Neural correlates of reward processing distinguish healthy youth at familial risk for bipolar disorder from youth at familial risk for major depressive disorder.

Youth at familial risk for bipolar disorder (BD-risk) and major depressive disorder (MDD-risk) have aberrant reward processing, a core feature of these mood disorders. Whether BD risk differentiates from MDD risk in reward processing merits further study. We compared neural activation and connectivity during anticipation and outcome of monetary gain and loss during fMRI using the Monetary Incentive Delay (MID) Task among BD-risk (n = 40), MDD-risk (n = 41), and healthy comparison youth (HC) (n = 45), in the absence of any lifetime or current history of psychopathology [mean age 13.09 ± 2.58, 56.3% female]. Participants completed the MID task at baseline and were followed for behavioral and clinical outcomes over 4.37 ± 2.29 years. Region-of-interest (ROI) analyses conducted using anatomically defined thalamus, ventrolateral prefrontal cortex, nucleus accumbens, and putamen seeds showed that relative to MDD-risk and HC, BD-risk had decreased activation of the thalamus during anticipation of monetary gain [F(2,118) = 4.64, p = 0.01 (FDR-corrected p = 0.04)]. Psychophysiological interaction analyses revealed that BD-risk had less connectivity between the thalamus and left middle frontal gyrus (Z > 3.1, p < 0.001) and left-superior temporal gyrus (Z > 3.1, p < 0.05) compared with MDD-risk. Voxelwise, BD-risk had decreased activation in the cerebellum during anticipation and outcome of monetary gain relative to MDD-risk and HC (Z > 3.1, p < 0.001; Z > 3.1, p < 0.01). In BD-risk, decreased thalamic connectivity was associated with increased impulsivity at baseline and reduced prosocial behavior at follow-up. Reduced thalamic activation and connectivity during reward processing may distinguish familial risk for BD from familial risk for MDD and represent early markers of vulnerability that may herald social dysfunction later in adolescence.

Therapeutic alliance in family therapy and clinical outcomes among adolescents at risk for mood disorders.

BACKGROUND: Family-focused therapy (FFT) is associated with longer intervals between mood episodes and reductions in suicidal ideation among adolescents at risk for bipolar disorders. However, the mediating processes underlying the efficacy of FFT are not well understood. In an open trial of an 18-week FFT program, we explored the association between the therapeutic alliance of adolescents/parents with their therapists and the symptomatic outcomes of adolescents over 18 weeks. METHOD: Participants were enrolled in a treatment development trial of FFT supplemented with a mobile app. We used the System for Observing Family Therapeutic Alliances (SOFTA) to rate alliance between adolescents, parents, and therapists using videotaped FFT sessions from the beginning and end of treatment. Pearson correlations were computed between SOFTA alliance ratings and changes in Children's Depression Rating Scale, Revised (CDRS-R) scores over 18 weeks of treatment. RESULTS: SOFTA ratings were obtained from sessions conducted with 17 adolescents (mean age 14.9+/-2.0 years; 41.2% female) and 22 parents. CDRS-R ratings were obtained from 16 adolescents at baseline and 18 weeks. Parents had significantly higher levels of engagement and emotional connection with therapists than their offspring. Adolescents' therapeutic engagement scores were significantly correlated with reductions in CDRS scores over 18 weeks (r(14) = -0.58, p = 0.018; N = 16). LIMITATIONS: We could not draw conclusions about the causal relationship between therapeutic alliance and improvement in depression. CONCLUSIONS: Among high-risk adolescents undergoing FFT, therapeutic alliance is associated with clinical improvement over 4 months. Strategies to enhance adolescent engagement may strengthen the long-term effects of family interventions.

Nimodipine improves cortical efficiency during working memory in healthy subjects.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; PFWE < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.