Gabbay, V. | bioRxiv Science

bioRxiv2021

Adrenergic Attenuation of Immune Activity is Associated with Anhedonia in Adolescents

While inflammation has been implicated in psychopathology, relationships between immune-suppressing processes and psychiatric constructs remain elusive. This study sought to assess whether {beta}2-agonist clenbuterol (CBL) would attenuate immune activation in adolescents with mood and anxiety symptoms following ex vivo exposure of whole blood to lipopolysaccharide (LPS). Our focus on adolescents aimed to target a critical developmental period when psychiatric conditions often emerge and prior to chronicity effects. To capture a diverse range of immunologic and symptomatologic phenotypes, we included 97 psychotropic-medication free adolescents with mood and anxiety symptoms and 33 healthy controls. All participants had comprehensive evaluations and dimensional assessments of psychiatric symptoms. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, then analyzed for 41 cytokines, chemokines, and hematopoietic growth factors. Comparison analyses used Bonferroni-corrected nonparametric tests. Levels of nine immune biomarkers--including IL-1RA, IL-1{beta}, IL-6, IP-10, MCP-1, MIP-1, MIP-1{beta}, TGF-, and TNF---were significantly reduced by CBL treatment compared to LPS alone. Exploratory factor analysis reduced 41 analytes into 5 immune factors in each experimental condition, and their relationships with psychiatric symptoms were examined as a secondary aim. CBL+LPS Factor 4--comprising EGF, PDGF-AA, PDGF-AB/BB, sCD40L, and GRO--significantly correlated with anticipatory and consummatory anhedonia, even after controlling for depression severity. This study supports the possible inhibitory effect of CBL on immune activation. Using a data-driven method, distinctive relationships between CBL-affected immune biomarkers and dimensional anhedonia were reported, further elucidating the role of {beta}2-agonism in adolescent affective symptomatology.

neuroscience↗

bioRxiv2020

Neural Correlates of Positive and Negative Valence System Dysfunction in Adolescents Revealed by Data-Driven Parcellation and Resting-State Network Modeling

ObjectiveAdolescence is a period of rapid brain development when symptoms of mood, anxiety, and other disorders often first emerge, suggesting disruptions in maturing reward circuitry may play a role in mental illness onset. Here, we characterized associations between resting-state network properties and psychiatric symptomatology in medication-free adolescents with a wide range of symptom severity. MethodsAdolescents (age 12-20) with mood and/or anxiety symptoms (n=68) and healthy controls (n=19) completed diagnostic interviews, depression/anhedonia/anxiety questionnaires, and 3T resting-state fMRI (10min/2.3mm/TR=1s). Data were preprocessed (HCP Pipelines), aligned (MSMAll), and parcellated into 750 nodes encompassing the entire cortex/subcortex (Cole-Anticevic Brain-wide Network Partition). Weighted graph theoretical metrics (Strength Centrality=CStr; Eigenvector Centrality=CEig; Local Efficiency=ELoc) were estimated within Whole Brain and task-derived Reward Anticipation/Attainment/Prediction Error networks. Associations with clinical status and symptoms were assessed non-parametrically (two-tailed pFWE<0.05). ResultsRelative to controls, clinical adolescents had increased ventral striatum CEig within the Reward Attainment network. Across subjects, depression correlated with subgenual cingulate CStr and ELoc, anhedonia correlated with ventromedial prefrontal CStr and lateral amygdala ELoc, and anxiety negatively correlated with parietal operculum CEig and medial amygdala ELoc within the Whole Brain network. ConclusionsUsing a data-driven analysis approach, high-quality parcellation, and clinically diverse adolescent cohort, we found that symptoms within positive and negative valence system constructs differentially associated with resting-state network abnormalities: depression and anhedonia, as well as clinical status, involved greater influence and communication efficiency in prefrontal and limbic reward areas, whereas anxiety was linked to reduced influence/efficiency in amygdala and cortical regions involved in stimulus monitoring.

neuroscience↗