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.

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

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

Neural response to social but not monetary reward predicts increases in depressive symptoms during the COVID-19 pandemic.

The prevalence of depressive symptoms has increased during the COVID-19 pandemic, especially among those with greater pandemic-related stress exposure; however, not all individuals exposed to pandemic stress will develop depression. Determining which individuals are vulnerable to depressive symptoms as a result of this stress could lead to an improved understanding of the etiology of depression. This study sought to determine whether neural sensitivity to monetary and/or social reward prospectively predicts depressive symptoms during periods of high stress. 121 participants attended pre-pandemic laboratory visits where they completed monetary and social reward tasks while electroencephalogram was recorded. Subsequently, from March to August 2020, we sent eight questionnaires probing depressive symptoms and exposure to pandemic-related stressors. Using repeated-measures multilevel models, we evaluated whether neural response to social or monetary reward predicted increases in depressive symptoms across the early course of the pandemic. Furthermore, we examined whether neural response to social or monetary reward moderated the association between pandemic-related episodic stressors and depressive symptoms. Pandemic-related stress exposure was strongly associated with depressive symptoms. Additionally, we found that blunted neural response to social but not monetary reward predicted increased depressive symptoms during the pandemic. However, neither neural response to social nor monetary reward moderated the association between episodic stress exposure and depressive symptoms. Our findings indicate that neural response to social reward may be a useful predictor of depressive symptomatology under times of chronic stress, particularly stress with a social dimension.

Associations between peer stress in early adolescence and multiple event-related potentials elicited during social feedback processing.

Interpersonal stress in adolescence has been associated with alterations in neural responses to peer feedback, and increased vulnerability to psychopathology. However, it is unclear whether the associations of interpersonal problems with neural responses are global across event-related potentials (ERPs) or might result in alterations only in specific ERPs. We examined associations between multiple informants of peer stress (self-reported, parent-reported, and peer-reported) and multiple ERPs (N1, P2, RewP, and LPP) to social feedback in a sample of 46 early adolescents (aged 12-13 years). Reports of peer stress were only moderately correlated with one another, indicating different informants capture different aspects of peer stress. Regressions using informant reports to predict ERPs revealed greater parent-reported peer stress was associated with a smaller RewP, whereas self-reported stress was associated with a smaller P2, to acceptance. In contrast, greater peer-reported stress was associated with larger P2, RewP, and LPP to acceptance. Findings suggest that different sources of stress measurement are differentially associated with ERPs. Future research using social feedback-related ERPs should consider multiple sources of information as well as multiple ERP components across the time-course of feedback processing, to gain a clearer understanding of the effects of peer stress on neural responses to feedback.

Internal consistency reliability of the P300 to novelty in infants: The influence of trial number and data loss due to artifacts.

The P300 is an event-related potential component that reflects attention to motivationally salient stimuli and may be a promising tool to examine individual differences in cognitive-affective processing very early in development. However, the psychometric properties of the P300 in infancy are unknown, a fact that limits the component's utility as an individual difference measure in developmental research. To address this gap, 38 infants completed an auditory three-stimulus oddball task that included frequent standard, infrequent deviant, and novel stimuli. We quantified the P300 at a single electrode site and at region of interest (ROI) and examined the internal consistency reliability of the component, both via split-half reliability and as a function of trial number. Results indicated that the P300 to standard, deviant, and novel stimuli fell within moderate to high internal consistency reliability thresholds, and that scoring the component at an ROI led to slightly higher estimates of reliability. However, the percentage of data loss due to artifacts increased across the course of the task, suggesting that including more trials will not necessarily improve the reliability of the P300. Together, these results suggest that robust and reliable measurement of the P300 will require designing tasks that minimize trial number and maximize infant tolerability.

Resting posterior alpha power and adolescent major depressive disorder.

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

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

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

Predicting Depression Symptoms in Families at Risk for Depression: Interrelations of Posterior EEG Alpha and Religion/Spirituality.

BACKGROUND: Posterior EEG alpha has been identified as a putative biomarker of clinical outcomes in major depression (MDD). Separately, personal importance of religion and spirituality (R/S) has been shown to provide protective benefits for individuals at high familial risk for MDD. This study directly explored the joint value of posterior alpha and R/S on predicting clinical health outcomes of depression. METHODS: Using a mixed-effects model approach, we obtained virtual estimates of R/S at age 21 using longitudinal data collected at 5 timepoints spanning 25 years. Current source density and frequency principal component analysis was used to quantify posterior alpha in 72-channel resting EEG (eyes open/closed). Depression severity was measured between 5 and 10 years after EEG collection using PHQ-9 and IDAS-GD scales. RESULTS: Greater R/S (p = .008, η2p = 0.076) and higher alpha (p = .02, η2p = 0.056) were separately associated with fewer symptoms across scales. However, an interaction between alpha and R/S (p = .02, η2p = 0.062) was observed, where greater R/S predicted fewer symptoms with low alpha but high alpha predicted fewer symptoms with lower R/S. LIMITATIONS: Small-to-medium effect sizes and homogeneity of sample demographics caution overall interpretation and generalizability. CONCLUSIONS: Findings revealed a complementary role of R/S and alpha in that either variable exerted protective effects only if the other was present at low levels. These findings confirm the relevance of R/S importance and alpha oscillations as predictors of depression symptom severity. More research is needed on the neurobiological mechanism underlying the protective effects of R/S importance for MDD.