Left ventrolateral prefrontal cortical activity during reward expectancy predicts mania risk up to one year post scan.

INTRODUCTION: Identification of neural markers associated with risk for manic symptoms is an important challenge for neuropsychiatric research. Previous work has highlighted the association between predisposition for mania/hypomania and elevated reward sensitivity. Elevated activity in the left ventrolateral prefrontal cortex (L vlPFC) during reward expectancy (RE) is associated with measures predictive of risk for manic/hypomanic symptoms. However, no studies have examined this relationship longitudinally. The goal of this study was to identify a neural marker associated with longitudinal risk for manic/hypomanic symptoms. METHODS: We used a card guessing functional magnetic resonance imaging (fMRI) paradigm to examine RE-related L vlPFC activity. One hundred and three young adults who were either healthy or experiencing psychological distress completed a single baseline fMRI scan and self-report measures of manic/hypomanic symptoms. Self-report measures were repeated up to two follow up visits over one year. RESULTS: We identified a significant positive relationship between baseline RE-related L vlPFC activity and MOODS Manic Domain scores up to one-year post scan. This relationship was specific to manic symptoms and was not present for MOODS depression-related domains. LIMITATIONS: This study was not designed to predict conversion to bipolar disorder, but rather the more proximal construct of lifetime risk for mania/hypomania. CONCLUSIONS: RE-related L vlPFC activity may serve as an important marker of risk for future manic/hypomanic symptoms and may also be a potential target for intervention.

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.

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.

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 (BDECONT: 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.