Altruism and "love of neighbor" offer neuroanatomical protection against depression.

We prospectively investigate protective benefits against depression of cortical thickness across nine regions of a Ventral Frontotemporal Network (VFTN), previously associated with spiritual experience. Seventy-two participants at high and low risk for depression (Mean age 41 years; 22-63 years; 40 high risk, 32 low risk) were drawn from a three-generation, thirty-eight year study. FreeSurfer estimated cortical thickness over anatomical MRIs of the brain (Year 30) for each of the nine ROIs. Depression (MDD with SAD-L; symptoms with PHQ; Years 30 and 38) and spirituality (self-report on five phenotypes; Year 35), respectively, were associated with the weighted average of nine regions of interest. VFTN thickness was: 1) positively associated (p<0.01) with two of five spiritual phenotypes, altruism and love of neighbor, interconnectedness at a trend level, but neither commitment nor practice, 2) inversely associated with a diagnosis of MDD (SADS-L Year 30, for any MDD in the past ten years), and 3) prospectively neuroanatomically protective against depressive symptoms (PHQ-9 Year 38) for those at high familial risk.

Predicting Depression Symptoms in Families at Risk for Depression: Interrelations of Posterior EEG Alpha and Religion/Spirituality.

BACKGROUND: Posterior EEG alpha has been identified as a putative biomarker of clinical outcomes in major depression (MDD). Separately, personal importance of religion and spirituality (R/S) has been shown to provide protective benefits for individuals at high familial risk for MDD. This study directly explored the joint value of posterior alpha and R/S on predicting clinical health outcomes of depression. METHODS: Using a mixed-effects model approach, we obtained virtual estimates of R/S at age 21 using longitudinal data collected at 5 timepoints spanning 25 years. Current source density and frequency principal component analysis was used to quantify posterior alpha in 72-channel resting EEG (eyes open/closed). Depression severity was measured between 5 and 10 years after EEG collection using PHQ-9 and IDAS-GD scales. RESULTS: Greater R/S (p = .008, η2p = 0.076) and higher alpha (p = .02, η2p = 0.056) were separately associated with fewer symptoms across scales. However, an interaction between alpha and R/S (p = .02, η2p = 0.062) was observed, where greater R/S predicted fewer symptoms with low alpha but high alpha predicted fewer symptoms with lower R/S. LIMITATIONS: Small-to-medium effect sizes and homogeneity of sample demographics caution overall interpretation and generalizability. CONCLUSIONS: Findings revealed a complementary role of R/S and alpha in that either variable exerted protective effects only if the other was present at low levels. These findings confirm the relevance of R/S importance and alpha oscillations as predictors of depression symptom severity. More research is needed on the neurobiological mechanism underlying the protective effects of R/S importance for MDD.

Understanding self-reported importance of religion/spirituality in a North American sample of individuals at risk for familial depression: A principal component analysis.

Several studies have shown protective effects between health outcomes and subjective reports of religious/spiritual (R/S) importance, as measured by a single self-report item. In a 3-generation study of individuals at high or low familial risk for depression, R/S importance was found to be protective against depression, as indicated by clinical and neurobiological outcomes. The psychological components underlying these protective effects, however, remain little understood. Hence, to clarify the meaning of answering the R/S importance item, we employed a comprehensive set of validated scales assessing religious beliefs and experiences and exploratory factor analysis to uncover latent R/S constructs that strongly and independently correlated with the single-item measure of R/S importance. A Varimax-rotated principal component analysis (PCA) resulted in a 23-factor solution (Eigenvalue > 1; 71.5% explained variance) with 8 factors that, respectively, accounted for at least 3% of the total variance. The first factor (15.8%) was directly related to the R/S importance item (r = .819), as well as personal relationship with the Divine, forgiveness by God, religious activities, and religious coping, while precluding gratitude, altruism, and social support, among other survey subscales. The corresponding factor scores were greater in older individuals and those at low familial risk. Moreover, Spearman rank-order correlations between the R/S importance item and other subscales revealed relative consistency across generations and risk groups. Taken together, the single R/S importance item constituted a robust measure of what may be generally conceived of as "religious importance," ranking highest among a diverse latent factor structure of R/S. As this suggests adequate single-item construct validity, it may be adequate for use in health studies lacking the resources for more extensive measures. Nonetheless, given that this single item accounted for only a small fraction of the total survey variance, results based on the item should be interpreted and applied with caution.

Current Understanding of Religion, Spirituality, and Their Neurobiological Correlates.

Religion and spirituality (R/S) have been prominent aspects of most human cultures through the ages; however, scientific inquiry into this phenomenon has been limited. We conducted a systematic literature review of research on the neurobiological correlates of R/S, which resulted in 25 reports studying primarily R/S with electroencephalography, structural neuroimaging (MRI), and functional neuroimaging (fMRI, PET). These studies investigated a wide range of religions (e.g., Christianity, Buddhism, Islam) and R/S states and behaviors (e.g., resting state, prayer, judgments) and employed a wide range of methodologies, some of which (e.g., no control group, varying measures of religiosity, small sample sizes) raise concerns about the validity of the results. Despite these limitations, the findings of these studies collectively suggest that the experience of R/S has specific neurobiological correlates and that these correlates are distinct from non-R/S counterparts. The findings implicate several brain regions potentially associated with R/S development and behavior, including the medial frontal cortex, orbitofrontal cortex, precuneus, posterior cingulate cortex, default mode network, and caudate. This research may suggest future clinical applications and interventions related to R/S and various disorders, including mood, anxiety, psychotic, pain, and vertiginous disorders. Further studies with more rigorous study designs are warranted to elucidate the neurobiological mechanisms of R/S and their potential clinical applications.

Multidimensional understanding of religiosity/spirituality: relationship to major depression and familial risk.

BACKGROUND: Previous research has shown prospectively that religiosity/spirituality protects against depression, but these findings are commonly critiqued on two grounds, namely: (1) apparent religiosity/spirituality reflects merely an original absence of depression or elevated mood and (2) religiosity/spirituality too often is measured as a global construct. The current study investigates the relationship between depression and religiosity/spirituality by examining its multidimensional structural integrity. METHOD: Confirmatory factor analyses with a previously observed cross-cultural factor structure of religiosity/spirituality variables were conducted on an independent sample, diagnostic and familial risk subgroups from this sample, and a subsample of the original cross-cultural sample. Linear regressions onto a previous diagnosis of major depressive disorder (MDD) 5 years prior to assess the potential attenuating impact of a previous depression was explored. RESULTS: Across familial risk groups and clinical subgroups, each of the previously validated religiosity/spirituality domains was confirmed, namely: religious/spiritual commitment, contemplative practice, sense of interconnectedness, the experience of love, and altruistic engagement. Previous MDD diagnosis was associated with a lower religious/spiritual commitment among high-risk individuals, higher contemplation among low-risk individuals, and lower importance of religion or spirituality regardless of risk group. CONCLUSIONS: Structural integrity was found across familial risk groups and diagnostic history for a multidimensional structure of religiosity/spirituality. Differential associations between a previous diagnosis of MDD and level of religiosity/spirituality across domains suggest a complex and interactive relation between depression, familial risk, and religiosity/spirituality. Accounting for an empirically valid, multidimensional understanding of religiosity/spirituality may advance research on mechanisms underlying the relationship between religiosity/spirituality and mental health.

Family Risk for Depression and Prioritization of Religion or Spirituality: Early Neurophysiological Modulations of Motivated Attention.

The personal importance of religion or spirituality (R/S) has been associated with a lower risk for major depression (MDD), suicidal behavior, reduced cortical thinning and increased posterior EEG alpha, which has also been linked to antidepressant treatment response in MDD. Building on prior event-related potential (ERP) findings using an emotional hemifield paradigm, this study examined whether abnormal early (preconscious) responsivity to negative arousing stimuli, which is indicative of right parietotemporal dysfunction in both MDD patients and individuals at clinical high risk for MDD, is likewise moderated by R/S. We reanalyzed 72-channel ERP data from 127 individuals at high or low family risk for MDD (Kayser et al., 2017, NeuroImage Clin. 14, 692-707) after R/S stratification (low R/S importance, low/high risk, n = 38/61; high R/S importance, n = 15/13). ERPs were transformed to reference-free current source density (CSD) and quantified by temporal principal components analysis (tPCA). This report focused on N2 sink (peak latency 212 ms), the earliest prominent CSD-tPCA component previously found to be sensitive to emotional content. While overall N2 sink reflected activation of occipitotemporal cortex (prestriate/cuneus), as estimated via a distributed inverse solution, affective significance was marked by a relative (i.e., superimposed) positivity. Statistical analyses employed both non-parametric permutation tests and repeated measures ANOVA for mixed factorial designs with unstructured covariance matrix, including sex, age, and clinical covariates. Participants with low R/S importance, independent of risk status, showed greater ERP responsivity to negative than neutral stimuli, particularly over the right hemisphere. In contrast, early emotional ERP responsivity and asymmetry was substantially reduced for high risk individuals with high R/S importance, however, enhanced for low risk individuals with high R/S importance. Hemifield modulations of these effects (i.e., emotional ERP enhancements with left visual field/right hemisphere stimulus presentations) further corroborated these observations. Results suggest down-regulation of a right-lateralized network for salience detection at an early processing stage in high risk and high R/S importance individuals, presumably to prevent overactivation of ventral brain regions further downstream. These findings may point to a neurophysiological mechanism underlying resilience of families at risk for depression with high R/S prioritization.

Genetic Correlates of Spirituality/Religion and Depression: A Study in Offspring and Grandchildren at High and Low Familial Risk for Depression.

RATIONALE: Possible genetic correlates of spirituality and depression have been identified in community samples. We investigate some of the previously identified candidates in a sample of families at both high and low-risk for depression. METHOD: Offspring and grandchildren of individuals at high and low-risk for depression, participating in a multi-wave thirty-year longitudinal study, were assessed for seven SNPS drawn from four single gene candidates associated with systems implicated in both depression and spirituality: Serotonin (5-HT1B and 5-HT2A), Dopamine (DRD2), Oxytocin (OT) and Monoamine Vesicular Transporter (VMAT1). RESULTS: Dopamine (DRD2) Serotonin (5-HT1B), their Transporter (VMAT1) and Oxytocin (OXTR) were positively associated with a high level of importance of spirituality or religion (S/R) in the group at low familial risk for depression. DRD2 minor allele was associated with both lifetime major depressive disorder (MDD) and spirituality in the low-risk group for depression. No SNPs were related to S/R in the group at high familial risk for depression. OXTR was associated with lifetime MDD in the full sample. CONCLUSION: Genes for dopamine, serotonin, their vesicular transporter, and oxytocin may be associated with S/R in people at low familial risk for depression. Genes for dopamine may be associated both with S/R and increased risk for depression in people at low-risk for depression, suggesting a common pathway or physiology to mild to moderate depression. MDD is associated with oxytocin across risk groups. In the high-risk group, phenotypic expression of S/R may be suppressed. IMPLICATIONS: The shared association of DRD2 by S/R and depression, generally found to be inversely related, calls for further research on their common physiological pathways, and the phenotypic expression of these pathways based upon use and environment. Prevention for offspring at high familial risk for depression might include support for the development of child spirituality.

Neuroanatomical correlates of familial risk-for-depression and religiosity/spirituality.

OBJECTIVE: To examine potential neural substrates that underlie the interplay between religiosity/spirituality and risk-for-depression. A new wave of data from a longitudinal, three generation study of individuals at high risk for depression is presented. In addition to providing new longitudinal data, we extend previous findings by employing additional (surface-based) methods for examining cortical volume. MEASURES PARTICIPANTS AND METHODS: Magnetic resonance imaging (MRI) scans were collected on 106 second and third generation family members at high or low risk for major depression defined by the presence or absence of depression in the first generation. Religiosity/spirituality measures were collected at the same time as the MRI scans and comprised self-report ratings of personal religious/spiritual (R/S) importance and frequency of religious attendance. Analyses were carried out with Freesurfer. Interactive effects of religiosity/spirituality and risk-for-depression were examined on measures of cortical thickness and cortical surface area. RESULTS: A high degree of belief in the importance of religion/spirituality was associated with both a thicker cortex and a larger pial surface area in persons at high risk for familial depression. No significant association was found between cortical regions and religious attendance in either risk group. CONCLUSIONS AND RELEVANCE: The results support previous findings of an association between R/S importance and cortical thickness in individuals at high risk for depression, and extend the findings to include an association between R/S importance and greater pial surface area. Moreover, the findings suggest these cortical changes may confer protective benefits to religious/spiritual individuals at high risk for depression.

Association of posterior EEG alpha with prioritization of religion or spirituality: A replication and extension at 20-year follow-up.

A prior report (Tenke et al., 2013 Biol. Psychol. 94:426-432) found that participants who rated religion or spirituality (R/S) highly important had greater posterior alpha after 10 years compared to those who did not. Participants who subsequently lowered their rating also had prominent alpha, while those who increased their rating did not. Here we report EEG findings 20 years after initial assessment. Clinical evaluations and R/S ratings were obtained from 73 (52 new) participants in a longitudinal study of family risk for depression. Frequency PCA of current source density transformed EEG concisely quantified posterior alpha. Those who initially rated R/S as highly important had greater alpha compared to those who did not, even if their R/S rating later increased. Furthermore, changes in religious denomination were associated with decreased alpha. Results suggest the possibility of a critical stage in the ontogenesis of R/S that is linked to posterior resting alpha.

Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response.

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.

Religious and spiritual importance moderate relation between default mode network connectivity and familial risk for depression.

Individuals at high risk for depression have increased default mode network (DMN) connectivity, as well as reduced inverse connectivity between the DMN and the central executive network (CEN) [8]. Other studies have indicated that the belief in the importance of religion/spirituality (R/S) is protective against depression in high risk individuals [5]. Given these findings, we hypothesized that R/S importance would moderate DMN connectivity, potentially reducing DMN connectivity or increasing DMN-CEN inverse connectivity in individuals at high risk for depression. Using resting-state functional connectivity MRI (rs-fcMRI) in a sample of 104 individuals (aged 11-60) at high and low risk for familial depression, we previously reported increased DMN connectivity and reduced DMN-CEN inverse connectivity in high risk individuals. Here, we found that this effect was moderated by self-report measures of R/S importance. Greater R/S importance in the high risk group was associated with decreased DMN connectivity. These results may represent a protective neural adaptation in the DMN of individuals at high risk for depression, and may have implications for other meditation-based therapies for depression.

Neuroanatomical correlates of religiosity and spirituality: a study in adults at high and low familial risk for depression.

IMPORTANCE: We previously reported a 90% decreased risk in major depression, assessed prospectively, in adult offspring of depressed probands who reported that religion or spirituality was highly important to them. Frequency of church attendance was not significantly related to depression risk. Our previous brain imaging findings in adult offspring in these high-risk families also revealed large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere. OBJECTIVE: To determine whether high-risk adults who reported high importance of religion or spirituality had thicker cortices than those who reported moderate or low importance of religion or spirituality and whether this effect varied by family risk status. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, retrospective cohort, familial study of 103 adults (aged 18-54 years) who were the second- or third-generation offspring of depressed (high familial risk) or nondepressed (low familiar risk) probands (first generation). Religious or spiritual importance and church attendance were assessed at 2 time points during 5 years, and cortical thickness was measured on anatomical images of the brain acquired with magnetic resonance imaging at the second time point. MAIN OUTCOMES AND MEASURES: Cortical thickness in the parietal regions by risk status. 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.

Religiosity and major depression in adults at high risk: a ten-year prospective study.

OBJECTIVE: Previously the authors found that personal importance of religion or spirituality was associated with a lower risk for major depression in a study of adults with and without a history of depression. Here the authors examine the association of personal importance of religion or spirituality with major depression in the adult offspring of the original sample using a 10-year prospective longitudinal design. METHOD: Participants were 114 adult offspring of depressed and nondepressed parents, followed longitudinally. The analysis covers the period from the 10-year to the 20-year follow-up assessments. Diagnosis was assessed with the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. Religiosity measures included personal importance of religion or spirituality, frequency of attendance at religious services, and denomination (all participants were Catholic or Protestant). In a logistic regression analysis, major depression at 20 years was used as the outcome measure and the three religiosity variables at 10 years as predictors. RESULTS: Offspring who reported at year 10 that religion or spirituality was highly important to them had about one-fourth the risk of experiencing major depression between years 10 and 20 compared with other participants. Religious attendance and denomination did not significantly predict this outcome. The effect was most pronounced among offspring at high risk for depression by virtue of having a depressed parent; in this group, those who reported a high importance of religion or spirituality had about one-tenth the risk of experiencing major depression between years 10 and 20 compared with those who did not. The protective effect was found primarily against recurrence rather than onset of depression. CONCLUSIONS: A high self-report rating of the importance of religion or spirituality may have a protective effect against recurrence of depression, particularly in adults with a history of parental depression.

Families at high and low risk for depression: a three-generation startle study.

BACKGROUND: Anxiety symptoms might be a vulnerability factor for the development of major depressive disorder (MDD). Because elevated startle magnitude in threatening contexts is a marker for anxiety disorder, the present study investigated the hypothesis that enhanced startle reactivity would also be found in children and grandchildren of individuals with MDD. METHODS: The magnitude of startle was investigated in two tests (anticipation of an unpleasant blast of air and during darkness) in children (second generation) and grandchildren (third generation) of probands with (high risk) or without (low risk) MDD (first generation). RESULTS: Startle discriminated between the low- and high-risk groups. In the probands' children, the high-risk group showed increased startle magnitude throughout the fear-potentiated startle test. In the probands' grandchildren, a gender-specific abnormality was found in the high-risk group with high-risk girls, but not boys, exhibiting elevated startle magnitude throughout the procedure. CONCLUSIONS: Increased startle reactivity in threatening contexts, previously found in patients with anxiety disorder and in children of parents with an anxiety disorder, might also constitute a vulnerability marker for MDD. These findings suggest that there might be common biologic diatheses underlying depression and anxiety.