Differential role of fusiform gyrus coupling in depressive and anxiety symptoms during emotion perception.

Anxiety and depression co-occur; the neural substrates of shared and unique components of these symptoms are not understood. Given emotional alterations in internalizing disorders, we hypothesized that function of regions associated with emotion processing/regulation, including the anterior cingulate cortex (ACC), amygdala and fusiform gyrus (FG), would differentiate these symptoms. Forty-three adults with depression completed an emotional functional magnetic resonance imaging task and the Hamilton Depression and Anxiety Scales. We transformed these scales to examine two orthogonal components, one representing internalizing symptom severity and the other the type of internalizing symptoms (anxiety vs depression). We extracted blood oxygen level dependent signal from FG subregions, ACC, and amygdala and performed generalized psychophysiological interaction analyses to assess relationships between symptoms and brain function. Type of internalizing symptoms was associated with FG3-FG1 coupling (F = 8.14, P = 0.007). More coupling was associated with a higher concentration of depression, demonstrating that intra-fusiform coupling is differentially associated with internalizing symptom type (anxiety vs depression). We found an interaction between task condition and internalizing symptoms and dorsal (F = 4.51, P = 0.014) and rostral ACC activity (F = 4.27, P = 0.012). Post hoc comparisons revealed that less activity was associated with greater symptom severity during emotional regulation. Functional coupling differences during emotional processing are associated with depressive relative to anxiety symptoms and internalizing symptom severity. These findings could inform future treatments for depression.

Randomized trial of brief interpersonal psychotherapy and cognitive behavioral therapy for depression delivered both in-person and by telehealth.

BACKGROUND: Expert consensus guidelines recommend Cognitive Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT), interventions that were historically delivered face-to-face, as first-line treatments for Major Depressive Disorder (MDD). Despite the ubiquity of telehealth following the COVID-19 pandemic, little is known about differential outcomes with CBT versus IPT delivered in-person (IP) or via telehealth (TH) or whether working alliance is affected. METHODS: Adults meeting DSM-5 criteria for MDD were randomly assigned to either 8 sessions of IPT or CBT (group). Mid-trial, COVID-19 forced a change of therapy delivery from IP to TH (study phase). We compared changes in Hamilton Rating Scale for Depression (HRSD-17) and Working Alliance Inventory (WAI) scores for individuals by group and phase: CBT-IP (n = 24), CBT-TH (n = 11), IPT-IP (n = 25) and IPT-TH (n = 17). RESULTS: HRSD-17 scores declined significantly from pre to post treatment (pre: M = 17.7, SD = 4.4 vs. post: M = 11.7, SD = 5.9; p < .001; d = 1.45) without significant group or phase effects. WAI scores did not differ by group or phase. Number of completed therapy sessions was greater for TH (M = 7.8, SD = 1.2) relative to IP (M = 7.2, SD = 1.6) (Mann-Whitney U = 387.50, z = -2.24, p = .025). LIMITATIONS: Participants were not randomly assigned to IP versus TH. Sample size is small. CONCLUSIONS: This study provides preliminary evidence supporting the efficacy of both brief IPT and CBT, delivered by either TH or IP, for depression. It showed that working alliance is preserved in TH, and delivery via TH may improve therapy adherence. Prospective, randomized controlled trials are needed to definitively test efficacy of brief IPT and CBT delivered via TH versus IP.

Neural reactivity to neutral and aversive stimuli: Evidence for altered precuneus function in internalizing psychopathologies.

Individuals with internalizing psychopathologies (IPs) demonstrate a negativity bias in emotion and self-related processing that contributes to negative interpretation of neutral information. However, most neuroimaging studies of emotional experience in IPs do not specifically investigate reactivity to neutral stimuli. Thus, little is known about the neural processes underlying emotional experience for neutral stimuli and how those processes may differ between groups and during neutral versus negative stimuli. To address this gap, we asked: (1) does neural reactivity to neutral and negative stimuli differ between IPs and control groups in brain regions associated with emotional and self-referential processing, and (2) does neural activity during neutral condition relate to clinical symptoms? Adults with IPs (n = 103) and healthy volunteers (HVs; n = 40) completed a well-validated fMRI task probing neural responses to neutral and negative images. A flexible factorial model revealed a significant group-by-condition interaction, such that individuals with IPs had less precuneus activation during the neutral condition relative to HVs. In IPs, precuneus activation during the neutral condition was negatively correlated with depression symptom severity. Individuals with IPs demonstrate abnormal precuneus reactivity to neutral stimuli that is associated with depression symptoms. This may reflect altered default mode network activity and/or self-referential processing in IPs.

Personality and psychopathology: In defense of a practical path toward integrating psychometric and biological approaches to advance a comprehensive model.

Personality and psychopathology each reflect patterns of internal experience and outward behavior that differ between people and affect functioning. Drawing strict distinctions between the two concepts is not only difficult, but it may prove unnecessary for advancing an integrated model of psychological experiences associated with mental illness. We argue that developing such a model will be critical for improving treatment outcomes, and we discuss a practical path forward. Proponents of psychometric approaches to developing models of psychological experience focus on observable phenotypes and utilize statistical methods to describe patterns of covariation among a broad range of symptoms and dispositions. Advocates of biologically based approaches emphasize neuroscientific tools for identifying abnormalities in brain function that give rise to an individual's experience. There is substantial evidence that measures of personality and measures of symptoms capture nonoverlapping, clinically important information for understanding how and for whom treatments for mental illness work. In this article, we highlight the importance of combining psychometric and neurobiological approaches in order to understand which features of an individual those measures reflect, which aspects of neurobiology generate and maintain those features, how they relate to each other, and critically, how best to alter them to reduce distress and dysfunction.

Toward Causal Understanding of Therapist-Client Relationships: A Study of Language Modality and Social Entrainment.

The relationship between a therapist and their client is one of the most critical determinants of successful therapy. The working alliance is a multifaceted concept capturing the collaborative aspect of the therapist-client relationship; a strong working alliance has been extensively linked to many positive therapeutic outcomes. Although therapy sessions are decidedly multimodal interactions, the language modality is of particular interest given its recognized relationship to similar dyadic concepts such as rapport, cooperation, and affiliation. Specifically, in this work we study language entrainment, which measures how much the therapist and client adapt toward each other's use of language over time. Despite the growing body of work in this area, however, relatively few studies examine causal relationships between human behavior and these relationship metrics: does an individual's perception of their partner affect how they speak, or does how they speak affect their perception? We explore these questions in this work through the use of structural equation modeling (SEM) techniques, which allow for both multilevel and temporal modeling of the relationship between the quality of the therapist-client working alliance and the participants' language entrainment. In our first experiment, we demonstrate that these techniques perform well in comparison to other common machine learning models, with the added benefits of interpretability and causal analysis. In our second analysis, we interpret the learned models to examine the relationship between working alliance and language entrainment and address our exploratory research questions. The results reveal that a therapist's language entrainment can have a significant impact on the client's perception of the working alliance, and that the client's language entrainment is a strong indicator of their perception of the working alliance. We discuss the implications of these results and consider several directions for future work in multimodality.

Differentiating white matter measures that protect against vs. predispose to bipolar disorder and other psychopathology in at-risk youth.

Bipolar disorder (BD) is highly heritable. Identifying objective biomarkers reflecting pathophysiological processes predisposing to, versus protecting against BD, can help identify BD risk in offspring of BD parents. We recruited 21 BD participants with a first-degree relative with BD, 25 offspring of BD parents, 27 offspring of comparison parents with non-BD psychiatric disorders, and 32 healthy offspring of healthy parents. In at-risk groups, 23 had non-BD diagnoses and 29, no Axis-I diagnoses(healthy). Five at-risk offspring who developed BD post scan(Converters) were included. Diffusion imaging(dMRI) analysis with tract segmentation identified between-group differences in the microstructure of prefrontal tracts supporting emotional regulation relevant to BD: forceps minor, anterior thalamic radiation(ATR), cingulum bundle(CB), and uncinate fasciculus(UF). BD participants showed lower fractional anisotropy (FA) in the right CB (anterior portion) than other groups (q < 0.05); and in bilateral ATR (posterior portion) versus at-risk groups (q < 0.001). Healthy, but not non-BD, at-risk participants showed significantly higher FA in bilateral ATR clusters than healthy controls (qs < 0.05). At-risk groups showed higher FA in these clusters than BD participants (qs < 0.05). Non-BD versus healthy at-risk participants, and Converters versus offspring of BD parents, showed lower FA in the right ATR cluster (qs < 0.05). Low anterior right CB FA in BD participants versus other groups might result from having BD. High bilateral ATR FA in at-risk groups, and in healthy at-risk participants, versus healthy controls might protect against BD/other psychiatric disorders. Absence of elevated right ATR FA in non-BD versus healthy at-risk participants, and in Converters versus non-converter offspring of BD parents, might lower protection against BD in at-risk groups.

Neural function during emotion regulation and future depressive symptoms in youth at risk for affective disorders.

Affective disorders (AD, including bipolar disorder, BD, and major depressive disorder) are severe recurrent illnesses. Identifying neural markers of processes underlying AD development in at-risk youth can provide objective, "early-warning" signs that may predate onset or worsening of symptoms. Using data (n = 34) from the Bipolar Offspring Study, we examined relationships between neural response in regions supporting executive function, and those supporting self-monitoring, during an emotional n-back task (focusing on the 2-back face distractor versus the 0-back no-face control conditions) and future depressive and hypo/manic symptoms across two groups of youth at familial risk for AD: Offspring of parents with BD (n = 15, age = 14.15) and offspring of parents with non-BD psychopathology (n = 19, age = 13.62). Participants were scanned and assessed twice, approximately 4 years apart. Across groups, less deactivation in the mid-cingulate cortex during emotional regulation (Rate Ratio = 3.07(95% CI:1.09-8.66), χ2(1) = 4.48, p = 0.03) at Time-1, and increases in functional connectivity from Time-1 to 2 (Rate Ratio = 1.45(95% CI:1.15-1.84), χ2(1) = 8.69, p = 0.003) between regions that showed deactivation during emotional regulation and the right caudate, predicted higher depression severity at Time-2. Both effects were robust to sensitivity analyses controlling for clinical characteristics. Decreases in deactivation between Times 1 and 2 in the right putamen tail were associated with increases in hypo/mania at Time-2, but this effect was not robust to sensitivity analyses. Our findings reflect neural mechanisms of risk for worsening affective symptoms, particularly depression, in youth across a range of familial risk for affective disorders. They may serve as potential objective, early-warning signs of AD in youth.

Goals, Tasks, and Bonds: Toward the Computational Assessment of Therapist Versus Client Perception of Working Alliance.

Early client dropout is one of the most significant challenges facing psychotherapy: recent studies suggest that at least one in five clients will leave treatment prematurely. Clients may terminate therapy for various reasons, but one of the most common causes is the lack of a strong working alliance. The concept of working alliance captures the collaborative relationship between a client and their therapist when working toward the progress and recovery of the client seeking treatment. Unfortunately, clients are often unwilling to directly express dissatisfaction in care until they have already decided to terminate therapy. On the other side, therapists may miss subtle signs of client discontent during treatment before it is too late. In this work, we demonstrate that nonverbal behavior analysis may aid in bridging this gap. The present study focuses primarily on the head gestures of both the client and therapist, contextualized within conversational turn-taking actions between the pair during psychotherapy sessions. We identify multiple behavior patterns suggestive of an individual's perspective on the working alliance; interestingly, these patterns also differ between the client and the therapist. These patterns inform the development of predictive models for self-reported ratings of working alliance, which demonstrate significant predictive power for both client and therapist ratings. Future applications of such models may stimulate preemptive intervention to strengthen a weak working alliance, whether explicitly attempting to repair the existing alliance or establishing a more suitable client-therapist pairing, to ensure that clients encounter fewer barriers to receiving the treatment they need.

Does the unified protocol really change neuroticism? Results from a randomized trial.

BACKGROUND: Neuroticism is associated with the onset and maintenance of a number of mental health conditions, as well as a number of deleterious outcomes (e.g. physical health problems, higher divorce rates, lost productivity, and increased treatment seeking); thus, the consideration of whether this trait can be addressed in treatment is warranted. To date, outcome research has yielded mixed results regarding neuroticism's responsiveness to treatment, perhaps due to the fact that study interventions are typically designed to target disorder symptoms rather than neuroticism itself. The purpose of the current study was to explore whether a course of treatment with the unified protocol (UP), a transdiagnostic intervention that was explicitly developed to target neuroticism, results in greater reductions in neuroticism compared to gold-standard, symptom focused cognitive behavioral therapy (CBT) protocols and a waitlist (WL) control condition. METHOD: Patients with principal anxiety disorders (N = 223) were included in this study. They completed a validated self-report measure of neuroticism, as well as clinician-rated measures of psychological symptoms. RESULTS: At week 16, participants in the UP condition exhibited significantly lower levels of neuroticism than participants in the symptom-focused CBT (t(218) = -2.17, p = 0.03, d = -0.32) and WL conditions(t(207) = -2.33, p = 0.02, d = -0.43), and these group differences remained after controlling for simultaneous fluctuations in depression and anxiety symptoms. CONCLUSIONS: Treatment effects on neuroticism may be most robust when this trait is explicitly targeted.

Functional disruption in prefrontal-striatal network in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. While a cortico-striatal-limbic network has been implicated in the pathophysiology of OCD, the neural correlates of this network in OCD are not well understood. In this study, we examined resting state functional connectivity among regions within the cortico-striatal-limbic OCD neural network, including the rostral anterior cingulate cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, thalamus and caudate, in 44 OCD and 43 healthy participants. We then examined relationships between OCD neural network connectivity and OCD symptom severity in OCD participants. OCD relative to healthy participants showed significantly greater connectivity between the left caudate and bilateral dorsolateral prefrontal cortex. We also found a positive correlation between left caudate-bilateral dorsolateral prefrontal cortex connectivity and depression scores in OCD participants, such that greater positive connectivity was associated with more severe symptoms. This study makes a significant contribution to our understanding of functional networks and their relationship with depression in OCD.

Functional Disruption of Cerebello-thalamo-cortical Networks in Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. Neuroimaging studies have implicated altered connectivity among the functional networks of the cerebral cortex in the pathophysiology of OCD. However, there has been no comprehensive investigation of the cross-talk between the cerebellum and functional networks in the cerebral cortex. METHODS: This functional neuroimaging study was completed by 44 adult participants with OCD and 43 healthy control participants. We performed large-scale data-driven brain network analysis to identify functional connectivity patterns using resting-state functional magnetic resonance imaging data. RESULTS: Participants with OCD showed lower functional connectivity within the somatomotor network and greater functional connectivity among the somatomotor network, cerebellum, and subcortical network (e.g., thalamus and pallidum; all p < .005). Network-based statistics analyses demonstrated one component comprising connectivity within the somatomotor network that showed lower connectivity and a second component comprising connectivity among the somatomotor network, and motor regions in particular, and the cerebellum that showed greater connectivity in participants with OCD relative to healthy control participants. In participants with OCD, abnormal connectivity across both network-based statistics-derived components positively correlated with OCD symptom severity (p = .006). CONCLUSIONS: To our knowledge, this study is the first comprehensive investigation of large-scale network alteration across the cerebral cortex, subcortical regions, and cerebellum in OCD. Our findings highlight a critical role of the cerebellum in the pathophysiology of OCD.

Assessing Relationships Among Impulsive Sensation Seeking, Reward Circuitry Activity, and Risk for Psychopathology: A Functional Magnetic Resonance Imaging Replication and Extension Study.

BACKGROUND: High trait impulsive sensation seeking (ISS), the tendency to engage in behavior without forethought and to seek out new or extreme experiences, is a transdiagnostic risk factor for externalizing and mood disorders, particularly bipolar disorder. We published a positive association between trait ISS and reward expectancy-related activity in the left ventrolateral prefrontal cortex (L vlPFC) and the ventral striatum. We aimed to replicate this finding and extend it by testing for mediation effects of ISS on relationships between reward expectancy-related activity and measures denoting hypomania. METHODS: A transdiagnostic sample of 127 adults, 18 to 25 years of age, completed a card-guessing functional magnetic resonance imaging task as well as measures of ISS (inattention, motor impulsivity, fun seeking, positive and negative urgency) and the Moods Spectrum as a measure of hypomania. An original sample of 98 was included for confirmatory and mediation analyses. RESULTS: We replicated a positive relationship between reward expectancy-related L vlPFC activity and negative urgency, an ISS component (ß = .28, t = 2.44, p = .0169). We combined these data with the original sample, confirming this finding (ß = .27, t = 2.41, p = .0184). Negative urgency statistically mediated the relationship between reward expectancy-related L vlPFC activity and Moods Spectrum factors associated with hypomania. No other associations between ISS measures and reward expectancy-related activity were replicated. CONCLUSIONS: We replicated findings showing that reward expectancy-related L vlPFC activity is a biomarker for negative urgency, the tendency to react with frustration during distressing conditions. Negative urgency also statistically mediated the relationship between L vlPFC activity and measures indicative of hypomanic symptoms.

Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression (HSRD) over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on week-8 depression levels (Fs ≥ 9.67, ps ≤ 0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pretreatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pretreatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.

Momentary fluctuations in impulsivity domains: Associations with a history of childhood ADHD, heavy alcohol use, and alcohol problems.

BACKGROUND: The current study examined if fluctuation in in-the-moment impulsivity was more pronounced for adults with, versus without, a childhood history of ADHD and if ADHD group moderated the association between fluctuation in impulsivity and alcohol use behaviors. METHODS: Two hundred and eleven adult drinkers (52% ADHD) completed a 10-day, 6 times/day, momentary assessment of state impulsivity. Self-reported trait impulsivity, alcohol problems, and frequency of 5+ drinks in the past 12 months were also assessed. RESULTS: The ADHD group had more variability in three domains of state impulsivity (negative urgency, positive urgency, sensation seeking) compared to the nonADHD group. After including global trait impulsivity, the ADHD and nonADHD groups only differed on state sensation seeking. Fluctuation in two domains of state impulsivity were related to frequency of 5+ drinks (lack of planning: ADHD RR = 3.60, p < 0.001, nonADHD RR=0.90, p = 0.81; negative urgency: ADHD RR=4.32, p = 0.01, nonADHD RR=0.49, p = 0.24) and number of different alcohol problems (lack of planning: ADHD RR=4.87, p < 0.001, nonADHD RR=0.58, p = 0.29; negative urgency: ADHD RR=4.96, p = 0.01, nonADHD RR=0.24, p = 0.04) for participants with a history of ADHD but were not related (or related to fewer problems) for those without childhood ADHD. Higher variability in positive urgency was related to more alcohol problems for the participants with childhood ADHD but not the nonADHD participants (ADHD RR=3.00, p = 0.03, nonADHD RR=0.50, p = 0.25). CONCLUSIONS: Findings highlight the importance of assessing fluctuation in several domains of impulsivity and may elucidate important treatment targets for alcohol problems for adults with ADHD histories.

Decoupling Personality and Acute Psychiatric Symptoms in a Depressed Sample and a Community Sample.

The association between depression and neuroticism is complex, but due to the difficulty in assessing neuroticism during mood episodes, the mechanisms underlying this relationship remain poorly understood. In this study, we sought to decompose neuroticism into finer-grained elements that were uncorrelated with psychiatric symptoms and to examine the incremental validity of those elements in explaining deficits in interpersonal functioning. A bifactor model with one general factor and six specific factors fit the data well in both a depressed (N=807) and a community (N=1,284) sample, and the specific factors were relatively independent of acute symptoms. Moreover, two specific factors (Angry Hostility and Self-Consciousness) accounted for incremental variance in interpersonal functioning problems in the community sample and in a subgroup of depressed participants. The results demonstrate that neuroticism can be decomposed into components that are distinct from symptoms and that are incrementally associated with deficits in interpersonal functioning.

Personalized prediction of antidepressant v. placebo response: evidence from the EMBARC study.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits. METHODS: Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics. RESULTS: Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58). CONCLUSIONS: A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

Haste or Speed? Alterations in the Impact of Incentive Cues on Task Performance in Remitted and Depressed Patients With Bipolar Disorder.

A variety of evidence suggests that bipolar disorder is associated with disruptions of reward related processes, although the properties, and scope of these changes are not well understood. In the present study, we aimed to address this question by examining performance of patients with bipolar disorder (30 depressed bipolar; 35 euthymic bipolar) on a motivated choice reaction time task. We compared performance with a group of healthy control individuals (n = 44) and a group of patients with unipolar depression (n = 41), who were matched on several demographic variables. The task consists of an "odd-one-out" discrimination, in the presence of a cue signaling the probability of reward on a given trial (10, 50, or 90%) given a sufficiently fast response. All groups showed similar reaction time (RT) performance, and similar shortening of RT following the presentation of a reward predictive cue. However, compared to healthy individuals, the euthymic bipolar group showed a relative increase in commission errors during the high reward compared to low condition. Further correlational analysis revealed that in the healthy control and unipolar depression groups, participants tended either to shorten RTs for the high rather than low reward cue a relatively large amount with an increase in error rate, or to shorten RTs to a lesser extent but without increasing errors to the same degree. By contrast, reward-related speeding and reward-related increase in errors were less well coupled in the bipolar groups, significantly so in the BPD group. These findings suggest that although RT performance on the present task is relatively well matched, there may be a specific failure of individuals with bipolar disorder to calibrate RT speed and accuracy in a strategic way in the presence of reward-related stimuli.

Test-retest reliability of cerebral blood flow in healthy individuals using arterial spin labeling: Findings from the EMBARC study.

INTRODUCTION: Previous investigations of test-retest reliability of cerebral blood flow (CBF) at rest measured with pseudo-continuous Arterial Spin Labeling (pCASL) demonstrated good reliability, but are limited by the use of similar scanner platforms. In the present study we examined test-retest reliability of CBF in regions implicated in emotion and the default mode network. MATERIAL AND METHODS: We measured absolute and relative CBF at rest in thirty-one healthy subjects in two scan sessions, one week apart, at four different sites and three different scan platforms. We derived CBF from pCASL images with an automated algorithm and calculated intra-class correlation coefficients (ICCs) across sessions for regions of interest. In addition, we investigated site effects. RESULTS: For both absolute and relative CBF measures, ICCs were good to excellent (i.e. >0.6) in most brain regions, with highest values observed for the subgenual anterior cingulate cortex and ventral striatum. A leave-one-site-out cross validation analysis did not show a significant effect for site on whole brain CBF and there was no proportional bias across sites. However, a significant site effect was present in the repeated measures ANOVA. CONCLUSIONS: The high test-retest reliability of CBF measured with pCASL in a range of brain regions implicated in emotion and salience processing, emotion regulation, and the default mode network, which have been previously linked to depression symptomatology supports its use in studies that aim to identify neuroimaging biomarkers of treatment response.

Neuroticism and Individual Differences in Neural Function in Unmedicated Major Depression: Findings from the EMBARC Study.

BACKGROUND: Personality dysfunction represents one of the only predictors of differential response between active treatments for depression to have replicated. In this study, we examine whether depressed patients with higher neuroticism scores, a marker of personality dysfunction, show differences versus depressed patients with lower scores in the functioning of two brain regions associated with treatment response, the anterior cingulate and anterior insula cortices. METHODS: Functional magnetic resonance imaging data during an emotional Stroop task were collected from 135 adults diagnosed with major depressive disorder at four academic medical centers participating in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. Secondary analyses were conducted including a sample of 28 healthy individuals. RESULTS: In whole-brain analyses, higher neuroticism among depressed adults was associated with increased activity in and connectivity with the right anterior insula cortex to incongruent compared to congruent emotional stimuli (ks>281, ps<0.05 FWE corrected), covarying for concurrent psychiatric distress. We also observed an unanticipated relationship between neuroticism and reduced activity in the precuneus (k=269, p<0.05 FWE corrected). Exploratory analyses including healthy individuals suggested that associations between neuroticism and brain function may be nonlinear over the full range of neuroticism scores. CONCLUSIONS: This study provides convergent evidence for the importance of the right anterior insula cortex as a brain-based marker of clinically meaningful individual differences in neuroticism among adults with depression. This is a critical next step in linking personality dysfunction, a replicated clinical predictor of differential antidepressant treatment response, with differences in underlying brain function.