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.

The impact of targeted cathodal transcranial direct current stimulation on reward circuitry and affect in Bipolar Disorder.

Bipolar Disorder is costly and debilitating, and many treatments have side effects. Transcranial Direct Current Stimulation (tDCS) is a well-tolerated neuromodulation technique that may be a useful treatment for Bipolar Disorder if targeted to neural regions implicated in the disorder. One potential region is the left ventrolateral prefrontal cortex (vlPFC), which shows abnormally elevated activity during reward expectancy in individuals with Bipolar Disorder. We used a counterbalanced repeated measures design to assess the impact of cathodal (inhibitory) tDCS over the left vlPFC on reward circuitry activity, functional connectivity, and affect in adults with Bipolar Disorder, as a step toward developing novel interventions for individuals with the disorder. -1mA cathodal tDCS was administered over the left vlPFC versus a control region, left somatosensory cortex, concurrently with neuroimaging. Affect was assessed pre and post scan in remitted Bipolar Disorder (n = 27) and age/gender-matched healthy (n = 31) adults. Relative to cathodal tDCS over the left somatosensory cortex, cathodal tDCS over the left vlPFC lowered reward expectancy-related left ventral striatal activity (F(1,51) = 9.61, p = 0.003), and was associated with lower negative affect post scan, controlling for pre-scan negative affect, (F(1,49) = 5.57, p = 0.02) in all participants. Acute cathodal tDCS over the left vlPFC relative to the left somatosensory cortex reduces reward expectancy-related activity and negative affect post tDCS. Build on these findings, future studies can determine whether chronic cathodal tDCS over the left vlPFC has sustained effects on mood in individuals with Bipolar Disorder, to guide new treatment developments for the disorder.

Reduced focal fiber collinearity in the cingulum bundle in adults with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling condition, often associated with a chronic course. Given its role in attentional control, decision-making, and emotional regulation, the anterior cingulate cortex is considered to have a key role in the pathophysiology of the disorder. Notably, the cingulum bundle, being the major white matter tract connecting to this region, has been historically a target for the surgical treatment of intractable OCD. In this study, we aimed to identify the extent to which focal-more than diffuse-abnormalities in fiber collinearity of the cingulum bundle could distinguish 48 adults with OCD (mean age [SD] = 23.3 [4.5] years; F/M = 30/18) from 45 age- and sex-matched healthy control adults (CONT; mean age [SD] = 23.2 [3.8] years; F/M = 28/17) and further examine if these abnormalities correlated with symptom severity. Use of tract-profiles rather than a conventional diffusion imaging approach allowed us to characterize white matter microstructural properties along (100 segments), as opposed to averaging these measures across, the entire tract. To account for these 100 different segments of the cingulum bundle, a repeated measures analysis of variance revealed a main effect of group (OCD < CONT; F[1,87] = 5.3; P = 0.024) upon fractional anisotropy (FA, a measure of fiber collinearity and/or white matter integrity), in the cingulum bundle, bilaterally. Further analyses revealed that these abnormalities were focal (middle portion) within the left and right cingulum bundle, although did not correlate with symptom severity in OCD. Findings indicate that focal abnormalities in connectivity between the anterior cingulate cortex and other prefrontal cortical regions may represent neural mechanisms of OCD.

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.

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.

Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14.

CONTEXT: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms. OBJECTIVE: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members. DESIGN: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING: General US community, with research performed in a university tertiary care hospital. SUBJECTS: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURES: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage. RESULTS: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected). CONCLUSION: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334