Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.Massachusetts Institute of Technology (Janet and Sheldon Razin Fellowship

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Individual differences in the frontal-striatal reward network : decision-making and psychiatric disease

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2015.Cataloged from PDF version of thesis.Includes bibliographical references (pages 81-93).The frontal-striatal reward network is involved in many reward-related behaviors, including decision-making and those related to psychiatric disease. One important class of decisions involves the conflict between immediate rewards and delayed gratification. Temporal discounting preferences reflect how a person makes decisions that involve tradeoffs over time. A fundamental question is how people vary and what accounts for this variation in temporal discounting preferences, both behaviorally and neurobiologically. In addition, psychiatric diseases, such as social anxiety, are associated with deficits in behaviors that involve social reward. Here I report two experiments that provide evidence for two major factors that contribute differences in temporal discounting preferences: personality traits and the underlying frontal-striatal reward network, both during task and at rest. Finally, I report underlying differences in the organization of the frontal-striatal reward network in social anxiety disorder. In the first study, I investigated the frontal-striatal reward network that underlies personality traits and the association of personality with temporal discounting preferences. Higher neuroticism was associated with a greater preference for immediate rewards and greater impulsivity, and higher conscientiousness with a greater preference for delayed rewards and less impulsivity. Executive-control and reward regions in the frontal-striatal reward network were more activated when higher conscientiousness participants selected a smaller-sooner reward and, conversely, when higher neuroticism participants selected a larger-later reward. Both cases involved choices that went against predispositions implied by personality. In the second study, I investigated how restingstate intrinsic functional brain organization (functional connectivity) of the frontal-striatal reward network varies with temporal discounting preferences. Increased patience and decreased impulsivity were associated with stronger functional connectivity between the nucleus accumbens and prefrontal executive control regions, including the dorsolateral prefrontal cortex. These findings reveal that the intrinsic strength of the frontal-striatal network is associated with differences in temporal discounting preferences. In the third network in social anxiety disorder. There was decreased functional connectivity between the nucleus accumbens and other reward regions, including the ventromedial prefrontal cortex, and decreased functional connectivity between the ventromedial prefrontal cortex and executive control regions of the prefrontal cortex. Taken together, these results indicate that the frontal-striatal reward network is associated with individual differences in reward-related behavior.by Joshua Manning.Ph. D

Personality influences temporal discounting preferences: Behavioral and brain evidence

Personality traits are stable predictors of many life outcomes that are associated with important decisions that involve tradeoffs over time. Therefore, a fundamental question is how tradeoffs over time vary from person to person in relation to stable personality traits. We investigated the influence of personality, as measured by the Five-Factor Model, on time preferences and on neural activity engaged by intertemporal choice. During functional magnetic resonance imaging (fMRI), participants made choices between smaller-sooner and larger-later monetary rewards. For each participant, we estimated a constant-sensitivity discount function that dissociates impatience (devaluation of future consequences) from time sensitivity (consistency with rational, exponential discounting). Overall, higher neuroticism was associated with a relatively greater preference for immediate rewards and higher conscientiousness with a relatively greater preference for delayed rewards. Specifically, higher conscientiousness correlated positively with lower short-term impatience and more exponential time preferences, whereas higher neuroticism (lower emotional stability) correlated positively with higher short-term impatience and less exponential time preferences. Cognitive-control and reward brain regions were more activated when higher conscientiousness participants selected a smaller-sooner reward and, conversely, when higher neuroticism participants selected a larger-later reward. The greater activations that occurred when choosing rewards that contradicted personality predispositions may reflect the greater recruitment of mental resources needed to override those predispositions. These findings reveal that stable personality traits fundamentally influence how rewards are chosen over time.National Institute on Aging (K01 AG040197