Introduction:Neuroinflammatory processes have been extensively implicated in the underlying neurobiology of numerous neuropsychiatric disorders. Elevated C-reactive protein (CRP), an indicator of non-specific inflammation commonly utilized in clinical practice, has been associated with depression in adults. In adolescents, our group previously found CRP to be associated with altered neural reward function but not with mood and anxiety symptoms assessed cross-sectionally. We hypothesized that the distinct CRP findings in adolescent vs. adult depression may be due to chronicity, with neuroinflammatory effects on psychiatric disorders gradually accumulating over time. Here, we conducted a longitudinal study to evaluate if CRP levels predicted future onset or progression of depression in adolescents.Methods:Participants were 53 adolescents (ages 14.74 ± 1.92, 35 female), 40 with psychiatric symptoms and 13 healthy controls. At baseline, participants completed semi-structured diagnostic evaluations; dimensional assessments for anxiety, depression, anhedonia, and suicidality severity; and bloodwork to quantify CRP levels. Clinical assessments were repeated at longitudinal follow-up after approximately 1.5 years. Spearman's correlation between CRP levels and follow-up symptom severity were controlled for BMI, age, sex, and follow-up interval and considered significant at the two-tailed, Bonferroni-adjusted p < 0.05 level.Results:After correction for multiple comparisons, no relationships were identified between baseline CRP levels and follow-up symptom severity.Conclusion:CRP levels were not significantly associated with future psychiatric symptoms in adolescents in this preliminary analysis. This may suggest that CRP is not a useful biomarker for adolescent depression and anxiety. However, future longitudinal studies with larger sample sizes and incorporating additional indicators of neuroinflammation are needed.

Reward dysfunction has been hypothesized to play a key role in the development of psychiatric conditions during adolescence. To help capture the complexity of reward function in youth, we used the Reward Flanker fMRI Task, which enabled us to examine neural activity during expectancy and attainment of both certain and uncertain rewards. Participants were 84 psychotropic-medication-free adolescents, including 67 with diverse psychiatric conditions and 17 healthy controls. Functional MRI used high-resolution acquisition and high-fidelity processing techniques modeled after the Human Connectome Project. Analyses examined neural activation during reward expectancy and attainment, and their associations with clinical measures of depression, anxiety, and anhedonia severity, with results controlled for family-wise errors using non-parametric permutation tests. As anticipated, reward expectancy activated regions within the fronto-striatal reward network, thalamus, occipital lobe, superior parietal lobule, temporoparietal junction, and cerebellum. Unexpectedly, however, reward attainment was marked by widespread deactivation in many of these same regions, which we further explored using cosine similarity analysis. Across all subjects, striatum and thalamus activation during reward expectancy negatively correlated with anxiety severity, while activation in numerous cortical and subcortical regions during reward attainment positively correlated with both anxiety and depression severity. These findings highlight the complexity and dynamic nature of neural reward processing in youth.

Adolescence is a period of rapid brain development when psychiatric symptoms often first emerge. Studying adolescents may therefore facilitate the identification of neural alterations early in the course of psychiatric conditions. Here, we sought to utilize new, high-quality brain parcellations and data-driven graph theory approaches to characterize associations between resting-state networks and the severity of depression, anxiety, and anhedonia symptoms—salient features across psychiatric conditions. As reward circuitry matures considerably during adolescence, we examined both Whole Brain and three task-derived reward networks. Subjects were 87 psychotropic-medication-free adolescents (age = 12–20) with diverse psychiatric conditions (n = 68) and healthy controls (n = 19). All completed diagnostic interviews, dimensional clinical assessments, and 3T resting-state fMRI (10 min/2.3 mm/TR = 1 s). Following high-quality Human Connectome Project-style preprocessing, multimodal surface matching (MSMAll) alignment, and parcellation via the Cole-Anticevic Brain-wide Network Partition, weighted graph theoretical metrics (Strength Centrality = CStr; Eigenvector Centrality = CEig; Local Efficiency = ELoc) were estimated within each network. Associations with symptom severity and clinical status were assessed non-parametrically (two-tailed pFWE < 0.05). Across subjects, depression scores correlated with ventral striatum CStr within the Reward Attainment network, while anticipatory anhedonia correlated with CStr and ELoc in the subgenual anterior cingulate, dorsal anterior cingulate, orbitofrontal cortex, caudate, and ventral striatum across multiple networks. Group differences and associations with anxiety were not detected. Using detailed functional and clinical measures, we found that adolescent depression and anhedonia involve increased influence and communication efficiency in prefrontal and limbic reward areas. Resting-state network properties thus reflect positive valence system anomalies related to discrete reward sub-systems and processing phases early in the course of illness.

Introduction: Increased peripheral inflammation has been consistently documented in both adult and pediatric depression. However, elevated levels of C-reactive protein (CRP), a nonspecific biomarker for inflammation, have been primarily reported in adults; whether CRP plays a similar role in adolescent depression has not been conclusively established. In our prior work, we identified relationships between CRP and reward neurocircuitry in adolescents with psychiatric symptoms (N = 64) but not with depressive symptoms. Extending this work, we sought to examine CRP across the full range of mood and anxiety symptom severity in a larger, clinically diverse cohort of psychotropic medication-free adolescents and healthy controls (HCs). Methods: Subjects were adolescents (N = 127, age: 15.17 ± 2.19 years, 78 female) with psychiatric symptoms (n = 96, including previous cohort of 64) and HC (n = 31). All completed a semi-structured psychiatric evaluation and dimensional assessments for depression, anxiety, anhedonia, and suicidality. Group-comparison and correlation analyses utilized nonparametric statistics controlled for body mass index, sex, and age at pFWE < 0.05. Results: No group differences were identified in CRP levels between the clinical cohort and HCs. In addition, correlations between CRP and clinical symptomatology were not significant in either the whole sample or the psychiatric group. Conclusions: We found that, unlike in adults, CRP was not associated with depressive symptoms. This suggests that inflammation in pediatric depression is more narrowly delimited at the onset of psychiatric symptoms and may only become systemic with chronicity.

Objective Adolescence 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. Methods Adolescents (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). Results Relative 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. Conclusions Using 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.

BACKGROUND:Adolescent depression varies considerably in its course. However, there remain no biobehavioral predictors of illness trajectory, and follow-up studies in depressed youth are sparse. Here, we sought to examine whether reward function would predict future clinical outcomes in adolescents with depressive symptoms. We utilized the reward flanker fMRI task to assess brain function during distinct reward processes of anticipation, attainment, and positive prediction error (PPE, i.e. receiving uncertain rewards).METHODS:Subjects were 29 psychotropic-medication-free adolescents with mood and anxiety symptoms and 14 healthy controls (HC). All had psychiatric evaluations at baseline and approximately 24-month follow-up. Thirty-two participants (10 HC) had usable fMRI data. Correlation and hierarchical regression models examined baseline symptom severity measures as predictors of follow-up clinical outcomes. Whole-brain analyses examined relationships between neural reward processes and follow-up outcomes.RESULTS:Clinically, anhedonia, but not irritability, predicted future depression and suicidal ideation. Among reward processes, only baseline neural activation during PPE correlated with follow-up depression and anhedonia severity. Specifically, activation in the left angular gyrus-a component of the default mode network-was associated with future depression, while activation in the dorsal anterior cingulate, operculum, and left insula-key salience and pain network regions-was associated with future anhedonia, even when controlling for baseline anhedonia.LIMITATIONS:The small sample size and variable follow-up intervals limit the generalizability of conclusions.CONCLUSIONS:This research suggests that reward dysfunction, indexed by anhedonia, may predict worse clinical trajectories in depressed youth. Adolescents presenting with significant anhedonia should be carefully monitored for illness progression.

Introduction: Increased inflammation has been implicated in many psychiatric conditions across ages. We previously reported relationships between blood cytokine levels and anhedonia, the decreased capacity to experience pleasure, as well as with reward-related brain activation in adolescents with psychiatric symptoms. Here, we sought to extend this work in a larger cohort of adolescents with psychiatric symptoms and assess the relationships of C-Reactive Protein (CRP, inflammation biomarker) with clinical symptoms and reward-related brain activation.Methods: Subjects were 64 psychotropic-medication-free adolescents with psychiatric symptoms (ages: 15.17 & PLUSMN; 2.10, 44 female). All had psychiatric evaluations and dimensional assessments for anxiety, depression, anhedonia, and suicidality. Neuroimaging included the Reward Flanker fMRI Task examining brain activation during reward anticipation, attainment, and positive prediction error. Both whole-brain and ROI analyses focusing on reward circuitry were performed. All analyses were controlled for BMI, age, and sex at pFWE < 0.05.Results: No relationships were identified between CRP and clinical symptom severity. CRP was positively associated with brain activation during reward attainment in regions of the visual and dorsal attention networks, as well as during positive prediction error in the cerebellum. In ROI analyses, CRP was negatively correlated with brain activation during reward anticipation in the dorsal anterior cingulate cortex. When one subject with high CRP was excluded, CRP was also positively correlated with positive predication error activation in the nucleus accumbens.Conclusion: Despite the lack of association between CRP and clinical symptomatology, our fMRI findings suggest a relationship between inflammation and brain function early course of psychiatric conditions.