspring of the HR group.2 These findings led us to explore whether the regions where cortical thinning was located in the HR adults would be thicker in those who report a high personal importance of religion or spirituality and whether these findings would be significantly more prominent in persons at HR compared with low familial risk (LR) for MDD. A relatively thicker cortex in these regions could potentially account for the protection against depression that religion or spirituality seem to afford. (For ease of reading, we will refer to the personal importance of religion or spirituality simply as importance.)Numerous studies have found an inverse association between religiosity and depression, and additional studies have attempted to identify a neurobiological basis for religious and spiritual experiences.3- 9 In healthy individuals, for example, transcranial magnetic stimulation of the temporoparietal regions evoked feelings of sensed presence.10 A study11 on older adults using structural MRI prospectively associated born-again status, life-changing religious experiences, and Catholicism with subsequent greater atrophy in the hippocampus. Several functional neuroimaging studies2,12- 15 of healthy adults using functional MRI and single-photon emission computed tomography revealed that the intensity of self-evoked religious experiences during MRI was associated with increased blood flow in various subregions of the prefrontal and parietal cortices. These neurobiological correlates of religious and spiritual experiences, however, have yet to be investigated in terms of the risk and protective benefits that they confer for MDD.In the present study, we followed adults for more than 30 years adults were at either HR or LR for MDD, during which time the participants self-reported importance and frequency of attendance at services and were assessed for symptoms of depression. We assessed the associations of importance with measures of cortical thickness measured on MRIs of the brain acquired at the 25-year follow-up. In addition to reporting thinner cortices in HR adults that averaged nearly 30% across the lateral surface of the right hemisphere and mesial wall of the left, we also previously reported that thinner cortices in the HR group were state independent (ie, a thinner cortex was independent of whether participants were ever depressed and therefore was likely an endophenotype for MDD) and that the cortical thickness mediated the associations of familial risk for MDD with inattention and difficulty recalling social stimuli, cognitive disturbances that in turn were associated with increased symptoms of anxiety and depression.2,15We therefore hypothesized that adults with self-reported high importance compared with those with low or moderate importance would have thicker cortices in brain regions, which was previously identified as an endophenotype for familial MDD. Because we have previously found that the effects of religious importance in protecting against MDD are greater in HR compared with LR adults, we further hypothesized that the HR compared with the LR participants would have larger expanses of the brain in which cortical thickness correlated positively with religious importance.