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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.

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.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.High-risk offspring had thinner bilateral superior and middle frontal gyri, and left inferior parietal lobule, at both time-points. High intra-subject correlation (0.60r0.91) and intra-class correlation (0.72-0.78) of thickness measures across time points was detected within the above regions; rank order by effect size and region was also preserved across time. The thinning was stable despite changes in scanning platform (Siemens Sonata vs. GE Signa), field-strength (1.5 vs. 3T), and participant age and clinical course. Thinning at the first time-point predicted anger and hostility at the second, and mediated the relationship between familial risk and these traits.The study provides evidence for cortical thinning as a stable biomarker for familial vulnerability for depressive illness, which supports the ability to detect persistent and clinically relevant anatomical findings irrespective of MRI platform.

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., Highlights • Emotional hemifield ERP task with 127 individuals at high and low family risk for MDD • CSD-PCA methods summarized affective modulation of late positive potential (LPP). • High risk and prior diagnosis of MDD or anxiety disorder independently reduced LPP. • Suggested hypoarousal (top-down) of right temporoparietal and other emotional regions • Left hemifield (bottom-up) modulations of early emotional asymmetries were preserved.

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 (one-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.

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.

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

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 ± 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 [ r SB ] = .834, Pearson's r = .718), and showed excellent reliability for adults ( r SB = .918; r = 0.848). Net alpha showed acceptable reliability for adults ( r SB = .750; r = .600). Hemispheric asymmetries (right-minus-left hemisphere) of posterior overall alpha showed significant correlations, but revealed acceptable reliability only for adults ( r SB = .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.

Despite the recognition that the surface Laplacian may counteract adverse effects of volume conduction and recording reference for surface potential data, electrophysiology as a discipline has been reluctant to embrace this approach for data analysis. The reasons for such hesitation are manifold but often involve unfamiliarity with the nature of the underlying transformation, as well as intimidation by a perceived mathematical complexity, and concerns of signal loss, dense electrode array requirements, or susceptibility to noise. We revisit the pitfalls arising from volume conduction and the mandated arbitrary choice of EEG reference, describe the basic principle of the surface Laplacian transform in an intuitive fashion, and exemplify the differences between common reference schemes (nose, linked mastoids, average) and the surface Laplacian for frequently-measured EEG spectra (theta, alpha) and standard event-related potential (ERP) components, such as N1 or P3. We specifically review common reservations against the universal use of the surface Laplacian, which can be effectively addressed by employing spherical spline interpolations with an appropriate selection of the spline flexibility parameter and regularization constant. We argue from a pragmatic perspective that not only are these reservations unfounded but that the continued predominant use of surface potentials poses a considerable impediment on the progress of EEG and ERP research.

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.

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.

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.

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.

Objective EEG topographies may be distorted by electrode bridges, typically caused by electrolyte spreading between adjacent electrodes. We therefore sought to determine the prevalence of electrode bridging and its potential impact on the EEG literature. Methods Five publicly-available EEG datasets were evaluated for evidence of bridging using a new screening method that employs the temporal variance of pairwise difference waveforms (electrical distance). Distinctive characteristics of electrical distance frequency distributions were used to develop an algorithm to identify electrode bridges in datasets with different montages (22–64 channels) and noise properties. Results The extent of bridging varied substantially across datasets: 54% of EEG recording sessions contained an electrode bridge, and the mean percentage of bridged electrodes in a montage was as high as 18% in one of the datasets. Furthermore, over 40% of the recording channels were bridged in 9 of 203 sessions. These findings were independently validated by visual inspection. Conclusions The new algorithm conveniently, efficiently, and reliably identified electrode bridges across different datasets and recording conditions. Electrode bridging may constitute a substantial problem for some datasets. Significance Given the extent of the electrode bridging across datasets, this problem may be more widespread than commonly thought. However, when used as an automatic screening routine, the new algorithm will prevent pitfalls stemming from unrecognized electrode bridges.

The topographic ambiguity and reference-dependency that has plagued EEG/ERP research throughout its history are largely attributable to volume conduction, which may be concisely described by a vector form of Ohm’s Law. This biophysical relationship is common to popular algorithms that infer neuronal generators via inverse solutions. It may be further simplified as Poisson’s source equation, which identifies underlying current generators from estimates of the second spatial derivative of the field potential (Laplacian transformation). Intracranial current source density (CSD) studies have dissected the “cortical dipole” into intracortical sources and sinks, corresponding to physiologically-meaningful patterns of neuronal activity at a sublaminar resolution, much of which is locally cancelled (i.e., closed field). By virtue of the macroscopic scale of the scalp-recorded EEG, a surface Laplacian reflects the radial projections of these underlying currents, representing a unique, unambiguous measure of neuronal activity at scalp. Although the surface Laplacian requires minimal assumptions compared to complex, model-sensitive inverses, the resulting waveform topographies faithfully summarize and simplify essential constraints that must be placed on putative generators of a scalp potential topography, even if they arise from deep or partially-closed fields. CSD methods thereby provide a global empirical and biophysical context for generator localization, spanning scales from intracortical to scalp recordings.

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 one 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 (PCA) of current source density (CSD) 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.

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 100-200 ms 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 (age 13-68 years; 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 (212 ms peak latency), P3 source (385 ms) and a late centroparietal source (630 ms), 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.

Background Despite recent success in pharmacologic treatment of depression, the inability to predict individual treatment response remains a liability. This study replicates and extends findings relating pretreatment electroencephalographic (EEG) alpha to treatment outcomes for serotonergic medications. Methods Resting EEG (eyes-open and eyes-closed) was recorded from a 67-electrode montage in 41 unmedicated depressed patients and 41 healthy control subjects. Patients were tested before receiving antidepressants including a serotonergic mode of action (selective serotonin reuptake inhibitor [SSRI], serotonin and norepinephrine reuptake inhibitor, or SSRI plus norepinephrine and dopamine reuptake inhibitor). EEG was quantified by frequency principal components analysis of spectra derived from reference-free current source density (CSD) waveforms, which sharpens and simplifies EEG topographies, disentangles them from artifact, and yields measures that more closely represent underlying neuronal current generators. Results Patients who did not respond to treatment had significantly less alpha CSD compared with responders or healthy control subjects, localizable to well-defined posterior generators. The alpha difference between responders and nonresponders was greater for eyes-closed than eyes-open conditions and was present across alpha subbands. A classification criterion based on the median alpha for healthy control subjects showed good positive predictive value (93.3) and specificity (92.3). There was no evidence of differential value for predicting response to an SSRI alone or dual treatment targeting serotonergic plus other monoamine neurotransmitters. Conclusions Findings confirm the value of EEG alpha amplitude as a viable predictor of antidepressant response and suggest that personalized treatments for depression may be identified using simple electrophysiologic CSD measures.

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.

Studies of regional hemispheric asymmetries point to relatively less activity in left frontal and right posterior regions in depression. Anxiety was associated with increased right posterior activity, which may be related to arousal and, in anxious-depressed individuals, offset the posterior asymmetry typically seen in depression. These asymmetries have been indexed by resting EEG or inferred through the use of lateralized auditory and visual tasks (e.g., dichotic listening and chimeric faces). However, associations between regional EEG activity and neurocognitive function in depression or anxiety remain unclear. The present study used matched verbal (Word Finding) and spatial (Dot Localization) tasks to compare task-related alpha asymmetries in depressed patients grouped according to level of trait anxiety. EEG and behavioral performance were recorded from depressed patients with high anxiety (n=14) or low anxiety (n=14) and 21 age- and education-matched healthy adults during the two tasks, and alpha power was averaged within each task. As predicted, the two patient groups exhibited opposite patterns of regional hemispheric alpha asymmetry. Greater right than left central-parietal activation was seen in the high-anxiety depressed group during the spatial task, whereas greater left than right frontal-central activation was found in the low-anxiety depressed group during the verbal task. Group differences in task performance were in the expected direction but did not reach statistical significance. These results are consistent with Heller's two-dimensional model of depression and anxiety and highlight the sensitivity of task-related EEG alpha in discriminating among subgroups of depressed patients differing in trait anxiety.

Posterior cortical activity may be related to individual differences in temperamental emotionality, especially traits implicated in depression vulnerability. We previously reported that electroencephalographic (EEG) indices of cortical activity in posterior regions were associated with temperamental positive emotionality (PE) in early childhood. This project examined whether EEG indices of regional cortical activity, assessed at age 5–6, were associated with child temperament and cognitive vulnerability to depression, assessed at age 7. Asymmetry in posterior cortical activity measured at age 5–6 was associated with PE at follow-up at age 7, and with greater helplessness during a standardised laboratory task simulating a mild interpersonal rejection. Findings provide further support for the notion that low PE and depression are associated with similar patterns of cortical activity. Furthermore, these patterns of activity may have observable behavioural and cognitive correlates that are meaningfully linked...

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.

To clarify polarity, topography, and time course of recognition memory ERP old/new effects during matched visual and auditory continuous word recognition tasks, unrestricted temporal PCA jointly analyzed stimulus- and responselocked, reference-free current source densities (31-channel, N 5 40). Randomization tests provided unbiased statistics for complete factor topographies. Old/new left parietal source effects were complemented by lateral frontocentral sink effects in both modalities, overlapping modality-specific P3 sources 160 ms preresponse. A mid-frontal sink 45 ms postresponse terminated the frontoparietal generator pattern, showed old/new effects consistent with bilateral activation of anterior cingulate and SMA, and preceded similar activity extending posteriorly along the longitudinal fissure. These methods separated old/new stimulus source (preresponse) and response sink (postresponse) effects from motor and modality-specific ERPs. Descriptors: Recognition memory, Event-related potential (ERP), Current source density (CSD), Principal components analysis (PCA), Stimulus- and response-locked, Visual and auditory modality

Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5-44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5-8 Hz) and alpha2 (10.5-12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.

In our recent invited editorial (Kayser and Tenke, 2005), we placed the contributions of a simulation study by Dien et al. (2005) in the broader context of what we perceive as a renaissance of PCA methodology in electrophysiology. This editorial also addressed several misrepresentations and apparent misunderstandings of Dien et al. (2005) regarding the research strategy and recommendations given in our previous article (Kayser and Tenke, 2003). In his response to our critical explanations, Dien (this journal) shows a much better understanding of our recommendations than when his simulation study was published. Indeed, a number of statements in his letter now paraphrase our own, although the need for such a picturesque repetition eludes us. While we prefer a more scientific language appropriate to the nature of the data, we suspect that some of his argumentation and style were and are merely rhetorical. Unfortunately, even though some of his points are well taken, he still attributes conclusions or recommendations to us that are incorrect, and we gladly accepted the invitation to respond to his letter. First and foremost, we are in complete agreement with Dien on the value of PCA for ERPs. Promoting more objective approaches to the analyses of ERP data, PCA methodology being just one example, appears to be a common goal to which we will continue to contribute. Secondly, Dien (this journal) identifies two areas of disagreement, namely factor scaling and factor restriction, and also provides additional comments regarding the Promax rotation. We will underscore our consensus on the specific methodological issue of scaling choices. However, we will argue for the sensibility of using unrestricted PCA solutions in light of empirical evidence, and restate our reasons and provide additional considerations for not enthusiastically endorsing Promax rotation for empirical ERP data at this time.

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.

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≤ r ≤.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.

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.

Surface Laplacian (SL) methods offer advantages in spectral analysis owing to the well-known implications of volume conduction. Although recognition of the superiority of SL over reference-dependent measures is widespread, well-reasoned cautions have precluded their universal adoption. Notably, the expected selectivity of SL for superficial rather than deep generators has relegated SL to the role of an add-on to conventional analyses, rather than as an independent area of inquiry, despite empirical findings supporting the consistency and replicability of physiological effects of interest. It has also been reasoned that the contrast-enhancing effects of SL necessarily make it insensitive to broadly distributed generators, including those suspected for oscillatory rhythms such as EEG alpha. These concerns are further exacerbated for phase-sensitive measures (e.g., phase-locking, coherence), where key features of physiological generators have yet to be evaluated. While the neuronal generators of empirically-derived EEG measures cannot be precisely known due to the inverse problem, simple dipole generator configurations can be simulated using a 4-sphere head model and linearly combined. We simulated subdural and deep generators and distributed dipole layers using sine and cosine waveforms, quantified at 67-scalp sites corresponding to those used in previous research. Reference-dependent (nose, average, mastoids reference) EEG and corresponding SL topographies were used to probe signal fidelity in the topography of the measured amplitude spectra, phase and coherence of sinusoidal stimuli at and between “active” recording sites. SL consistently outperformed the conventional EEG measures, indicating that continued reluctance by the research community is unfounded.

Surface Laplacian methodology has been used to reduce the impact of volume conduction and arbitrary choice of EEG recording reference for the analysis of surface potentials. However, the empirical implications of employing these different transformations to the same EEG data remain obscure. This study directly compared the statistical effects of four commonly-used (nose, linked mastoids, average) or recommended (reference electrode standardization technique [REST]) references and their spherical spline current source density (CSD) transformation for a large data set stemming from a well-understood experimental manipulation. ERPs (72 sites) recorded from 130 individuals during a visual half-field paradigm with highly-controlled emotional stimuli were characterized by mid-parietooccipital N1 (125 ms peak latency) and event-related synchronization (ERS) of theta/delta (160 ms), which were most robust over the contralateral hemisphere. All five data transformations were rescaled to the same covariance and submitted to a single temporal or time-frequency PCA (Varimax) to yield simplified estimates of N1 or theta/delta ERS. Unbiased nonparametric permutation tests revealed that these hemifield-dependent asymmetries were by far most focal and prominent for CSD data, despite all transformations showing maximum effects at mid-parietooccipital sites. Employing smaller subsamples (signal-to-noise) or window-based ERP/ERS amplitudes did not affect these comparisons. Furthermore, correlations between N1 and theta/delta ERS at these sites were strongest for CSD and weakest for nose-referenced data. Contrary to the common notion that the spatial high pass filter properties of a surface Laplacian reduce important contributions of neuronal generators to the EEG signal, the present findings demonstrate that instead volume conduction inherent in surface potentials weakens the representation of neuronal activation patterns at scalp that directly reflect regional brain activity.

Background: This study compares event-related potentials for paranoid patients (n = 13) versus matched undifferentiated patients and unmedicated patients (n = 14) versus matched healthy adults. Methods: Event-related potentials of right-handed patients and control subjects were recorded from 30 electrodes during oddball tasks using consonant-vowel syllables or complex tones. Patients were also assessed using the Positive and Negative Syndrome Scale, the Thought Disorder Index, and the Wechsler Memory Scale. Results: Paranoid patients did not differ from undifferentiated patients in N1 or P3 amplitude but showed larger N2 at frontocentral sites to phonetic stimuli, as well as larger N2 over left than right hemisphere. Unmedicated patients showed reduced N2, but not N1 or P3, compared to control subjects. Conclusions: The N2 findings are consistent with neuropsychological evidence of greater verbal abilities and left hemisphere dominance in paranoid than nonparanoid schizophrenia. The findings also confirm the relationship of P3 to total Brief Psychiatric Rating Scale score, negative symptoms, and verbal associative memory.

Background: Prior studies using simple target detection ("oddball") tasks with pure tones have reported asymmetric reduction of the P3 event-related potential (ERP). This study investigated the time course and topography of ERPs recorded during both tonal and phonetic oddball tasks. Methods: Event-related potentials of 66 patients (14 unmedicated) diagnosed with schizophrenia ( n = 46) or schizoaffective disorder ( n = 20) and 32 healthy adults were recorded from 30 scalp electrodes during two oddball tasks using consonant–vowel syllables or complex tones. Overlapping ERP components were identified and measured by covariance-based principal components analysis. Results: Schizophrenic patients showed marked, task-independent reductions of early negative potentials (N1, N2) but not reduced P3 amplitude or abnormal P3 asymmetry. Task-related hemispheric asymmetries of the N2/P3 complex were similar in healthy adults and schizophrenic patients. Poorer task performance in patients was related to ERP amplitudes, but could not account for reductions of early negativities. Conclusions: The findings suggest that both patients and control subjects activated lateralized cortical networks required for pitch (right frontotemporal) and phoneme (left parietotemporal) discrimination. Task-independent reductions of negativities between 80 and 280 msec after stimulus onset suggest a deficit of automatic stimulus classification in schizophrenia, which may be partly compensated by later effortful processing.

%Background:Recent reports suggest the value of electroencephalographic and dichotic listening measures as predictors of response to antidepressants. This study examines the potential of electroencephalographic alpha asymmetry and dichotic measures of perceptual asymmetry as predictors of clinical response to 12 weeks of treatment with fluoxetine (Prozac). Methods:Resting electroencephalography (eyes open and eyes closed) and dichotic listening with word or complex tone stimuli were assessed in depressed outpatients during a pretreatment period. Results:Fluoxetine responders ( n = 34) differed from nonresponders ( n = 19) in favoring left over right hemisphere processing of dichotic stimuli. They also differed in their resting electroencephalographic alpha asymmetry, particularly in the eyes open condition. Nonresponders showed an alpha asymmetry indicative of overall greater activation of the right hemisphere than the left, whereas responders did not. The relationship between hemispheric asymmetry and treatment response interacted with gender, being evident among depressed women but not men. Conclusions:The results are consistent with the hypothesis that a characteristic tendency toward greater left than right hemisphere activation is associated with favorable response to fluoxetine, whereas the opposite hemispheric asymmetry predicts poor response.

Dense electrode arrays offer numerous advantages over single channel electroencephalogram/event-related potential (EEG/ERP) recordings, but also exaggerate the influence of common error sources arising from the preparation of scalp placements. Even with conventional low density recordings (e.g. 30-channel Electro-Cap), over-application of electrode gel may result in electrolyte leakage and create low impedance bridges, particularly at vertically-aligned sites (e.g. inferior-lateral). The ensuing electrical short produces an artificial similarity of ERPs at neighboring sites that distorts the ERP topography. This artifact is not immediately apparent in group averages, and may even go undetected after visual inspection of the individual ERP waveforms. Besides adding noise variance to the topography, this error source also has the capacity to introduce systematic, localized artifacts (e.g. add or remove evidence of lateralized activity). Electrolyte bridges causing these artifacts can be easily detected by a simple variant of the Hjorth algorithm (intrinsic Hjorth), in which spatial interelectrode distances are replaced by an electrical analog of distance (i.e. the variances of the difference waveforms for all pairwise combinations of electrodes). When a low impedance bridge exists, the Hjorth algorithm identifies all affected sites as flat lines that are readily distinguishable from Hjorth waveforms at unbridged electrodes.

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.

Regional brain activity was measured using quantitative electroencephalography (EEG) in six patients with obsessive-compulsive disorder (OCD) during live and imaginal exposure to feared contaminants. OCD symptoms increased significantly from baseline levels during live and imaginal exposures. However, live exposure provoked significantly more OCD symptoms than imaginal exposure. There was a significant change in the anterior-to-posterior scalp distribution of alpha power during live exposure. These preliminary results suggest that: (1) live exposure is more effective than imaginal exposure in altering behavioral and electrophysiological measures; and (2) live exposure is associated with regional EEG changes in OCD.

Depression may involve dysfunction of right parietotemporal cortex, a region activated during perception of affective stimuli. To further test this hypothesis, event-related brain potentials (ERPs) were measured in a paradigm previously shown to produce ERP asymmetries to affective stimuli over parietal sites in healthy adults. Pictures of patients with dermatological diseases showing disordered or healed facial areas before (negative) or after (neutral) surgical treatment were briefly exposed for 250 ms to either the left or right hemifield. ERPs of 30 unmedicated, unipolar depressed patients and 16 healthy adults, all right-handed, were recorded from 30 electrodes. A principal components analysis extracted factors which closely corresponded to distinctive ERP components previously reported for this task (N1, N2, early P3, late P3, slow wave). Significant effects of emotional content, i.e. enhanced amplitudes to negative than neutral stimuli, were found for early and late P3. Control subjects showed significant hemispheric asymmetries of emotional processing for late P3 (peak latency 460 ms), with the largest emotional content effects over the right parietal region. In striking contrast to control subjects, depressed patients did not show an increase in late P3 for negative compared to neutral stimuli over either hemisphere and had smaller late P3 amplitude than control subjects. Patients did, however, show larger early P3 (peak latency 330 ms) to negative than neutral stimuli. Results suggest intact early discrimination but abnormal late appraisal of affective content in depression, which may arise from selective inhibition of right parietal regions integral for perceiving and evaluating emotional stimuli.

There are few clinical or biologic predictors of response to treatments for depression. This article reviews growing evidence that electrophysiologic and neurocognitive measures of brain function may be of value as predictors of therapeutic response to antidepressants. Initial studies using dichotic listening, quantitative electroencephalography, or event-related brain potential measures have found differences between treatment responsive and nonresponsive subgroups of depressed patients. The neurophysiologic basis for these differences and the potential clinical utility of electrophysiologic and dichotic predictors of treatment out come remain to be determined in future studies.

Event-related potentials to binaural complex tones were recorded from 40 depressed outpatients and 22 normal control participants at 30 electrode sites. Patients did not differ from control participants in N1 or P3 amplitude but showed greater N2. N2 was greater over right than over the left hemisphere at lateral sites in patients and control participants. A P3 asymmetry was found for control participants and patients with low scores on a physical anhedonia scale, but not for patients with high anhedonia scores. Topographic (local Laplacian) maps corresponding to P3 showed greater radial current flow over right than over left central regions in control participants. Patients with high anhedonia did not show this asymmetry, whereas patients with low anhedonia showed an intermediate asymmetry. These findings support the hypothesis that anhedonic depression is associated with dysfunction of right hemisphere mechanisms mediating the processing of complex pitch information.