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Neural function underlying reward expectancy and attainment in adolescents with diverse psychiatric symptoms

Liu, Qi; Ely, Benjamin A; Stern, Emily R; Xu, Junqian; Kim, Joo-Won; Pick, Danielle G; Alonso, Carmen M; Gabbay, Vilma
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.
PMCID:9668660
PMID: 36451362
ISSN: 2213-1582
CID: 5374062

Lack of Associations Between C-Reactive Protein and Mood and Anxiety Symptoms in Adolescents

Liu, Qi; Ely, Benjamin A; Simkovic, Sherry; Alonso, Carmen M; Gabbay, Vilma
PMID: 34166062
ISSN: 1557-8992
CID: 4918682

Data-driven parcellation and graph theory analyses to study adolescent mood and anxiety symptoms

Ely, Benjamin A; Liu, Qi; DeWitt, Samuel J; Mehra, Lushna M; Alonso, Carmen M; Gabbay, Vilma
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.
PMCID:8093238
PMID: 33941762
ISSN: 2158-3188
CID: 4866102

Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms

Liu, Qi; Ely, Benjamin; Simkovic, Sherry; Tao, Annie; Wolchok, Rachel; Alonso, Carmen M; Gabbay, Vilma
Introduction/UNASSIGNED: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 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/UNASSIGNED:< 0.05. Results/UNASSIGNED: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 dorsal anterior cingulate cortex. When subject with high CRP was excluded, CRP was also positively correlated with positive predication error activation in nucleus accumbens. Conclusion/UNASSIGNED:Despite lack of associations of CRP with clinical symptomatology, our fMRI findings suggest a relationship between inflammation and brain function early course of psychiatric conditions.
PMCID:7771888
PMID: 33381770
ISSN: 2666-3546
CID: 4731912

Reward function as an outcome predictor in youth with mood and anxiety symptoms

Liu, Qi; Ely, Benjamin A; Schwartz, Joshua J; Alonso, Carmen M; Stern, Emily R; Gabbay, Vilma
BACKGROUND:Adolescent depression varies considerably in the course. However, there are no biobehavioral predictors of illness trajectories, 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 participants with mood and anxiety symptoms and 14 healthy controls (HC). All had psychiatric evaluations at baseline and approximately 24-month follow-up. Thirty-two adolescents (10 HC) had usable fMRI data. Correlation and hierarchical regression models examined symptom severity as predictors for follow-up clinical outcomes. Whole-brain analyses examined the relationships between neural reward processes and follow-up outcomes. RESULTS:Clinically, anhedonia, but not irritability, predicted future depression and suicidal ideations. Among reward processes, only neural activation during PPE was correlated with future depression and anhedonia severity. Specifically, activation in the left angular gyrus-a component of default mode network-was associated with future depression, while activation in the dorsal anterior cingulate, operculum and left insula-key regions within the salience and pain networks-was associated with future anhedonia, even when controlling baseline anhedonia. LIMITATIONS/CONCLUSIONS:Small sample size and variability in follow-up intervals limit the generalizability of conclusions. CONCLUSIONS:This research suggests the anhedonia and reward dysfunction may predict a worse course in adolescent depression. The adolescents with anhedonia should be monitored more carefully for a longer period.
PMID: 33010568
ISSN: 1573-2517
CID: 4626442

Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms

Bradley, Kailyn A; Stern, Emily R; Alonso, Carmen M; Xie, Hui; Kim-Schulze, Seunghee; Gabbay, Vilma
BACKGROUND:Inflammation has been hypothesized to contribute to reward dysfunction across psychiatric conditions, but little is known about this relationship in youth. Therefore, the present study investigated the associations between general and specific markers of inflammation and neural activation during reward processing, including anticipation and attainment, in youth with diverse psychiatric symptoms. METHODS:Forty-six psychotropic medication-free youth with diverse psychiatric symptoms underwent a blood draw to measure 41 cytokines, as well as structural and functional magnetic resonance imaging. The Reward Flanker Task examined neural activation during reward anticipation and attainment. Relationships between inflammation and neural activation were assessed using data reduction techniques across the whole-brain, as well as in specific reward regions of interest (basal ganglia, anterior and mid-cingulate cortex [ACC/MCC]). RESULTS:Whole-brain principal component analyses showed that factor 3 (12 cytokines: FGF-2, Flt3-L, fractalkine, GM-CSF, IFN-α2, IFN-γ, IL-3, IL-4, IL-7, IL-17A, MDC, and VEGF) was negatively correlated with precuneus/posterior cingulate cortex activity during anticipation. Factor 2 (11 cytokines: eotaxin, IL-1α, IL-1Rα, IL-2, IL-5, IL-9, IL-12p40, IL-13, IL-15, MCP-3, and TNF-β) was negatively correlated with angular gyrus activity during attainment. ROI analyses additionally showed that multiple cytokines were related to activity in the basal ganglia (EGF, FGF-2, Flt-3L, IL-2, IL-13, IL-15, IL-1Rα, MCP-3) and ACC/MCC (Flt-3L) during attainment. C-reactive protein (CRP) was not associated with neural activation. CONCLUSIONS:Investigation of specific markers of immune function showed associations between inflammatory processes and activation of posterior default mode network, prefrontal cortex, and basal ganglia regions during multiple phases of reward processing.
PMCID:6660409
PMID: 30953769
ISSN: 1090-2139
CID: 4021922

Elevated striatal γ-aminobutyric acid in youth with major depressive disorder

Bradley, Kailyn A; Alonso, Carmen M; Mehra, Lushna M; Xu, Junqian; Gabbay, Vilma
BACKGROUND:Alterations in γ-aminobutyric acid (GABA) have been hypothesized to play a role in the pathogenesis of psychiatric illness. Our previous work has specifically linked anterior cingulate cortex (ACC) GABA deficits with anhedonia in youth with major depressive disorder (MDD). As anhedonia reflects alterations within the reward circuitry, we sought to extend this investigation and examine GABA levels in another key reward-related region, the striatum, in the same adolescent population. METHODS:H MRS) whereby GABA levels were measured in striatal and ACC voxels. GABA levels were compared between groups and between voxel positions and were examined in relation to clinical symptomatology, such as depression severity, anhedonia, anxiety, and suicidality. RESULTS:Depressed youth had unexpectedly higher GABA levels in the striatum compared to HC. In both depressed and healthy youth, GABA levels were higher in the striatum than in the ACC, while the differences in depressed youth were greater. Moreover, in depressed youth, higher striatal GABA above the mean of HCs was correlated with lower ACC GABA below the mean of HCs. Striatal GABA was not correlated with clinical symptomatology in this small sample. CONCLUSIONS:Together, these findings suggest that higher striatal GABA levels may serve some compensatory function as a result of lower ACC GABA in depressed adolescents. It is also possible that, like lower ACC GABA, higher striatal GABA might simply be another pathological feature of adolescent depression.
PMID: 29890194
ISSN: 1878-4216
CID: 3167022

Anhedonia as a Clinical Correlate of Inflammation in Adolescents across Psychiatric Conditions

Freed, Rachel D; Mehra, Lushna M; Laor, Daniel; Patel, Manishkumar; Alonso, Carmen M; Kim-Schulze, Seunghee; Gabbay, Vilma
Objectives Peripheral inflammation has been associated with multiple psychiatric disorders, particularly with depression. However, findings remain inconsistent and unreproducible, most likely due to the disorder's heterogeneity in phenotypic presentation. Therefore, in the present study, in an effort to account for inter-individual differences in symptom severity, we utilised a dimensional approach to assess the relationships between a broad panel of inflammatory cytokines and key psychiatric symptoms (i.e., depression, anhedonia, anxiety, fatigue, and suicidality) in adolescents across psychiatric disorders. We hypothesised that only anhedonia-reflecting deficits of reward function-will be associated with inflammation. Methods Participants were 54 psychotropic medication-free adolescents with diverse psychiatric conditions and 22 healthy control (HC) adolescents, ages 12-20. We measured 41 cytokines after in-vitro lipopolysaccharide stimulation. Mann-Whitney U and Spearman correlation tests examined group comparison and associations, respectively, while accounting for multiple comparisons and confounds, including depression severity. Results There were no group differences in cytokine levels. However, as hypothesised, within the psychiatric group, only anhedonia was associated with 19 cytokines, including hematopoietic growth factors, chemokines, and pro-inflammatory cytokines. Conclusions Our findings suggest that general inflammation may induce reward dysfunction, which plays a salient role across psychiatric conditions, rather than be specific to one categorical psychiatric disorder.
PMID: 29843560
ISSN: 1814-1412
CID: 3165842

A Double-Blind Placebo-Controlled Trial of Omega-3 Fatty Acids as a Monotherapy for Adolescent Depression

Gabbay, Vilma; Freed, Rachel D; Alonso, Carmen M; Senger, Stefanie; Stadterman, Jill; Davison, Beth A; Klein, Rachel G
OBJECTIVE:Reports are mixed on the efficacy of omega-3 fatty acids (O3FA) for the treatment of major depressive disorder (MDD), with only limited data in adolescents. The present trial aimed to investigate systematically the efficacy of O3FA as a monotherapy, compared to a placebo, in adolescents with MDD. Secondarily, we explored O3FA effects on anhedonia, irritability, and suicidality-all key features of adolescent MDD. METHODS:Fifty-one psychotropic medication-free adolescents with DSM-IV-TR diagnoses of MDD (aged 12-19 years; 57% female) were randomized to receive O3FA or a placebo for 10 weeks. Data were collected between January 2006 and June 2013. O3FA and a placebo were administered on a fixed-flexible dose titration schedule based on clinical response and side effects. The initial dose of 1.2 g/d was increased 0.6 g/d every 2 weeks, up to a maximum of 3.6 g/d. Clinician-rated and self-rated depression severity, along with treatment response, served as primary outcome measures. Additionally, we examined O3FA effects on depression-related symptoms, including anhedonia, irritability, and suicidality. Treatment differences were analyzed via intent-to-treat analyses. RESULTS:O3FA were not superior to a placebo on any clinical feature, including depression severity and levels of anhedonia, irritability, or suicidality. Additionally, response rates were comparable between treatment groups. Within-treatment analyses indicated that both treatments were associated with significant improvement in depression severity on self- (O3FA: t = -4.38, P < .001; placebo: t = -3.52, P = .002) and clinician (O3FA: t = -6.47, P < .001; placebo: t = -8.10, P < .001) ratings. CONCLUSIONS:In adolescents with MDD, O3FA do not appear to be superior to placebo. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier: NCT00962598.
PMID: 29985566
ISSN: 1555-2101
CID: 3192232

Neural correlates of self-perceptions in adolescents with major depressive disorder

Bradley, Kailyn A L; Colcombe, Stan; Henderson, Sarah E; Alonso, Carmen M; Milham, Michael P; Gabbay, Vilma
Alteration in self-perception is a salient feature in major depression. Hyperactivity of anterior cortical midline regions has been implicated in this phenomenon in depressed adults. Here, we extend this work to depressed adolescents during a developmental time when neuronal circuitry underlying the sense of self matures by using task-based functional magnetic resonance imaging (fMRI) and connectivity analyses. Twenty-three depressed adolescents and 18 healthy controls (HC) viewed positive and negative trait words in a scanner and judged whether each word described them ('self' condition) or was a good trait to have ('general' condition). Self-perception scores were based on participants' endorsements of positive and negative traits during the fMRI task. Depressed adolescents exhibited more negative self-perceptions than HC. Both groups activated cortical midline regions in response to self-judgments compared to general-judgments. However, depressed adolescents recruited the posterior cingulate cortex/precuneus more for positive self-judgments. Additionally, local connectivity of the dorsal medial prefrontal cortex was reduced during self-reflection in depressed adolescents. Our findings highlight differences in self-referential processing network function between depressed and healthy adolescents and support the need for further investigation of brain mechanisms associated with the self, as they may be paramount to understanding the etiology and development of major depressive disorder.
PMCID:4912932
PMID: 26943454
ISSN: 1878-9307
CID: 2046392