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.

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.

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.

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.

Posterior EEG alpha at rest and during task performance: Comparison of current source density and field potential measures.

Resting and task-related EEG alpha are used in studies of cognition and psychopathology. Although Laplacian methods have been applied, apprehensions about loss of global activity dissuade researchers from greater use except as a supplement to reference-dependent measures. The unfortunate result has been continued reliance on reference strategies that differ across labs, and a systemic preference for a montage-dependent average reference over true reference-free measures. We addressed these concerns by comparing resting- and task-related EEG alpha using three EEG transformations: nose- (NR) and average-referenced (AR) EEG, and the corresponding CSD. Amplitude spectra of resting and prestimulus task-related EEG (novelty oddball) and event-related spectral perturbations were scaled to equate each transformation. Alpha measures quantified for 8-12 Hz bands were: 1) net amplitude (eyes-closed minus eyes-open) and 2) overall amplitude (eyes-closed plus eyes-open); 3) task amplitude (prestimulus baseline) and 4) task event-related desynchronization (ERD). Mean topographies unambiguously represented posterior alpha for overall, net and task, as well as poststimulus alpha ERD. Topographies were similar for the three transformations, but differed in dispersion, CSD being sharpest and NR most broadly distributed. Transformations also differed in scale, AR showing less attenuation or spurious secondary maxima at anterior sites, consistent with simulations of distributed posterior generators. Posterior task alpha and alpha ERD were positively correlated with overall alpha, but not with net alpha. CSD topographies consistently and appropriately represented posterior EEG alpha for all measures.

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.

ERP generator patterns in schizophrenia during tonal and phonetic oddball tasks: effects of response hand and silent count.

Greater left than right reductions of P3 amplitude in schizophrenia during auditory oddball tasks have been interpreted as evidence of left-lateralized dysfunction. However, the contributions of methodological factors (response mode, stimulus properties, recording reference), which affect event-related potential (ERP) topographies, remain unclear. We recorded 31-channel ERPs from 23 schizophrenic patients and 23 age- and gender-matched healthy controls (all right-handed) during tonal and phonetic oddball tasks, varying response mode (left press, right press, silent count) within subjects. Performance accuracy was high in both groups but patients were slower. ERP generator patterns were summarized by temporal Principal Components Analysis (PCA; unrestricted Varimax) from reference-free current source density (CSD; spherical spline Laplacians) waveforms, which sharpen scalp topographies. CSD represents the magnitude of the radial current flow entering (source) and leaving (sink) the scalp. Both patients and controls showed asymmetric frontolateral and parietotemporal N2 sinks peaking at 240 ms and asymmetric parietal P3 sources (355 ms) for targets (tonal R > L, phonetic L > R), but frontocentral N2 sinks and parietal P3 sources were bilaterally reduced in patients. A response-related midfrontal sink and accompanying centroparietal source (560 ms) were highly comparable across groups. However, a superimposed left temporal source was larger for silent count compared to button press, and this difference was smaller in patients. In both groups, left or right press produced opposite, region-specific asymmetries originating from central sites, modulating the N2/P3 complex. The results suggest bilaterally reduced neural generators of N2 and P3 in schizophrenia during auditory oddball tasks, but both groups showed comparable topographic effects of task and response mode. However, additional working memory demands during silent count may partially overlap in time the generation of the N2/P3 complex and differentially affect the asymmetry of P3 subcomponents, particularly when employing conventional ERP measures.

Reduced brain responses to novel sounds in depression: P3 findings in a novelty oddball task.

There have been conflicting findings as to whether the P3 brain potential to targets in oddball tasks is reduced in depressed patients. The P3 to novel distracter stimuli in a three-stimulus oddball task has a more frontocentral topography than P3 to targets and is associated with different cognitive operations and neural generators. The novelty P3 potential was predicted to be reduced in depressed patients. EEG was recorded from 30 scalp electrodes (nose reference) in 20 unmedicated depressed patients and 20 matched healthy controls during a novelty oddball task with three stimuli: infrequent target tones (12%), frequent standard tones (76%) and nontarget novel stimuli, e.g., animal or environment sounds (12%). Novel stimuli evoked a P3 potential with shorter peak latency and more frontocentral topography than the parietal-maximum P3b to target stimuli. The novelty P3 was markedly reduced in depressed patients compared to controls. Although there was a trend for patients to also have smaller parietal P3b to targets, this group difference was not statistically significant. Nor was there a group difference in the earlier N1 or N2 potentials. The novelty P3 reduction in depressed patients is indicative of a deficit in orienting of attention and evaluation of novel environmental sounds.

Stimulus- and response-locked neuronal generator patterns of auditory and visual word recognition memory in schizophrenia.

Examining visual word recognition memory (WRM) with nose-referenced EEGs, we reported a preserved ERP 'old-new effect' (enhanced parietal positivity 300-800 ms to correctly-recognized repeated items) in schizophrenia ([Kayser, J., Bruder, G.E., Friedman, D., Tenke, C.E., Amador, X.F., Clark, S.C., Malaspina, D., Gorman, J.M., 1999. Brain event-related potentials (ERPs) in schizophrenia during a word recognition memory task. Int. J. Psychophysiol. 34(3), 249-265.]). However, patients showed reduced early negative potentials (N1, N2) and poorer WRM. Because group differences in neuronal generator patterns (i.e., sink-source orientation) may be masked by choice of EEG recording reference, the current study combined surface Laplacians and principal components analysis (PCA) to clarify ERP component topography and polarity and to disentangle stimulus- and response-related contributions. To investigate the impact of stimulus modality, 31-channel ERPs were recorded from 20 schizophrenic patients (15 male) and 20 age-, gender-, and handedness-matched healthy adults during parallel visual and auditory continuous WRM tasks. Stimulus- and response-locked reference-free current source densities (spherical splines) were submitted to unrestricted Varimax-PCA to identify and measure neuronal generator patterns underlying ERPs. Poorer (78.2+/-18.7% vs. 87.8+/-11.3% correct) and slower (958+/-226 vs. 773+/-206 ms) performance in patients was accompanied by reduced stimulus-related left-parietal P3 sources (150 ms pre-response) and vertex N2 sinks (both overall and old/new effects) but modality-specific N1 sinks were not significantly reduced. A distinct mid-frontal sink 50-ms post-response was markedly attenuated in patients. Reductions were more robust for auditory stimuli. However, patients showed increased lateral-frontotemporal sinks (T7 maximum) concurrent with auditory P3 sources. Electrophysiologic correlates of WRM deficits in schizophrenia suggest functional impairments of posterior cortex (stimulus representation) and anterior cingulate (stimulus categorization, response monitoring), primarily affecting memory for spoken words.

Principal components analysis of Laplacian waveforms as a generic method for identifying ERP generator patterns: I. Evaluation with auditory oddball tasks.

OBJECTIVE: To evaluate the effectiveness and comparability of PCA-based simplifications of ERP waveforms versus their reference-free Laplacian transformations for separating task- and response-related ERP generator patterns during auditory oddball tasks. METHODS: Nose-referenced ERPs (31 sites total) were recorded from 66 right-handed adults during oddball tasks using syllables or tones. Response mode (left press, right press, silent count) and task was varied within subjects. Spherical spline current source density (CSD) waveforms were computed to sharpen ERP scalp topographies and eliminate volume-conducted contributions. ERP and CSD data were submitted to separate covariance-based, unrestricted temporal PCAs (Varimax) to disentangle temporally and spatially overlapping ERP and CSD components. RESULTS: Corresponding ERP and CSD factors were unambiguously related to known ERP components. For example, the dipolar organization of a central N1 was evident from factorized anterior sinks and posterior sources encompassing the Sylvian fissure. Factors associated with N2 were characterized by asymmetric frontolateral (tonal: frontotemporal R > L) and parietotemporal (phonetic: parietotemporal L > R) sinks for targets. A single ERP factor summarized parietal P3 activity, along with an anterior negativity. In contrast, two CSD factors peaking at 360 and 560 ms distinguished a parietal P3 source with an anterior sink from a centroparietal P3 source with a sharply localized Fz sink. A smaller parietal but larger left temporal P3 source was found for silent count compared to button press. Left or right press produced opposite, region-specific asymmetries originating from central sites, modulating the N2/P3 complex. CONCLUSIONS: CSD transformation is shown to be a valuable preprocessing step for PCA of ERP data, providing a unique, physiologically meaningful solution to the ubiquitous reference problem. By reducing ERP redundancy and producing sharper, simpler topographies, and without losing or distorting any effects of interest, the CSD-PCA solution replicated and extended previous task- and response-related findings. SIGNIFICANCE: Eliminating ambiguities of the recording reference, the combined CSD-PCA approach systematically bridges between montage-dependent scalp potentials and distinct, anatomically-relevant current generators, and shows promise as a comprehensive, generic strategy for ERP analysis.

Principal components analysis of Laplacian waveforms as a generic method for identifying ERP generator patterns: II. Adequacy of low-density estimates.

OBJECTIVE: To evaluate the comparability of high- and low-density surface Laplacian estimates for determining ERP generator patterns of group data derived from a typical ERP sample size and paradigm. METHODS: High-density ERP data (129 sites) recorded from 17 adults during tonal and phonetic oddball tasks were converted to a 10-20-system EEG montage (31 sites) using spherical spline interpolations. Current source density (CSD) waveforms were computed from the high- and low-density, but otherwise identical, ERPs, and correlated at corresponding locations. CSD data were submitted to separate covariance-based, unrestricted temporal PCAs (Varimax of covariance loadings) to identify and effectively summarize temporally and spatially overlapping CSD components. Solutions were compared by correlating factor loadings and scores, and by plotting ANOVA F statistics derived from corresponding high- and low-resolution factor scores using representative sites. RESULTS: High- and low-density CSD waveforms, PCA solutions, and F statistics were remarkably similar, yielding correlations of .9 < or = r < or = .999 between waveforms, loadings, and scores for almost all comparisons at low-density locations except for low-signal CSD waveforms at occipital sites. Each of the first 10 high-density factors corresponded precisely to one factor of the first 10 low-density factors, with each 10-factor set accounting for the meaningful CSD variance (> 91.6%). CONCLUSIONS: Low-density surface Laplacian estimates were shown to be accurate approximations of high-density CSDs at these locations, which adequately and quite sufficiently summarized group data. Moreover, reasonable approximations of many high-density scalp locations were obtained for group data from interpolations of low-density data. If group findings are the primary objective, as typical for cognitive ERP research, low-resolution CSD topographies may be as efficient, given the effective spatial smoothing when averaging across subjects and/or conditions. SIGNIFICANCE: Conservative recommendations for restricting surface Laplacians to high-density recordings may not be appropriate for all ERP research applications, and should be re-evaluated considering objective, costs and benefits.

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.

Event-related brain potentials during auditory and visual word recognition memory tasks.

Event-related brain potentials (ERPs) recorded during presentation of a series of words or pictures show enhanced positivity between 300 and 800 ms after presentation of repeated items. However, little attention has been directed to the characterization of this ERP recognition memory effect using auditory stimuli. The present study directly compared the ERP 'old/new effect' for words presented in the visual and auditory modalities. Nose-referenced ERPs were recorded from 30 electrode sites while participants (N=16) were engaged in visual and auditory continuous word recognition memory tasks. Spatially and temporally overlapping ERP components were identified and measured by covariance-based principal components analysis. The expected old/new effect was observed in both modalities, with a comparable time course peaking at 560 ms, but having a more anterior scalp topography for visual items. This suggests a common cognitive process (i.e. successful retrieval of information from memory) associated with separable neural generators in each modality. Despite this temporal synchronization, the old/new effect overlapped ERP components having distinct scalp topographies (N2) or peak latencies (P3) for each modality. The positive-going old/new effect was preceded by an earlier negativity peaking at 370 ms that was greater across modalities for old than new words, likely reflecting semantic processing aspects of word recognition memory. A late (beyond 900 ms), broadly-distributed negativity was also greater for old than new words, prolonged for auditory items, and may represent activity of a post-retrieval process.