Feedback negativity and feedback-related P3 in individuals at risk for depression: Comparing surface potentials and current source densities.

Blunted responses to reward feedback have been linked to major depressive disorder (MDD) and depression risk. Using a monetary incentive delay task (win, loss, break-even), we investigated the impact of family risk for depression and lifetime history of MDD and anxiety disorder with 72-channel electroencephalograms (EEG) recorded from 29 high-risk and 32 low-risk individuals (15-58 years, 30 male). Linked-mastoid surface potentials (ERPs) and their corresponding reference-free current source densities (CSDs) were quantified by temporal principal components analysis (PCA). Each PCA solution revealed a midfrontal feedback negativity (FN; peak around 310 ms) and a posterior feedback-P3 (fb-P3; 380 ms) as two distinct reward processing stages. Unbiased permutation tests and multilevel modeling of component scores revealed greater FN to loss than win and neutral for all stratification groups, confirming FN sensitivity to valence. Likewise, all groups had greater fb-P3 to win and loss than neutral, confirming that fb-P3 indexes motivational salience and allocation of attention. By contrast, group effects were subtle, dependent on data transformation (ERP, CSD), and did not confirm reduced FN or fb-P3 for at-risk individuals. Instead, CSD-based fb-P3 was overall reduced in individuals with than without MDD history, whereas ERP-based fb-P3 was greater for high-risk individuals than for low-risk individuals for monetary, but not neutral outcomes. While the present findings do not support blunted reward processing in depression and depression risk, our side-by-side comparison underscores how the EEG reference choice affects the characterization of subtle group differences, strongly advocating the use of reference-free techniques.

Neurophysiological responses to emotional faces predict dynamic fluctuations in affect in adolescents.

The ability to accurately identify and interpret others' emotions is critical for social and emotional functioning during adolescence. Indeed, previous research has identified that laboratory-based indices of facial emotion recognition and engagement with emotional faces predict adolescent mood states. Whether socioemotional information processing relates to real-world affective dynamics using an ecologically sensitive approach, however, has rarely been assessed. In the present study, adolescents (N = 62; ages 13-18) completed a Facial Recognition Task, including happy, angry, and sad stimuli, while EEG data were acquired. Participants also provided ecological momentary assessment (EMA) data probing their current level of happiness, anger, and sadness for 1-week, resulting in indices of emotion (mean-level, inertia, instability). Analyses focused on relations between (1) accuracy for and (2) prolonged engagement with (LPP) emotional faces and EMA-reported emotions. Greater prolonged engagement with happy faces was related to less resistance to changes in happiness (i.e., less happiness inertia), whereas greater prolonged engagement with angry faces associated with more resistance to changes in anger (i.e., greater anger inertia). Results suggest that socioemotional processes captured by laboratory measures have real-world implications for adolescent affective states and highlight potentially actionable targets for novel treatment approaches (e.g., just-in-time interventions). Future studies should continue to assess relations among socioemotional informational processes and dynamic fluctuations in adolescent affective states.

Putamen Structure and Function in Familial Risk for Depression: A Multimodal Imaging Study.

BACKGROUND: The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression. METHODS: The study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N-acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively. RESULTS: After adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, ß-left = -0.17, ß-right = -0.15, ps = .002), N-acetylaspartate/creatine ratio (ß-left= -0.40, ß-right= -0.37, ps < .0001), and activation modulated by valence (ß-left = -0.22, ß-right = -0.27, ps < .05) than low-risk individuals. Volume differences were greater at younger ages, and N-acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (ß-left = -0.72, p = .013; ß-right = -0.83, p = .037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33). CONCLUSIONS: Findings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them.

A systematic data-driven approach to analyze sensor-level EEG connectivity: Identifying robust phase-synchronized network components using surface Laplacian with spectral-spatial PCA.

Although conventional averaging across predefined frequency bands reduces the complexity of EEG functional connectivity (FC), it obscures the identification of resting-state brain networks (RSN) and impedes accurate estimation of FC reliability. Extending prior work, we combined scalp current source density (CSD; spherical spline surface Laplacian) and spectral-spatial PCA to identify FC components. Phase-based FC was estimated via debiased-weighted phase-locking index from CSD-transformed resting EEGs (71 sensors, 8 min, eyes open/closed, 35 healthy adults, 1-week retest). Spectral PCA extracted six robust alpha and theta components (86.6% variance). Subsequent spatial PCA for each spectral component revealed seven robust regionally focused (posterior, central, and frontal) and long-range (posterior-anterior) alpha components (peaks at 8, 10, and 13 Hz) and a midfrontal theta (6 Hz) component, accounting for 37.0% of FC variance. These spatial FC components were consistent with well-known networks (e.g., default mode, visual, and sensorimotor), and four were sensitive to eyes open/closed conditions. Most FC components had good-to-excellent internal consistency (odd/even epochs, eyes open/closed) and test-retest reliability (ICCs ≥ .8). Moreover, the FC component structure was generally present in subsamples (session × odd/even epoch, or smaller subgroups [n = 7-10]), as indicated by high similarity of component loadings across PCA solutions. Apart from systematically reducing FC dimensionality, our approach avoids arbitrary thresholds and allows quantification of meaningful and reliable network components that may prove to be of high relevance for basic and clinical research applications.

Resting posterior alpha power and adolescent major depressive disorder.

For several decades, resting electroencephalogram (EEG) alpha oscillations have been used to characterize neurophysiological alterations related to major depressive disorder. Prior research has generally focused on frontal alpha power and asymmetry despite resting alpha being maximal over posterior electrode sites. Research in depressed adults has shown evidence of hemispheric asymmetry for posterior alpha power, however, the resting posterior alpha-depression link among adolescents remains unclear. To clarify the role of posterior alpha among depressed adolescents, the current study acquired eyes-closed 128-channel resting EEG data from 13 to 18 year-old depressed (n = 31) and healthy (n = 35) female adolescents. Results indicated a significant group by hemisphere interaction, as depressed adolescents exhibited significantly larger posterior alpha (i.e., lower brain activity) over the right versus left hemisphere, whereas healthy adolescents showed no hemispheric differences. Relatively greater alpha over the right versus left hemisphere correlated with depression symptoms, anhedonia symptoms, rumination, and self-criticism. Further, depressed adolescents had reduced overall posterior alpha compared to healthy youth; though, no associations with symptoms and related traits emerged. Resting posterior alpha may be a promising neurophysiological index of adolescent depression, and more broadly, may relate to risk factors characterized by enhanced perseveration.

Dissociating disorders of depression, anxiety, and their comorbidity with measures of emotional processing: A joint analysis of visual brain potentials and auditory perceptual asymmetries.

In a multigenerational study of families at risk for depression, individuals with a lifetime history of depression had: 1) abnormal perceptual asymmetry (PA; smaller left ear/right hemisphere [RH] advantage) in a dichotic emotion recognition task, and 2) reduced RH late positive potential (P3RH) during an emotional hemifield task. We used standardized difference scores for processing auditory (PA sad-neutral) and visual (P3RH negative-neutral) stimuli for 112 participants (52 men) in a logistic regression to predict history of depression, anxiety or comorbidity of both. Whereas comorbidity was separately predicted by reduced PA (OR = 0.527, p = .042) or P3RH (OR = 0.457, p = .013) alone, an interaction between PA and P3RH (OR = 2.499, p = .011) predicted depressive disorder. Follow-up analyses revealed increased probability of depression at low (lack of emotional differentiation) and high (heightened reactivity to negative stimuli) levels of both predictors. Findings suggest that reduced or heightened right-lateralized emotional responsivity to negative stimuli may be uniquely associated with depression.

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.

Frontal theta and posterior alpha in resting EEG: A critical examination of convergent and discriminant validity.

Prior research has identified two resting EEG biomarkers with potential for predicting functional outcomes in depression: theta current density in frontal brain regions (especially rostral anterior cingulate cortex) and alpha power over posterior scalp regions. As little is known about the discriminant and convergent validity of these putative biomarkers, a thorough evaluation of these psychometric properties was conducted toward the goal of improving clinical utility of these markers. Resting 71-channel EEG recorded from 35 healthy adults at two sessions (1-week retest) were used to systematically compare different quantification techniques for theta and alpha sources at scalp (surface Laplacian or current source density [CSD]) and brain (distributed inverse; exact low resolution electromagnetic tomography [eLORETA]) level. Signal quality was evaluated with signal-to-noise ratio, participant-level spectra, and frequency PCA covariance decomposition. Convergent and discriminant validity were assessed within a multitrait-multimethod framework. Posterior alpha was reliably identified as two spectral components, each with unique spatial patterns and condition effects (eyes open/closed), high signal quality, and good convergent and discriminant validity. In contrast, frontal theta was characterized by one low-variance component, low signal quality, lack of a distinct spectral peak, and mixed validity. Correlations between candidate biomarkers suggest that posterior alpha components constitute reliable, convergent, and discriminant biometrics in healthy adults. Component-based identification of spectral activity (CSD/eLORETA-fPCA) was superior to fixed, a priori frequency bands. Improved quantification and conceptualization of frontal theta is necessary to determine clinical utility.

Behavioral measures of attention and cognitive control during a new auditory working memory paradigm.

Proactive control is the ability to manipulate and maintain goal-relevant information within working memory (WM), allowing individuals to selectively attend to important information while inhibiting irrelevant distractions. Deficits in proactive control may cause multiple cognitive impairments seen in schizophrenia. However, studies of cognitive control have largely relied on visual tasks, even though the functional deficits in schizophrenia are more frequent and severe in the auditory domain (i.e., hallucinations). Hence, we developed an auditory analogue of a visual ignore/suppress paradigm. Healthy adults (N = 40) listened to a series of four letters (600-ms stimulus onset asynchrony) presented alternately to each ear, followed by a 3.2-s maintenance interval and a probe. Participants were directed either to selectively ignore (I) the to-be-presented letters at one ear, to suppress (S) letters already presented to one ear, or to remember (R) all presented letters. The critical cue was provided either before (I) or after (S) the encoding series, or simultaneously with the probe (R). The probes were encoding items presented to either the attended/not suppressed ear ("valid") or the ignored/suppressed ear ("lure"), or were not presented ("control"). Replicating prior findings during visual ignore/suppress tasks, response sensitivity and latency revealed poorer performance for lure than for control trials, particularly during the suppress condition. Shorter suppress than remember latencies suggested a behavioral advantage when discarding encoded items from WM. The paradigm-related internal consistencies and 1-week test-retest reliabilities (n = 38) were good to excellent. Our findings validate these auditory WM tasks as a reliable manipulation of proactive control and set the stage for studies with schizophrenia patients who experience auditory hallucinations.

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.

Pretreatment Rostral Anterior Cingulate Cortex Connectivity With Salience Network Predicts Depression Recovery: Findings From the EMBARC Randomized Clinical Trial.

BACKGROUND: Baseline rostral anterior cingulate cortex (rACC) activity is a well-replicated nonspecific predictor of depression improvement. The rACC is a key hub of the default mode network, which prior studies indicate is hyperactive in major depressive disorder. Because default mode network downregulation is reliant on input from the salience network and frontoparietal network, an important question is whether rACC connectivity with these systems contributes to depression improvement. METHODS: Our study evaluated this hypothesis in outpatients (N = 238; 151 female) enrolled in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) 8-week randomized clinical trial of sertraline versus placebo for major depressive disorder. Depression severity was measured using the Hamilton Rating Scale for Depression, and electroencephalography was recorded at baseline and week 1. Exact low-resolution electromagnetic tomography was used to compute activity from the rACC, and key regions within the default mode network (posterior cingulate cortex), frontoparietal network (left dorsolateral prefrontal cortex), and salience network (right anterior insula [rAI]). Connectivity in the theta band (4.5-7 Hz) and beta band (12.5-21 Hz) was computed using lagged phase synchronization. RESULTS: Stronger baseline theta-band rACC-rAI (salience network hub) connectivity predicted greater depression improvement across 8 weeks of treatment for both treatment arms (B = -0.57, 95% confidence interval = -1.07, -0.08, p = .03). Early increases in theta-band rACC-rAI connectivity predicted greater likelihood of achieving remission at week 8 (odds ratio = 2.90, p = .03). CONCLUSIONS: Among patients undergoing treatment, theta-band rACC-rAI connectivity is a prognostic, albeit treatment-nonspecific, indicator of depression improvement, and early connectivity changes may predict clinically meaningful outcomes.

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.

Resting EEG Measures of Brain Arousal in a Multisite Study of Major Depression.

Several studies have found upregulated brain arousal during 15-minute EEG recordings at rest in depressed patients. However, studies based on shorter EEG recording intervals are lacking. Here we aimed to compare measures of brain arousal obtained from 2-minute EEGs at rest under eyes-closed condition in depressed patients and healthy controls in a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). We expected that depressed patients would show stable and elevated brain arousal relative to controls. Eighty-seven depressed patients and 36 healthy controls from four research sites in the United States were included in the analyses. The Vigilance Algorithm Leipzig (VIGALL) was used for the fully automatic classification of EEG-vigilance stages (indicating arousal states) of 1-second EEG segments; VIGALL-derived measures of brain arousal were calculated. We found that depressed patients scored higher on arousal stability ( Z = -2.163, P = .015) and A stages (dominant alpha activity; P = .027) but lower on B1 stages (low-voltage non-alpha activity, P = .008) compared with healthy controls. No significant group differences were observed in Stage B2/3. In summary, we were able to demonstrate stable and elevated brain arousal during brief 2-minute recordings at rest in depressed patients. Results set the stage for examining the value of these measures for predicting clinical response to antidepressants in the entire EMBARC sample and evaluating whether an upregulated brain arousal is particularly characteristic for responders to antidepressants.

Temporal stability of posterior EEG alpha over twelve years.

OBJECTIVE: We previously identified posterior EEG alpha as a potential biomarker for antidepressant treatment response. To meet the definition of a trait biomarker or endophenotype, it should be independent of the course of depression. Accordingly, this report evaluated the temporal stability of posterior EEG alpha at rest. METHODS: Resting EEG was recorded from 70 participants (29 male; 46 adults), during testing sessions separated by 12 ±â€¯1.1 years. EEG alpha was identified, separated and quantified using reference-free methods that combine current source density (CSD) with principal components analysis (PCA). Measures of overall (eyes closed-plus-open) and net (eyes closed-minus-open) posterior alpha amplitude and asymmetry were compared across testing sessions. RESULTS: Overall alpha was stable for the full sample (Spearman-Brown [rSB] = .834, Pearson's r = .718), and showed excellent reliability for adults (rSB = .918; r = 0.848). Net alpha showed acceptable reliability for adults (rSB = .750; r = .600). Hemispheric asymmetries (right-minus-left hemisphere) of posterior overall alpha showed significant correlations, but revealed acceptable reliability only for adults (rSB = .728; r = .573). Findings were highly comparable between 29 male and 41 female participants. CONCLUSIONS: Overall posterior EEG alpha amplitude is reliable over long time intervals in adults. SIGNIFICANCE: The temporal stability of posterior EEG alpha oscillations at rest over long time intervals is indicative of an individual trait.

Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) remains challenging to treat. Although several clinical and demographic variables have been found to predict poor antidepressant response, these markers have not been robustly replicated to warrant implementation in clinical care. Increased pretreatment rostral anterior cingulate cortex (rACC) theta activity has been linked to better antidepressant outcomes. However, no prior study has evaluated whether this marker has incremental predictive validity over clinical and demographic measures. Objective: To determine whether increased pretreatment rACC theta activity would predict symptom improvement regardless of randomization arm. Design, Setting, and Participants: A multicenter randomized clinical trial enrolled outpatients without psychosis and with chronic or recurrent MDD between July 29, 2011, and December 15, 2015 (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care [EMBARC]). Patients were consecutively recruited from 4 university hospitals: 634 patients were screened, 296 were randomized to receive sertraline hydrochloride or placebo, 266 had electroencephalographic (EEG) recordings, and 248 had usable EEG data. Resting EEG data were recorded at baseline and 1 week after trial onset, and rACC theta activity was extracted using source localization. Intent-to-treat analysis was conducted. Data analysis was performed from October 7, 2016, to January 19, 2018. Interventions: An 8-week course of sertraline or placebo. Main Outcomes and Measures: The 17-item Hamilton Rating Scale for Depression score (assessed at baseline and weeks 1, 2, 3, 4, 6, and 8). Results: The 248 participants (160 [64.5%] women, 88 [35.5%] men) with usable EEG data had a mean (SD) age of 36.75 (13.15) years. Higher rACC theta activity at both baseline (b = -1.05; 95% CI, -1.77 to -0.34; P = .004) and week 1 (b = -0.83; 95% CI, -1.60 to -0.06; P < .04) predicted greater depressive symptom improvement, even when controlling for clinical and demographic variables previously linked with treatment outcome. These effects were not moderated by treatment arm. The rACC theta marker, in combination with clinical and demographic variables, accounted for an estimated 39.6% of the variance in symptom change (with 8.5% of the variance uniquely attributable to the rACC theta marker). Conclusions and Relevance: Increased pretreatment rACC theta activity represents a nonspecific prognostic marker of treatment outcome. This is the first study to date to demonstrate that rACC theta activity has incremental predictive validity. Trial Registration: clinicaltrials.gov Identifier: NCT01407094.

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.

Motivated attention and family risk for depression: Neuronal generator patterns at scalp elicited by lateralized aversive pictures reveal blunted emotional responsivity.

Behavioral and electrophysiologic evidence suggests that major depression (MDD) involves right parietotemporal dysfunction, a region activated by arousing affective stimuli. Building on prior event-related potential (ERP) findings (Kayser et al. 2016 NeuroImage 142:337-350), this study examined whether these abnormalities also characterize individuals at clinical high risk for MDD. We systematically explored the impact of family risk status and personal history of depression and anxiety on three distinct stages of emotional processing comprising the late positive potential (LPP). ERPs (72 channels) were recorded from 74 high and 53 low risk individuals (age 13-59 years, 58 male) during a visual half-field paradigm using highly-controlled pictures of cosmetic surgery patients showing disordered (negative) or healed (neutral) facial areas before or after treatment. Reference-free current source density (CSD) transformations of ERP waveforms were quantified by temporal principal components analysis (tPCA). Component scores of prominent CSD-tPCA factors sensitive to emotional content were analyzed via permutation tests and repeated measures ANOVA for mixed factorial designs with unstructured covariance matrix, including gender, age and clinical covariates. Factor-based distributed inverse solutions provided descriptive estimates of emotional brain activations at group level corresponding to hierarchical activations along ventral visual processing stream. Risk status affected emotional responsivity (increased positivity to negative-than-neutral stimuli) overlapping early N2 sink (peak latency 212 ms), P3 source (385 ms), and a late centroparietal source (630 ms). High risk individuals had reduced right-greater-than-left emotional lateralization involving occipitotemporal cortex (N2 sink) and bilaterally reduced emotional effects involving posterior cingulate (P3 source) and inferior temporal cortex (630 ms) when compared to those at low risk. While the early emotional effects were enhanced for left hemifield (right hemisphere) presentations, hemifield modulations did not differ between risk groups, suggesting top-down rather than bottom-up effects of risk. Groups did not differ in their stimulus valence or arousal ratings. Similar effects were seen for individuals with a lifetime history of depression or anxiety disorder in comparison to those without. However, there was no evidence that risk status and history of MDD or anxiety disorder interacted in their impact on emotional responsivity, suggesting largely independent attenuation of attentional resource allocation to enhance perceptual processing of motivationally salient stimuli. These findings further suggest that a deficit in motivated attention preceding conscious awareness may be a marker of 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.