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BDNF-Dependent Effects on Amygdala-Cortical Circuitry and Depression Risk in Children and Youth.

ABSTRACT: The brain-derived neurotrophic factor (BDNF) is critical for brain development, and the functional BDNF Val66Met polymorphism is implicated in risk for mood disorders. The objective of this study was to determine how the Val66Met polymorphism influences amygdala-cortical connectivity during neurodevelopment and assess the relevance for mood disorders. Age- and sex-specific effects of the BDNF Val66Met polymorphism on amygdala-cortical connectivity were assessed by examining covariance of amygdala volumes with thickness throughout the cortex in a sample of Caucasian youths ages 8-22 that were part of the Philadelphia Neurodevelopmental Cohort (n = 339). Follow-up analyses assessed corresponding BDNF genotype effects on resting-state functional connectivity (n = 186) and the association between BDNF genotype and major depressive disorder (MDD) (n = 2749). In adolescents, amygdala-cortical covariance was significantly stronger in Met allele carriers compared with Val/Val homozygotes in amygdala-cortical networks implicated in depression; these differences were driven by females. In follow-up analyses, the Met allele was also associated with stronger resting-state functional connectivity in adolescents and increased likelihood of MDD in adolescent females. The BDNF Val66Met polymorphism may confer risk for mood disorders in females through effects on amygdala-cortical connectivity during adolescence, coinciding with a period in the lifespan when onset of depression often occurs, more commonly in females.

SUBMITTER: Wheeler AL

PROVIDER: S-EPMC5907350 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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BDNF-Dependent Effects on Amygdala-Cortical Circuitry and Depression Risk in Children and Youth.

Wheeler Anne L AL Felsky Daniel D Viviano Joseph D JD Stojanovski Sonja S Ameis Stephanie H SH Szatmari Peter P Lerch Jason P JP Chakravarty M Mallar MM Voineskos Aristotle N AN

Cerebral cortex (New York, N.Y. : 1991) 20180501 5

The brain-derived neurotrophic factor (BDNF) is critical for brain development, and the functional BDNF Val66Met polymorphism is implicated in risk for mood disorders. The objective of this study was to determine how the Val66Met polymorphism influences amygdala-cortical connectivity during neurodevelopment and assess the relevance for mood disorders. Age- and sex-specific effects of the BDNF Val66Met polymorphism on amygdala-cortical connectivity were assessed by examining covariance of amygdal ...[more]

PMID: 28387866

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Project description:Typical adolescents have increased limbic engagement unchecked by regulatory medial prefrontal cortex (PFC) activity as well as heightened self-focus. The resulting emotion dysregulation and self-focused rumination make adolescents more susceptible to depression and suicide attempts. Heightened self-focus converges with mental illness among depressed adolescents, who deploy exaggerated attention to negative self-relevant stimuli and neglect positive ones as part of depression's phenomenology. This results in rigid negative self-representations during an identity formative period with potential lifetime repercussions. Current empirically supported treatments fail to allay recurrent depression. Evidence-based interventions for illnesses linked to suicide ideation and attempts (e.g., depression) underperform across the lifespan. This could be because current treatments are not successful in altering pervasive negative self-representations and affect dysregulation, which is known to be a risk factor of chronic depression. This study departs from the premise that increasing positive self-processing might be protective against chronic depression particularly during adolescence. The present research is a novel investigation of neurofeedback as a potential treatment alternative for adolescent depression. To enhance positive self-processing, we used the happy self-face as a cue to initiate neurofeedback from the bilateral amygdala and hippocampus and adolescents attempted to upregulate that limbic activity through the recall of positive autobiographical memories. We identified limbic functional circuitry engaged during neurofeedback and links to short-term symptoms' change in depression and rumination. We found that depressed youth showed greater right amygdala to right frontocortical connectivity and lower left amygdala to right frontocortical connectivity compared to healthy controls during neurofeedback vs. control conditions. Depressed youth also showed significant symptom reduction. Connectivity between the right amygdala and frontocortical regions was positively correlated with rumination and depression change, but connectivity between frontocortical regions and the left amygdala was negatively correlated with depression change. The results suggest that depressed youth might engage implicit emotion regulation circuitry while healthy youth recruit explicit emotion regulation circuits during neurofeedback. Our findings support a compensatory approach (i.e., target the right amygdala) during future neurofeedback interventions in depressed youth. Future work ought to include a placebo condition or group.

Project description:Introduction:Adequate sleep is essential for cognitive and emotion-related functioning, and 9 to 12 hr of sleep is recommended for children ages 6 to 12 years and 8 to 10 hr for children ages 13 to 18 years. However, national survey data indicate that older youth sleep for fewer hours and fall asleep later than younger youth. This shift in sleep duration and timing corresponds with a sharp increase in onset of emotion-related problems (e.g., anxiety, depression) during adolescence. Given that both sleep duration and timing have been linked to emotion-related outcomes, the present study tests the effects of sleep duration and timing, and their interaction, on resting-state functional connectivity (RS-FC) of corticolimbic emotion-related neural circuitry in children and adolescents. Methods:A total of 63 children and adolescents (6-17 years, 34 females) completed a weekend overnight sleep journal and a 10-min resting-state functional magnetic resonance imaging scan the next day (Sunday). Whole-brain RS-FC of the amygdala was computed, and the effects of sleep duration, timing (i.e., midpoint of sleep), and their interaction were explored using regression analyses. Results:Overall, we found that older youth tended to sleep later and for fewer hours than younger youth. Controlling for age, shorter sleep duration was associated with lower RS-FC between the amygdala and regions implicated in emotion regulation, including ventral anterior cingulate cortex, precentral gyrus, and superior temporal gyrus. Interestingly, midpoint of sleep was associated with altered connectivity in a distinct set of brain regions involved in interoception and sensory processing, including insula, supramarginal gyrus, and postcentral gyrus. Our data also indicate widespread interactive effects of sleep duration and midpoint on brain regions implicated in emotion regulation, sensory processing, and motor control. Conclusion:These results suggest that both sleep duration and midpoint of sleep are associated with next-day RS-FC within corticolimbic emotion-related neural circuitry in children and adolescents. The observed interactive effects of sleep duration and timing on RS-FC may reflect how homeostatic and circadian process interact in the brain and explain the complex patterns observed with respect to emotional health when considering sleep duration and timing. Sleep-related changes in corticolimbic circuitry may contribute to the onset of emotion-related problems during adolescence.

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BDNF-Dependent Effects on Amygdala-Cortical Circuitry and Depression Risk in Children and Youth.

Publications

BDNF-Dependent Effects on Amygdala-Cortical Circuitry and Depression Risk in Children and Youth.

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