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

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

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.

Brain laterality, depression and anxiety disorders: New findings for emotional and verbal dichotic listening in individuals at risk for depression.

Studies using dichotic listening tests and electroencephalographic (EEG) measures of hemispheric asymmetry have reported evidence of abnormal brain laterality in patients having depressive disorders. We present new findings from a multigenerational study of risk for depression, in which perceptual asymmetry was measured in dichotic listening tests of emotional and verbal processing. Biological offspring and grandchildren of probands with a major depressive disorder (MDD) who were at high risk and those of nondepressed controls who were at low risk were tested on dichotic emotional recognition and consonant-vowel syllable tests. In the emotion test, individuals with a lifetime diagnosis of MDD had a smaller right hemisphere advantage than those without a MDD, but there was no difference between high- and low-risk groups or between those with or without an anxiety disorder. In the syllable test, a smaller left hemisphere advantage was found in individuals with an anxiety disorder compared to those without an anxiety disorder, but there was no difference between high- and low-risk groups or between those with or without a MDD. This double dissociation indicates that lifetime diagnosis of MDD and anxiety disorders have a differential impact on lateralized hemispheric processing of emotional and verbal information.

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.

Abnormal functional brain asymmetry in depression: evidence of biologic commonality between major depression and dysthymia.

Prior studies have found abnormalities of functional brain asymmetry in patients having a major depressive disorder (MDD). This study aimed to replicate findings of reduced right hemisphere advantage for perceiving dichotic complex tones in depressed patients, and to determine whether patients having "pure" dysthymia show the same abnormality of perceptual asymmetry as MDD. It also examined gender differences in lateralization, and the extent to which abnormalities of perceptual asymmetry in depressed patients are dependent on gender. Unmedicated patients having either a MDD (n=96) or "pure" dysthymic disorder (n=42) and healthy controls (n=114) were tested on dichotic fused-words and complex-tone tests. Patient and control groups differed in right hemisphere advantage for complex tones, but not left hemisphere advantage for words. Reduced right hemisphere advantage for tones was equally present in MDD and dysthymia, but was more evident among depressed men than depressed women. Also, healthy men had greater hemispheric asymmetry than healthy women for both words and tones, whereas this gender difference was not seen for depressed patients. Dysthymia and MDD share a common abnormality of hemispheric asymmetry for dichotic listening.

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

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

Temporal stability of posterior EEG alpha over twelve years.

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

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

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

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

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

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

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

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

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

Neurocognitive predictors of antidepressant clinical response.

BACKGROUND: Executive dysfunction and psychomotor slowing in depressed patients have been associated with poor antidepressant clinical response, but little is known about the value of neurocognitive tests for differential prediction of response. METHODS: This report presents new findings for 70 depressed patients tested on neurocogntive tests before receiving treatment with a SSRI (escitalopram or citalopram), NDRI (bupropion) or dual mechanism therapy including a serotonergic agent, and for 57 healthy controls. RESULTS: As predicted from previous research, patients who did not respond to a SSRI or dual therapy showed poorer word fluency than responders, whereas this was not seen for patients treated with bupropion alone. Longer choice reaction time (RT) was also found in nonresponders to a SSRI or dual therapy, but the opposite trend was seen for bupropion. Using a combined index of word fluency and RT (with normative performance as a cutoff) yielded differential predictions of response. Equal to or above normal performance predicted good response to a SSRI or dual therapy, with high positive predictive value (90%) and specificity (78%) but lower sensitivity (53%). In contrast, less than normal performance predicted good response to bupropion alone (positive predictive value=82%; specificity=67%; sensitivity=90%). LIMITATIONS: Relatively small sample size, no placebo control, and combining across SSRI alone and dual treatments. CONCLUSIONS: Although findings are preliminary due to small sample size, brief tests of word fluency and psychomotor speed may help identify depressed patients who are unresponsive to a serotonergic agent, but who may respond to bupropion alone.