How Gains and Losses Influence the Brain and Behavior: Relations to Age, Risk for Depression, and Individual Differences

Behavioral and neural response to rewards and punishments has been the subject of a growing literature with particular interest within developmental, psychopathology, and individual difference domains. There is now mounting evidence suggesting that adolescents show heightened response to reward relative to adults, and that adolescents with Major Depressive Disorder (MDD), elevated depressive symptoms, or at high-risk for depression show reduced response to reward. However, it is unclear whether similar relations between response to incentives and development/psychopathology are observed during childhood. Here we examine behavioral, neural (functional magnetic resonance imaging - fMRI), and self-reported responsiveness to gain and loss of rewards within healthy children and young adults. We relate observed neural/behavioral incentive responsiveness to 1) developmental stage, 2) risk for depression, and 3) self-reported incentive sensitivity. First, studies investigating developmental stage indicated that responsiveness to gain and loss of reward feedback show differing relations with age. Specifically, while children show elevated behavioral and neural (dorsal/posterior insula) response to loss of reward relative to adults, response to reward was similar across age groups. Second, we observed similar levels of both gain approach and loss avoidance behavior between healthy children at relatively high and low-risk for MDD, based on a positive/negative maternal history of MDD respectively. Third, across several studies both elevated gain approach and elevated loss avoidance behavior related to elevated self-reported incentive sensitivity as assessed via different questionnaire types (i.e. hedonic capacity, Behavioral Inhibition System/Behavioral Activation System, and anhedonic depressive scales). Interestingly, gain approach and loss avoidance behavior predicted unique variance in self-reported incentive sensitivity (BAS drive) and relations between incentive sensitivity and behavior did not differ based on age or depression risk status. Together these results highlight the importance of responsiveness to feedback signaling the loss of reward from both developmental and incentive sensitivity perspectives. Future work is needed to examine how gain and loss responsiveness during childhood prospectively predicts changes in incentive responsiveness over development and incidence of depression/changes in depressive symptoms

Enhanced neural response to anticipation, effort and consummation of reward and aversion during Bupropion treatment

Background We have previously shown that the selective serotonergic re-uptake inhibitor, citalopram, reduces the neural response to reward and aversion in healthy volunteers. We suggest that this inhibitory effect might underlie the emotional blunting reported by patients on these medications. Bupropion is a dopaminergic and noradrenergic re-uptake inhibitor and has been suggested to have more therapeutic effects on reward-related deficits. However, how bupropion affects the neural responses to reward and aversion is unclear. Methods 17 healthy volunteers (9 female, 8 male) received 7 days of bupropion (150 mg/day) and 7 days of placebo treatment, in a double-blind crossover design. Our functional Magnetic Resonance Imaging task consisted of 3 phases; an anticipatory phase (pleasant or unpleasant cue), an effort phase (button presses to achieve a pleasant taste or to avoid an unpleasant taste) and a consummatory phase (pleasant or unpleasant tastes). Volunteers also rated wanting, pleasantness and intensity of the tastes. Results Relative to placebo, bupropion increased activity during the anticipation phase in the ventral medial prefrontal cortex (vmPFC) and caudate. During the effort phase, bupropion increased activity in the vmPFC, striatum, dorsal anterior cingulate cortex and primary motor cortex. Bupropion also increased medial orbitofrontal cortex, amygdala and ventral striatum activity during the consummatory phase. Conclusions Our results are the first to show that bupropion can increase neural responses during the anticipation, effort and consummation of rewarding and aversive stimuli. This supports the notion that bupropion might be beneficial for depressed patients with reward-related deficits and blunted affect

Brain-behavior relationships in the experience and regulation of negative emotion in healthy children: Implications for risk for childhood depression

Structural and functional alterations in a variety of brain regions have been associated with depression and risk for depression across the life span. A majority of these regions are associated with emotion reactivity and/or regulation. However, it is generally unclear what mechanistic role these alterations play in the etiology of depression. A first step toward understanding this is to characterize the relationships between variation in brain structure/function and individual differences in depression severity and related processes, particularly emotion regulation. To this end, the current study examines how brain structure and function predict concurrent and longitudinal measures of depression symptomology and emotion regulation skills in psychiatrically healthy school-age children (N = 60). Specifically, we found that smaller hippocampus volumes and greater responses to sad faces in emotion reactivity regions predict increased depressive symptoms at the time of scan, whereas larger amygdala volumes, smaller insula volumes, and greater responses in emotion reactivity regions predict decreased emotion regulation skills. In addition, larger insula volumes predict improvements in emotion regulation skills even after accounting for emotion regulation at the time of scan. Understanding brain–behavior relationships in psychiatrically healthy samples, especially early in development, will help inform normative developmental trajectories and neural alterations in depression and other affective pathology

Revising the BIS/BAS Scale to study development: Measurement invariance and normative effects of age and sex from childhood through adulthood.

Carver and White\u27s (1994) Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) Scales have been useful tools for studying individual differences in reward-punishment sensitivity; however, their factor structure and invariance across development have not been well tested. In the current study, we examined the factor structure of the BIS/BAS Scales across 5 age groups: 6- to 10-year-old children (N = 229), 11- to 13-year-old early adolescents (N = 311), 14- to 16-year-old late adolescents (N = 353), 18- to 22-year-old young adults (N = 844), and 30- to 45-year-old adults (N = 471). Given poor fit of the standard 4-factor model (BIS, Reward Responsivity, Drive, Fun Seeking) in the literature, we conducted exploratory factor analyses in half of the participants and identified problematic items across age groups. The 4-factor model showed poor fit in our sample, whereas removing the BAS Fun Seeking subscale and problematic items from the remaining subscales improved fit in confirmatory factor analyses conducted with the second half of the participants. The revised model showed strict invariance across age groups and by sex, indicating consistent factor structure, item loadings, thresholds, and unique or residual variances. Additionally, in our cross-sectional data, we observed nonlinear relations between age and subscale scores, where scores tended to be higher in young adulthood than in childhood and later adulthood. Furthermore, sex differences emerged across development; adolescent and adult females had higher BIS scores than males in this age range, whereas sex differences were not observed in childhood. These differences may help us to understand the rise in internalizing psychopathology in adolescence, particularly in females. Future developmental studies are warranted to examine the impact of rewording problematic items

Structure based modification of Bluetongue virus helicase protein VP6 to produce a viable VP6-truncated BTV.

Bluetongue virus core protein VP6 is an ATP hydrolysis dependent RNA helicase. However, despite much study, the precise role of VP6 within the viral capsid and its structure remain unclear. To investigate the requirement of VP6 in BTV replication, we initiated a structural and biological study. Multinuclear nuclear magnetic resonance spectra were assigned on his-tagged full-length VP6 (329 amino acid residues) as well as several truncated VP6 variants. The analysis revealed a large structured domain with two large loop regions that exhibit significant conformational exchange. One of the loops (amino acid position 34-130) could be removed without affecting the overall fold of the protein. Moreover, using a BTV reverse genetics system, it was possible to demonstrate that the VP6-truncated BTV was viable in BHK cells in the absence of any helper VP6 protein, suggesting that a large portion of this loop region is not absolutely required for BTV replication

Decreased anticipated pleasure correlates with increased salience network resting state functional connectivity in adolescents with depressive symptomatology

Previous studies have found dysfunctional resting state functional connectivity (RSFC) in depressed patients. Examining RSFC might aid biomarker discovery for depression. However RSFC in young people at risk of depression has yet to be examined. 35 healthy adolescents (13-18 yrs old.) were recruited. 17 scoring high on the Mood and Feelings Questionnaire (MFQ > 27 (High Risk: HR), and 18 scoring low on the MFQ < 15 (Low Risk: LR) matched on age and gender. We selected seed regions in the salience network (SN: amygdala and pregenual anterior cingulate cortex (pgACC)) and the central executive network (CEN: dorsal medial prefrontal cortex (dmPFC)). Mood and anhedonia measures were correlated with brain connectivity. We found decreased RSFC in the HR group between the amygdala and the pgACC and hippocampus and precuneus. We also found decreased RSFC in the HR group between the pgACC and the putamen and between the dmPFC and the precuneus. The pgACC RSFC with the insula/orbitofrontal cortex correlated inversely with the anticipation of pleasure in all subjects. Increased RSFC was observed between the pgACC and the prefrontal cortex and the amygdala and the temporal pole in the HR group compared to the LR group. Our findings are the first to show that adolescents with depression symptoms have dysfunctional RSFC between seeds in the SN and CEN with nodes in the Default Mode Network. As increased connectivity between the pgACC and the insula correlated with decreased ability to anticipate pleasure, we suggest this might be mechanism underlying the risk of experiencing anhedonia, a suggested biomarker for depression

Linking anhedonia symptoms with behavioural and neural reward responses in adolescent depression

Adolescence is a period of change that crucially increases vulnerability to depression. Studies report blunted neural responses to reward that relate to positive affect and depression symptoms in adolescents. However how these results relate to the symptom of anhedonia in adolescents is not entirely clear. Anhedonia is not a unitary construct, but is described as having different processes (e.g. wanting vs. liking) each underpinned by different neurobiological pathways. Current studies report inconsistencies in findings when trying to relate reward processing at the behavioural and neural level with symptoms. One reason for this is the lack of specificity of clinical, behavioural and neural tasks for measuring reward in depression. Links between the experience of anhedonia in adolescent depression and the behavioural and neural measures of reward could be improved with more detailed questionnaires, more detailed measurements of the components of reward for e.g. decreased motivation/effort and more ecologically valid tasks relevant to adolescents, in the MRI scanner

Role of RNA helicases in HIV-1 replication

Viruses are replication competent genomes which are relatively gene-poor. Even the largest viruses (i.e. Herpesviruses) encode only slightly >200 open reading frames (ORFs). However, because viruses replicate obligatorily inside cells, and considering that evolution may be driven by a principle of economy of scale, it is reasonable to surmise that many viruses have evolved the ability to co-opt cell-encoded proteins to provide needed surrogate functions. An in silico survey of viral sequence databases reveals that most positive-strand and double-stranded RNA viruses have ORFs for RNA helicases. On the other hand, the genomes of retroviruses are devoid of virally-encoded helicase. Here, we review in brief the notion that the human immunodeficiency virus (HIV-1) has adopted the ability to use one or more cellular RNA helicases for its replicative life cycle