Neuronal generator patterns at scalp elicited by lateralized aversive pictures reveal consecutive stages of motivated attention.

Event-related potential (ERP) studies have provided evidence for an allocation of attentional resources to enhance perceptual processing of motivationally salient stimuli. Emotional modulation affects several consecutive components associated with stages of affective-cognitive processing, beginning as early as 100-200ms after stimulus onset. In agreement with the notion that the right parietotemporal region is critically involved during the perception of arousing affective stimuli, some ERP studies have reported asymmetric emotional ERP effects. However, it is difficult to separate emotional from non-emotional effects because differences in stimulus content unrelated to affective salience or task demands may also be associated with lateralized function or promote cognitive processing. Other concerns pertain to the operational definition and statistical independence of ERP component measures, their dependence on an EEG reference, and spatial smearing due to volume conduction, all of which impede the identification of distinct scalp activation patterns associated with affective processing. Building on prior research using a visual half-field paradigm with highly controlled emotional stimuli (pictures of cosmetic surgery patients showing disordered [negative] or healed [neutral] facial areas before or after treatment), 72-channel ERPs recorded from 152 individuals (ages 13-68years; 81 female) were transformed into reference-free current source density (CSD) waveforms and submitted to temporal principal components analysis (PCA) to identify their underlying neuronal generator patterns. Using both nonparametric randomization tests and repeated measures ANOVA, robust effects of emotional content were found over parietooccipital regions for CSD factors corresponding to N2 sink (212ms peak latency), P3 source (385ms) and a late centroparietal source (630ms), all indicative of greater positivity for negative than neutral stimuli. For the N2 sink, emotional effects were right-lateralized and modulated by hemifield, with larger amplitude and asymmetry for left hemifield (right hemisphere) presentations. For all three factors, more positive amplitudes at parietooccipital sites were associated with increased ratings of negative valence and greater arousal. Distributed inverse solutions of the CSD-PCA-based emotional effects implicated a sequence of maximal activations in right occipitotemporal cortex, bilateral posterior cingulate cortex, and bilateral inferior temporal cortex. These findings are consistent with hierarchical activations of the ventral visual pathway reflecting subsequent processing stages in response to motivationally salient stimuli.

EEG measures of brain arousal in relation to symptom improvement in patients with major depressive disorder: Results from a randomized placebo-controlled clinical trial.

Hyperstable arousal regulation during a 15-min resting electroencephalogram (EEG) has been linked to a favorable response to antidepressants. The EMBARC study, a multicenter randomized placebo-controlled clinical trial, provides an opportunity to examine arousal stability as putative antidepressant response predictor in short EEG recordings. We tested the hypothesis that high arousal stability during a 2-min resting EEG at baseline is related to better outcome in the sertraline arm and explored the specificity of this effect. Outpatients with chronic/recurrent MDD were recruited from four university hospitals and randomized to treatment with sertraline (n = 100) or placebo (n = 104). The change in the Hamilton Rating Scale for Depression (HRSD-17) was the main outcome. Patients were stratified into high and low arousal stability groups. In mixed-model repeated measures (MMRM) analysis HRSD-17 change differed significantly between arousal groups, with high arousal stability being associated with a better outcome in the sertraline arm, and worse outcome in the placebo arm at week 4, with moderate effect sizes. When considering both treatment arms, a significant arousal group x time x treatment interaction emerged, highlighting specificity to the sertraline arm. Although findings indicate that arousal stability is likely to be a treatment-specific marker of response, further out-of-sample validation is warranted.

Relationship of resting EEG with anatomical MRI measures in individuals at high and low risk for depression.

Studies have found abnormalities of resting EEG measures of hemispheric activity in depressive disorders. Similar EEG findings and a prominent thinning of the cortical mantle have been reported for persons at risk for depression. The correspondence between EEG alpha power and magnetic resonance imaging (MRI) measures of cortical thickness was examined in a multigenerational study of individuals at risk for depression. Seventy-five participants underwent resting EEG and approximately 5 years later underwent MRI scanning. High-risk participants (n = 37) were biological descendants of probands having major depression and low-risk participants (n = 38) were descendants of individuals without a history of depression. EEG alpha power was interpolated across the surface of a template brain and coregistered with measures of cortical thickness. Voxel-wise correlations of cortical thickness and alpha power were computed while covarying for age and gender. The high-risk group, when compared to the low-risk group, showed greater alpha asymmetry in an eyes-closed condition, with relatively less activity over right parietal cortex. Alpha power correlated inversely with cortical thickness, particularly over the right posterior region, indicating that EEG evidence of reduced cortical activity was associated with increased cortical thinning. This is the first report of widespread correlation of EEG alpha activity with MRI measures of cortical thickness. Although both EEG and MRI measures are associated with risk for depression, we did not detect evidence that cortical thickness mediated the alpha asymmetry findings. Thus, alpha asymmetry, alone or in combination with MRI, may be a marker of vulnerability for a familial form of depression.

Do positive and negative temperament traits interact in predicting risk for depression? A resting EEG study of 329 preschoolers.

Researchers have long been interested in whether particular temperamental traits in childhood connote risk for depressive disorders. For example, children characterized as having high negative emotionality (NE; sadness, fear, anger) and low positive emotionality (PE; anhedonia, listlessness, and lack of enthusiasm) are hypothesized to be at risk for depression. Few studies, however, have examined whether (and how) these two temperamental dimensions interact to confer risk. In a sample of 329 preschoolers, the present study addressed this question by examining the relation between PE and NE and asymmetry in resting EEG activity in frontal and posterior regions, which are putative biomarkers for depression. Using a laboratory battery to define temperament, we found an interaction of PE and NE on posterior asymmetry. Specifically, when PE was high, NE was associated with greater relative right activity. When PE was low, NE was not related to posterior asymmetry. These results were driven by differences in EEG activity in right posterior regions, an area associated with emotional processing and arousal, and were specific to girls. We found no relation between temperament and frontal asymmetry. These findings suggest that, at least for girls, PE and NE may have an interactive effect on risk for 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.

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.

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.

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.

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.

Hemispatial PCA dissociates temporal from parietal ERP generator patterns: CSD components in healthy adults and depressed patients during a dichotic oddball task.

Event-related potentials (31-channel ERPs) were recorded from 38 depressed, unmedicated outpatients and 26 healthy adults (all right-handed) in tonal and phonetic oddball tasks developed to exploit the perceptual challenge of a dichotic stimulation. Tonal nontargets were pairs of complex tones (corresponding to musical notes G and B above middle C) presented simultaneously to each ear (L/R) in an alternating series (G/B or B/G; 2-s fixed SOA). A target tone (note A) replaced one of the pair on 20% of the trials (A/B, G/A, B/A, A/G). Phonetic nontargets were L/R pairs of syllables (/ba/, /da/) with a short voice onset time (VOT), and targets contained a syllable (/ta/) with a long VOT. Subjects responded with a left or right button press to targets (counterbalanced across blocks). Target detection was poorer in patients than controls and for tones than syllables. Reference-free current source densities (CSDs; spherical spline Laplacian) derived from ERP waveforms were simplified and measured using temporal, covariance-based PCA followed by unrestricted Varimax rotation. Target-related N2 sinks and mid-parietal P3 sources were represented by CSD factors peaking at 245 and 440 ms. The P3 source topography included a secondary, left-lateralized temporal lobe maximum for both targets and nontargets. However, a subsequent hemispheric spatiotemporal PCA disentangled temporal lobe N1 and P3 sources as distinct factors. P3 sources were reduced in patients compared with controls, even after using performance as a covariate. Results are consistent with prior reports of P3 reduction in depression and implicate distinct parietal and temporal generators of P3 when using a dichotic oddball paradigm.

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.

Grandchildren at high and low risk for depression differ in EEG measures of regional brain asymmetry.

BACKGROUND: Electrophysiologic studies have found abnormalities of alpha asymmetry in depressed adults and offspring of depressed parents, which have been hypothesized to be vulnerability markers of depression. Resting electroencephalogram (EEG) was measured in grandchildren participating in a multigenerational high-risk study. METHODS: Electroencephalogram from 12 electrodes at six homologous sites over each hemisphere (digitally linked-ears reference) was compared in right-handed grandchildren in three groups: 1) both parent and grandparent having major depressive disorder (MDD; n = 19); 2) either parent or grandparent having MDD (n = 14); and 3) neither having MDD (n = 16). RESULTS: Grandchildren with both depressed parent and grandparent showed greater alpha asymmetry, with relatively less right than left hemisphere activity, when compared with those with neither depressed parent nor grandparent. This difference was present over the parietal region in the eyes-closed condition. Grandchildren having either depressed parent or grandparent also tended to show heightened alpha asymmetry at parietal sites, but they did not differ significantly from those with neither depressed parent nor grandparent. Low-risk grandchildren with neither depressed parent nor grandparent showed no significant alpha asymmetry. CONCLUSIONS: High-risk grandchildren displayed a parietal alpha asymmetry similar to that seen in adolescents or adults having a MDD and in second-generation offspring of parents concordant for MDD. Its presence in high-risk offspring and grandchildren without a lifetime history of MDD supports the hypothesis that an alpha asymmetry indicative of relatively less right than left parietal activity is an endophenotypic marker of vulnerability to a familial form of major depression.

Reward sensitivity in depression: a biobehavioral study.

The approach-withdrawal model posits 2 neural systems of motivation and emotion and hypothesizes that these systems are responsible for individual differences in emotional reactivity, or affective styles. The model also proposes that depression is characterized by a deficit in reward-seeking behavior (i.e., approach motivation) and is associated with a relative decrease in left frontal brain activity. The authors tested aspects of this model by comparing the electroencephalogram alpha power of depressed and nondepressed individuals during a task that manipulated approach motivation. The study found that control participants and individuals with late-onset depression exhibited the hypothesized increase in left frontal activity during the approach task but individuals with early-onset depression did not. This suggests that early-onset depression may be associated with a deficit in the hypothesized approach motivation system.

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.

Stability of Cortical Thinning in Persons at Increased Familial Risk for Major Depressive Disorder Across 8 Years.

BACKGROUND: A biological marker of vulnerability should precede onset of illness and be independent of disease course. We previously reported that cortical thinning may serve as a potential biomarker for risk for familial depression. We now test stability of the cortical thinning across 8 years, and whether thinning mediates associations between familial risk and depressive traits. METHOD: Participants were from a 3-generation family study of depression, where 2nd and 3rd generation offspring were characterized as being at high- or low-risk for depression based on the presence/absence of major depression in the 1st generation. The analysis includes 82 offspring with anatomical MRI scans across two assessment waves, 7.8 (S.D.1.3, range: 5.2-10.9) years apart. RESULTS: High-risk offspring had thinner bilateral superior and middle frontal gyri, and left inferior parietal lobule, at both time-points. High intra-subject correlation (0.60

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.

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.

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.