Richelle Stiffler

Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder

Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT: F[1,41]=6.8; P=0.013) and RD (BDE>CONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.

Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study

OBJECTIVE Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures. METHOD A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals. RESULTS Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms. CONCLUSIONS The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.

Heterogeneity of amygdala response in major depressive disorder: the impact of lifetime subthreshold mania

BACKGROUND Patients with major depressive disorder (MDD) present with highly heterogeneous symptom profiles. We aimed to examine whether individual differences in amygdala activity to emotionally salient stimuli were related to heterogeneity in lifetime levels of depressive and subthreshold manic symptoms among adults with MDD. METHOD We compared age- and gender-matched adults with MDD (n = 26) with healthy controls (HC, n = 28). While undergoing functional magnetic resonance imaging, participants performed an implicit emotional faces task: they labeled a color flash superimposed upon initially neutral faces that dynamically morphed into one of four emotions (angry, fearful, sad, happy). Region of interest analyses examined group differences in amygdala activity. For conditions in which adults with MDD displayed abnormal amygdala activity versus HC, within-group analyses examined amygdala activity as a function of scores on a continuous measure of lifetime depression-related and mania-related pathology. RESULTS Adults with MDD showed significantly greater right-sided amygdala activity to angry and happy conditions than HC (p < 0.05, corrected). Multiple regression analyses revealed that greater right-amygdala activity to the happy condition in adults with MDD was associated with higher levels of subthreshold manic symptoms experienced across the lifespan (p = 0.002). CONCLUSIONS Among depressed adults with MDD, lifetime features of subthreshold mania were associated with abnormally elevated amygdala activity to emerging happy faces. These findings are a first step toward identifying biomarkers that reflect individual differences in neural mechanisms in MDD, and challenge conventional mood disorder diagnostic boundaries by suggesting that some adults with MDD are characterized by pathophysiological processes that overlap with bipolar disorder.

Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: Implications for mood disorders

The dorsomedial prefrontal cortex (MdPFC) and anterior cingulate cortices (ACC) play a critical role in implicit emotion regulation; however the understanding of the specific neurotransmitters that mediate such role is lacking. In this study, we examined relationships between MdPFC concentrations of two neurotransmitters, glutamate and γ-amino butyric acid (GABA), and BOLD activity in ACC during performance of an implicit facial emotion-processing task. Twenty healthy volunteers, aged 20-35 years, were scanned while performing an implicit facial emotion-processing task, whereby presented facial expressions changed from neutral to one of the four emotions: happy, anger, fear, or sad. Glutamate concentrations were measured before and after the emotion-processing task in right MdPFC using magnetic resonance spectroscopy (MRS). GABA concentrations were measured in bilateral MdPFC after the emotion-processing task. Multiple regression models were run to determine the relative contribution of glutamate and GABA concentration, age, and gender to BOLD signal in ACC to each of the four emotions. Multiple regression analyses revealed a significant negative correlation between MdPFC GABA concentration and BOLD signal in subgenual ACC (p<0.05, corrected) to sad versus shape contrast. For the anger versus shape contrast, there was a significant negative correlation between age and BOLD signal in pregenual ACC (p<0.05, corrected) and a positive correlation between MdPFC glutamate concentration (pre-task) and BOLD signal in pregenual ACC (p<0.05, corrected). Our findings are the first to provide insight into relationships between MdPFC neurotransmitter concentrations and ACC BOLD signal, and could further understanding of molecular mechanisms underlying emotion processing in healthy and mood-disordered individuals.

Accounting for Dynamic Fluctuations across Time when Examining fMRI Test-Retest Reliability: Analysis of a Reward Paradigm in the EMBARC Study.

Longitudinal investigation of the neural correlates of reward processing in depression may represent an important step in defining effective biomarkers for antidepressant treatment outcome prediction, but the reliability of reward-related activation is not well understood. Thirty-seven healthy control participants were scanned using fMRI while performing a reward-related guessing task on two occasions, approximately one week apart. Two main contrasts were examined: right ventral striatum (VS) activation fMRI BOLD signal related to signed prediction errors (PE) and reward expectancy (RE). We also examined bilateral visual cortex activation coupled to outcome anticipation. Significant VS PE-related activity was observed at the first testing session, but at the second testing session, VS PE-related activation was significantly reduced. Conversely, significant VS RE-related activity was observed at time 2 but not time 1. Increases in VS RE-related activity from time 1 to time 2 were significantly associated with decreases in VS PE-related activity from time 1 to time 2 across participants. Intraclass correlations (ICCs) in VS were very low. By contrast, visual cortex activation had much larger ICCs, particularly in individuals with high quality data. Dynamic changes in brain activation are widely predicted, and failure to account for these changes could lead to inaccurate evaluations of the reliability of functional MRI signals. Conventional measures of reliability cannot distinguish between changes specified by algorithmic models of neural function and noisy signal. Here, we provide evidence for the former possibility: reward-related VS activations follow the pattern predicted by temporal difference models of reward learning but have low ICCs.

A pathway linking reward circuitry, impulsive sensation-seeking and risky decision-making in young adults: identifying neural markers for new interventions

High trait impulsive sensation seeking (ISS) is common in 18–25-year olds, and is associated with risky decision-making and deleterious outcomes. We examined relationships among: activity in reward regions previously associated with ISS during an ISS-relevant context, uncertain reward expectancy (RE), using fMRI; ISS impulsivity and sensation-seeking subcomponents; and risky decision-making in 100, transdiagnostically recruited 18–25-year olds. ISS, anhedonia, anxiety, depression and mania were measured using self-report scales; clinician-administered scales also assessed the latter four. A post-scan risky decision-making task measured ‘risky’ (possible win/loss/mixed/neutral) fMRI-task versus ‘sure thing’ stimuli. ‘Bias’ reflected risky over safe choices. Uncertain RE-related activity in left ventrolateral prefrontal cortex and bilateral ventral striatum was positively associated with an ISS composite score, comprising impulsivity and sensation-seeking–fun-seeking subcomponents (ISSc; P⩽0.001). Bias positively associated with sensation seeking–experience seeking (ES; P=0.003). This relationship was moderated by ISSc (P=0.009): it was evident only in high ISSc individuals. Whole-brain analyses showed a positive relationship between: uncertain RE-related left ventrolateral prefrontal cortical activity and ISSc; uncertain RE-related visual attention and motor preparation neural network activity and ES; and uncertain RE-related dorsal anterior cingulate cortical activity and bias, specifically in high ISSc participants (all ps<0.05, peak-level, family-wise error corrected). We identify an indirect pathway linking greater levels of uncertain RE-related activity in reward, visual attention and motor networks with greater risky decision-making, via positive relationships with impulsivity, fun seeking and ES. These objective neural markers of high ISS can guide new treatment developments for young adults with high levels of this debilitating personality trait.

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.

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.

Mediation by anxiety of the relationship between amygdala activity during emotion processing and poor quality of life in young adults

Young adults often experience psychological distress and poor quality of life (QoL). Yet, there are no objective neural markers to accurately guide interventions to help improve these measures. We thus aimed to identify directional relationships between frontoamygdala emotional regulation circuitry activity during emotion processing, personality traits, and symptoms associated with psychological distress, and QoL. One hundred twenty 18–25-year olds, n=51 psychologically distressed and n=69 healthy individuals, completed a face emotion-processing task during functional magnetic resonance imaging, clinical and behavioral measures, and QoL assessment. Penalized regression, accounting for large numbers of independent variables, showed that increased state and trait anxiety, cohort and measures of general and anhedonic depression severity predicted poorer QoL (all exponents>0.87). Only state and trait anxiety predicted emotion processing-related frontoamygdala activity (all exponents=1.00). State and trait anxiety fully mediated the relationship between amygdala activity and QoL (P-value increased from 0.001 to 0.29: left amygdala, and from 0.003 to 0.94: right amygdala). State anxiety fully mediated the relationship between left ventrolateral prefrontal cortical (vlPFC) activity and QoL (P-value increased from 0.01 to 0.18). Testing an alternative mediational pathway showed that the relationship between state and trait anxiety and QoL was not mediated by amygdala or left vlPFC activity. We thereby identify specific, directional relationships linking amygdala and left vlPFC activity, state and trait anxiety, and poor QoL across different diagnoses. Our findings highlight roles of amygdala and left vlPFC activity as neural predictors of anxiety and poor QoL, and as potentially important targets for novel interventions to reduce anxiety and, in turn, improve QoL in young adults.