Comparing Symptoms of Major Depression in Youth with Confirmed Versus Suspected Bipolar Disorder.

Background: While numerous studies have compared symptoms of major depressive episodes (MDEs) associated with bipolar disorder (BD; i.e., bipolar depression) versus major depressive disorder (MDD; i.e., unipolar depression), little is known about this topic in youth. We compared MDE symptoms in youth with BD with youth with suspected BD who have similar clinical and familial characteristics aside from having BD. Methods: MDE symptoms based on Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS) Depression Rating Scale items for the most severe past episode were compared in youth, ages 13-21 years, with BD (n = 208) versus suspected BD (n = 165). Diagnoses were confirmed via semistructured interviews. Symptoms with between-group differences (p < 0.05) in univariate analyses were evaluated in a multivariate forward stepwise regression. All analyses controlled for age and sex. Results: Youth with BD had significantly higher (more severe) ratings on depressed mood (p = 0.001, η2 = 0.05), irritability (p = 0.037, η2 = 0.02), anhedonia (p = 0.004, η2 = 0.04), negative self-image (p < 0.001, η2 = 0.07), hopelessness (p = 0.04, η2 = 0.02), fatigue (p = 0.001, η2 = 0.05), hypersomnia (p = 0.001, η2 = 0.05), suicidal ideation (p = 0.04, η2 = 0.02), and recurrent thoughts of death (p < 0.001, η2 = 0.05). In regression analyses, the only symptom that remained significant in the BD group was depressed mood (p = 0.002). Conclusions: These findings demonstrate greater severity of depressive symptoms in youth with BD versus MDD across mood, and cognitive and neurovegetative symptom domains. These differences are especially noteworthy given that the MDD group was highly similar to the BD group, aside from BD diagnosis. Present findings emphasize the need for novel treatment approaches to bipolar depression in youth, and for studies examining potential mechanisms underlying the increased severity of bipolar depression.

Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder, Youth at High Risk for Bipolar Disorder, and Controls.

OBJECTIVE: There is a pronounced gap in knowledge regarding polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk scores (PRSs) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls. METHOD: Participants were 344 youths of European ancestry (13-20 years old), including 136 youths with BD, 121 HR youths, and 87 controls. PRSs for BD, schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs HR vs controls). All genetic analyses controlled for age, sex, and 2 genetic principal components. RESULTS: The BD group showed significantly higher BD-PRS than the control group (odds ratio = 1.54, 95% CI = 1.13-2.10, p = .006), with the HR group numerically intermediate. BD-PRS explained 7.9% of phenotypic variance. PRSs for schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were not significantly different among groups. In the BD group, BD-PRS did not significantly differ in relation to BD subtype, age of onset, psychosis, or family history of BD. CONCLUSION: BD-PRS derived from adult genome-wide summary statistics is elevated in youth with BD. Absence of significant between-group differences in PRSs for other psychiatric disorders supports the specificity of BD-PRS in youth. These findings add to the biological validation of BD in youth and could have implications for early identification and diagnosis. To enhance clinical utility, future genome-wide association studies that focus specifically on early-onset BD are warranted, as are studies integrating additional genetic and environmental factors. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Higher Levels of C-reactive Protein Are Associated With Higher Cortical Surface Area and Lower Cortical Thickness in Youth With Bipolar Disorder.

BACKGROUND: Inflammation is implicated in the neuropathology of bipolar disorder (BD). The association of C-reactive protein (CRP) with brain structure has been examined in relation to BD among adults but not youth. METHODS: Participants included 101 youth (BD, n = 55; control group [CG], n = 46; aged 13-20 years). Blood samples were assayed for levels of CRP. T1-weighted brain images were acquired to obtain cortical surface area (SA), volume, and thickness for 3 regions of interest (ROI; whole-brain cortical gray matter, prefrontal cortex, orbitofrontal cortex [OFC]) and for vertex-wise analyses. Analyses included CRP main effects and interaction effects controlling for age, sex, and intracranial volume. RESULTS: In ROI analyses, higher CRP was associated with higher whole-brain SA (ß = 0.16; P = .03) and lower whole-brain (ß = -0.31; P = .03) and OFC cortical thickness (ß = -0.29; P = .04) within the BD group and was associated with higher OFC SA (ß = 0.17; P = .03) within the CG. In vertex-wise analyses, higher CRP was associated with higher SA and lower cortical thickness in frontal and parietal regions within BD. A significant CRP-by-diagnosis interaction was found in frontal and temporal regions, whereby higher CRP was associated with lower neurostructural metrics in the BD group but higher neurostructural metrics in CG. CONCLUSIONS: This study found that higher CRP among youth with BD is associated with higher SA but lower cortical thickness in ROI and vertex-wise analyses. The study identified 2 regions in which the association of CRP with brain structure differs between youth with BD and the CG. Future longitudinal, repeated-measures studies incorporating additional inflammatory markers are warranted.

White matter microstructural integrity is associated with retinal vascular caliber in adolescents with bipolar disorder.

OBJECTIVE: Reduced white matter integrity is observed in bipolar disorder (BD), and is associated with cardiovascular risk in adults. This topic is underexplored in youth, and in BD, where novel microvascular measures may help to inform understanding of the vascular-brain connection. We therefore examined the association of retinal vascular caliber with white matter integrity in a cross-sectional sample of adolescents with and without BD. METHODS: Eighty-four adolescents (n = 42 BD, n = 42 controls) completed retinal imaging, yielding arteriolar and venular caliber. Diffusion tensor imaging measured white matter fractional anisotropy (FA). Multiple linear regression tested associations between retinal vascular caliber and FA in regions-of-interest; corpus callosum, anterior thalamic radiation, uncinate fasciculus, and superior longitudinal fasciculus. Complementary voxel-wise analyses were performed. RESULTS: Arteriolar caliber was elevated in adolescents with BD relative to controls (F(1,79) = 6.15, p = 0.02, η2p = 0.07). In the overall sample, higher venular caliber was significantly associated with lower corpus callosum FA (ß = -0.24, puncorrected = 0.04). In voxel-wise analyses, higher arteriolar caliber was significantly associated with lower corpus callosum and forceps minor FA in the overall sample (ß = -0.46, p = 0.03). A significant diagnosis-by-venular caliber interaction on FA was noted in 5 clusters including the right retrolenticular internal capsule (ß = 0.72, p = 0.03), corticospinal tract (ß = 0.72, p = 0.04), and anterior corona radiata (ß = 0.63, p = 0.04). In each instance, venular caliber was more positively associated with FA in BD vs. controls. CONCLUSION: Retinal microvascular measures are associated with white matter integrity in BD, particularly in the corpus callosum. This study was proof-of-concept, designed to guide future studies focused on the vascular-brain interface in BD.

Association of polygenic risk for bipolar disorder with resting-state network functional connectivity in youth with and without bipolar disorder.

Little is known regarding the polygenic underpinnings of anomalous resting-state functional connectivity (rsFC) in youth bipolar disorder (BD). The current study examined the association of polygenic risk for BD (BD-PRS) with whole-brain rsFC at the large-scale network level in youth with and without BD. 99 youth of European ancestry (56 BD, 43 healthy controls [HC]), ages 13-20 years, completed resting-state fMRI scans. BD-PRS was calculated using summary statistics from the latest adult BD genome-wide association study. Data-driven independent component analyses of the resting-state fMRI data were implemented to examine the association of BD-PRS with rsFC in the overall sample, and separately in BD and HC. In the overall sample, higher BD-PRS was associated with lower rsFC of the salience network and higher rsFC of the frontoparietal network with frontal and parietal regions. Within the BD group, higher BD-PRS was associated with higher rsFC of the default mode network with orbitofrontal cortex, and altered rsFC of the visual network with frontal and occipital regions. Within the HC group, higher BD-PRS was associated with altered rsFC of the frontoparietal network with frontal, temporal and occipital regions. In conclusion, the current study found that BD-PRS generated based on adult genetic data was associated with altered rsFC patterns of brain networks in youth. Our findings support the usefulness of BD-PRS to investigate genetically influenced neuroimaging markers of vulnerability to BD, which can be observed in youth with BD early in their course of illness as well as in healthy youth.

Risk-Sensitive Decision-Making and Self-Harm in Youth Bipolar Disorder.

Background: Youth with bipolar disorder (BD) are at high risk for suicide and have high rates of self-harm, which includes both suicide attempts and non-suicidal self-injury. Greater risk-taking has been associated with suicide attempts in youth with major depression, although there are no studies examining the relationship between risk-related decision-making and self-harm in youth with BD. We aimed to examine the association of suicide risk with risk-sensitive decision-making in a controlled sample of youth with BD.Methods: Eighty-one youth with BD (based on DSM-IV criteria; 52 youth with a history of self-harm [BDSH+]; 29 without a history of self-harm [BDSH-]) and 82 age- and sex-matched control youth aged 13-20 years were recruited between 2012 and 2020. Decision-making and risk-taking performance were assessed via the Cambridge Gambling Task within the Cambridge Neuropsychological Test Automated Battery (CANTAB). General linear models were used to examine differences between groups with control for age, sex, and IQ.Results: There was a significant difference in the overall proportion of points bet (F2,157 = 3.87, P = .02, η2 = 0.23) such that BDSH- youth performed better than both BDSH+ (P = .02) and control youth (P = .04). Mean latency was significant (F3,156 = 4.12, P = .017, η2 = 0.03), with BDSH- youth deliberating longer than controls (P = .03). Risk-taking significantly differed between groups (F2,157 = 3.83, P = .02, η2 = 0.23), with BDSH- youth showing greater self-control compared to BDSH+ (P = .01) and control youth (P = .01).Conclusions: BDSH- youth had greater self-control and lower risk-taking. We speculate this finding may be reflective of a compensatory process among BDSH- youth serving a protective role in suicide risk. Future longitudinal studies are needed to examine the temporal association of neurocognition and self-harm among youth with BD.

Classifying youth with bipolar disorder versus healthy youth using cerebral blood flow patterns.

BACKGROUND: Clinical neuroimaging studies often investigate group differences between patients and controls, yet multivariate imaging features may enable individual-level classification. This study aims to classify youth with bipolar disorder (BD) versus healthy youth using grey matter cerebral blood flow (CBF) data analyzed with logistic regressions. METHODS: Using a 3 Tesla magnetic resonance imaging (MRI) system, we collected pseudo-continuous, arterial spin-labelling, resting-state functional MRI (rfMRI) and T 1-weighted images from youth with BD and healthy controls. We used 3 logistic regression models to classify youth with BD versus controls, controlling for age and sex, using mean grey matter CBF as a single explanatory variable, quantitative CBF features based on principal component analysis (PCA) or relative (intensity-normalized) CBF features based on PCA. We also carried out a comparison analysis using rfMRI data. RESULTS: The study included 46 patients with BD (mean age 17 yr, standard deviation [SD] 1 yr; 25 females) and 49 healthy controls (mean age 16 yr, SD 2 yr; 24 females). Global mean CBF and multivariate quantitative CBF offered similar classification performance that was above chance. The association between CBF images and the feature map was not significantly different between groups (p = 0.13); however, the multivariate classifier identified regions with lower CBF among patients with BD (ΔCBF = -2.94 mL/100 g/min; permutation test p = 0047). Classification performance decreased when considering rfMRI data. LIMITATIONS: We cannot comment on which CBF principal component is most relevant to the classification. Participants may have had various mood states, comorbidities, demographics and medication records. CONCLUSION: Brain CBF features can classify youth with BD versus healthy controls with above-chance accuracy using logistic regression. A global CBF feature may offer similar classification performance to distinct multivariate CBF features.

Association of cannabis use with neurocognition in adolescents with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) and cannabis use are each associated with neurocognitive deficits in adolescents. However, little is known regarding the association of neurocognition with cannabis use among adolescents with BD. Therefore, we examined this topic in a sample of adolescents with BD and healthy control (HC) adolescents. METHODS: Participants included 121 adolescents (n = 32 with BD and lifetime cannabis use (BDCB+), n = 31 with BD and no lifetime cannabis use (BDCB-), n = 58 HC with no lifetime cannabis use), aged 14-20 years. Five neurocognitive subtests of the computerized CANTAB battery were assessed. Groups were compared using an analysis of covariance (ANCOVA) covarying for age, sex, and intelligence quotient. RESULTS: The three groups differed significantly on tests of visuospatial working memory (F = 4.41, p = 0.014, ηp2=0.07) and sustained attention (F = 5.15, p = 0.007, ηp2=0.08). Post hoc analyses revealed working memory scores were significantly worse in BDCB+ versus HC (p = 0.04, d = 0.59), and sustained attention was significantly worse in BDCB- versus HC (p = 0.006, d = 0.70). CONCLUSION: These preliminary findings suggest that cannabis use among adolescents with BD is associated with working memory deficits. Future studies in larger samples are warranted to evaluate causation versus predisposition to cannabis use, and to evaluate duration, quantity, and potency of cannabis on neurocognition among adolescents with BD.

Vascular Endothelial Growth Factor Polymorphism rs699947 Is Associated with Neurostructural Phenotypes in Youth with Bipolar Disorder.

Background: Vascular endothelial growth factor (VEGF) may be relevant to bipolar disorder (BD) and brain structure. We evaluated VEGF rs699947 single-nucleotide polymorphism in relation to structural neuroimaging phenotypes in youth BD. Methods: We collected 3 T anatomical magnetic resonance images from 154 youth (79 BD and 75 healthy control [HC]) genotyped for VEGF rs699947. The participants were age (BD = 17.28 ± 1.40 and HC = 17.01 ± 1.83, t = -1.02, p = 0.31) and sex (BD = 63.3% females and HC = 52.0% females, χ2 = 2.01, p = 0.16) matched. Cortical thickness, surface area (SA), and volume were examined by region-of-interest (ROI) and vertex-wise analyses using general linear models (GLMs). ROI investigations selected for the prefrontal cortex (PFC), amygdala, and hippocampus. Vertex-wise analyses controlled for age, sex, and intracranial volume. Results: ROI results found lower PFC SA (p = 0.003, ηp2 = 0.06) and volume (p = 0.04, ηp2 = 0.03) in BD and a main effect of rs699947 on hippocampal volume (p = 0.03, ηp2 = 0.05). The latter two findings did not survive multiple comparisons. Vertex-wise analyses found rs699947 main effects on left postcentral gyrus volume (p < 0.001), right rostral anterior cingulate SA (p = 0.004), and right superior temporal gyrus thickness (p = 0.004). There were significant diagnosis-by-genotype interactions in the left superior temporal, left caudal middle frontal, left superior frontal, right fusiform, and right lingual gyri, and the left insular cortex. Posthoc analyses revealed the AA allele was associated with larger brain structures among HC, but smaller brain structures in BD for most clusters. Conclusions: Overall, we found preliminary evidence of divergent associations between BD and HC youth in terms of neurostructural correlates of VEGF rs699947 encompassing highly relevant frontotemporal regions.

The association of CNR1 genetic variants with resting-state functional connectivity in youth bipolar disorder.

Cannabinoid 1 receptors coded by the CNR1 gene are implicated in mood disorders and addiction. Given the prevalence and negative correlates of cannabis use in bipolar disorder (BD), we examined CNR1 polymorphism rs1324072 in relation to resting-state functional connectivity (rsFC) in youth BD. Participants included 124 youth, ages 13-20 years: 17 BD G-carriers, 48 BD non-carriers, 16 healthy controls (HC) G-carriers, and 43 HC non-carriers. rsFC was obtained using 3T-MRI. General linear models examined main effects of diagnosis, gene, and diagnosis-by-gene interaction, controlling for age, sex, and race. Regions-of-interests in seed-to-voxel analyses included: bilateral amygdala, hippocampus, nucleus accumbens (NAc), and orbitofrontal cortex (OFC). Main effects of diagnosis were observed for rsFC between the right amygdala seed and right occipital pole, and between the left NAc seed and left superior parietal lobe. Interaction analyses identified 6 significant clusters. G-allele was associated with negative connectivity in BD and positive connectivity in HC for: left amygdala seed with right intracalcarine cortex; right NAc seed with left inferior frontal gyrus; and right hippocampal seed with bilateral cuneal cortex (all p<0.001). G-allele was associated with positive connectivity in BD and negative connectivity in HC for: right hippocampal seed with left central opercular cortex (p = 0.001), and left NAc seed with left middle temporal cortex (p = 0.002). In conclusion, CNR1 rs1324072 was differentially associated with rsFC in youth with BD in regions relevant to reward and emotion. Future studies powered to integrate CNR1 alongside cannabis use are warranted to examine the inter-relationship between rs1324072 G-allele, cannabis use, and BD.

Neurostructural and neurocognitive correlates of APOE ε4 in youth bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a clinical risk factor for Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4), a genetic risk factor for AD, has been associated with brain structure and neurocognition in healthy youth. AIMS: We evaluated whether there was an association between APOE ε4 with neurostructure and neurocognition in youth with BD. METHODS: Participants included 150 youth (78 BD:19 ε4-carriers, 72 controls:17 ε4-carriers). 3T-magnetic resonance imaging yielded measures of cortical thickness, surface area, and volume. Regions-of-interest (ROI) and vertex-wise analyses of the cortex were conducted. Neurocognitive tests of attention and working memory were examined. RESULTS: Vertex-wise analyses revealed clusters with a diagnosis-by-APOE ε4 interaction effect for surface area (p = 0.002) and volume (p = 0.046) in pars triangularis (BD ε4-carriers > BD noncarriers), and surface area (p = 0.03) in superior frontal gyrus (controls ε4-carriers > other groups). ROI analyses were not significant. A significant interaction effect for working memory (p = 0.001) appeared to be driven by nominally poorer performance in BD ε4-carriers but not control ε4-carriers; however, post hoc contrasts were not significant. CONCLUSIONS: APOE ε4 was associated with larger neurostructural metrics in BD and controls, however, the regional association of APOE ε4 with neurostructure differed between groups. The role of APOE ε4 on neurodevelopmental processes is a plausible explanation for the observed differences. Future studies should evaluate the association of APOE ε4 with pars triangularis and its neurofunctional implications among youth with BD.

A systematic review on the effectiveness of dialectical behavior therapy for improving mood symptoms in bipolar disorders.

BACKGROUND: Evidence-based psychotherapies available to treat patients with bipolar disorders (BD) are limited. Dialectical behavior therapy (DBT) may target several common symptoms of BD. We conducted a systematic review on the efficacy of DBT for mood symptoms in patients with BD. The systematic search used key words related to DBT and BD in Medline, Embase, PsycInfo, CINAHL, and Cochrane Library databases from 1980 to April 1st, 2022. We included studies that enrolled patients with a BD I or II diagnosis (DSM or ICD), age 12 and older who received a DBT-based intervention. Studies reviewed were clinical trials including observational studies that reported at least one outcome related to BD mood symptoms or severity. We did not exclude based upon psychiatric or physical co-morbidity. RESULTS: We screened 848 abstracts and reviewed 28 full texts; 10 publications with 11 studies met our pre-determined eligibility criteria. All but one were feasibility pilot studies and most included participants in all mood states except for mania. The studies provided preliminary evidence suggesting these interventions may be effective for improving several core symptoms of BD. Overall, all the studies consistently supported that DBT-based interventions are feasible and acceptable for patients with BD. CONCLUSION: DBT may be an effective treatment for BD; however, the confidence in this conclusion is limited by the small sample sizes, heterogeneity, and high risk of bias in all published trials. Larger well-designed RCTs are now required to establish the effectiveness of DBT in BD.

The association of genetic variation in CACNA1C with resting-state functional connectivity in youth bipolar disorder.

BACKGROUND: CACNA1C rs1006737 A allele, identified as a genetic risk variant for bipolar disorder (BD), is associated with anomalous functional connectivity in adults with and without BD. Studies have yet to investigate the association of CACNA1C rs1006737 with resting-state functional connectivity (rsFC) in youth BD. METHODS: Participants included 139 youth with BD-I, -II, or -not otherwise specified, ages 13-20 years, including 27 BD A-carriers, 41 BD non-carriers, 32 healthy controls (HC) A-carriers, and 39 HC non-carriers. Anterior cingulate cortex (ACC), amygdala, and orbitofrontal cortex (OFC) were examined as regions-of-interest in seed-to-voxel analyses. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and race. RESULTS: We observed a main effect of BD diagnosis on rsFC between the right amygdala and the right occipital pole (p = 0.02), and a main effect of rs1006737 genotypes on rsFC between the right OFC and bilateral occipital cortex (p < 0.001). Two significant BD diagnosis-by-CACNA1C rs1006737 interactions were also identified. The A allele was associated with positive rsFC between the right ACC and right amygdala in BD but negative rsFC in HC (p = 0.01), and negative rsFC between the left OFC and left putamen in BD but positive rsFC in HC (p = 0.01). CONCLUSION: This study found that the rs1006737 A allele, identified as a genetic risk variant for BD in adults, was differentially associated with rsFC in youth with BD in regions relevant to emotion, executive function, and reward. Future task-based approaches are warranted to better understand brain connectivity in relation to CACNA1C in BD.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Resting-state functional connectivity indicators of risk and resilience for self-harm in adolescent bipolar disorder.

BACKGROUND: Suicide is the second leading cause of death in all youth and among adults with bipolar disorder (BD). The risk of suicide in BD is among the highest of all psychiatric conditions. Self-harm, including suicide attempts and non-suicidal self-injury, is a leading risk factor for suicide. Neuroimaging studies suggest reward circuits are implicated in both BD and self-harm; however, studies have yet to examine self-harm related resting-state functional connectivity (rsFC) phenotypes within adolescent BD. METHODS: Resting-state fMRI data were analyzed for 141 adolescents, ages 13-20 years, including 38 with BD and lifetime self-harm (BDSH+), 33 with BD and no self-harm (BDSH-), and 70 healthy controls (HC). The dorsolateral prefrontal cortex (dlPFC), orbitofrontal cortex (OFC) and amygdala were examined as regions of interest in seed-to-voxel analyses. A general linear model was used to explore the bivariate correlations for each seed. RESULTS: BDSH- had increased positive rsFC between the left amygdala and left lateral occipital cortex, and between the right dlPFC and right frontal pole, and increased negative rsFC between the left amygdala and left superior frontal gyrus compared to BDSH+ and HC. BDSH+ had increased positive rsFC of the right OFC with the precuneus and left paracingulate gyrus compared to BDSH- and HC. CONCLUSIONS: This study provides preliminary evidence of altered reward-related rsFC in relation to self-harm in adolescents with BD. Between-group differences conveyed a combination of putative risk and resilience connectivity patterns. Future studies are warranted to evaluate changes in rsFC in response to treatment and related changes in self-harm.

Neurovascular correlates of retinal microvascular caliber in adolescent bipolar disorder.

BACKGROUND: The connection between vascular and brain metrics is well-studied in older adults, but neglected in youth and in psychiatric populations at increased cardiovascular risk. We therefore examined the association of retinal vascular caliber with cerebral blood flow (CBF) in adolescents with and without bipolar disorder (BD). METHODS: Ninety-four adolescents (n = 48 BD, n = 46 controls) completed retinal fundus imaging, yielding estimates of arteriolar and venular diameter. Arterial spin labelling MRI was performed to measure CBF. We tested for associations between retinal vascular caliber and CBF in regions of interest; anterior cingulate cortex (ACC), middle frontal gyrus, and hippocampus in BD and controls separately. Complementary voxel-wise analyses were also performed. RESULTS: In the BD group, higher arteriovenous ratio (AVR) was associated with greater ACC CBF (ß = 0.34, puncorrected = 0.02), after controlling for age, sex, and BMI, however this finding did not survive correction for multiple comparisons. The control group did not show any associations (ß = 0.13, puncorrected = 0.40). Voxel-wise analyses within the BD group detected a significant positive association between AVR and regional CBF in two distinct clusters: i) left hippocampus (p < 0.0001); ii) right middle temporal gyrus (p = 0.04). LIMITATIONS: Limited sample size; young, medically healthy sample limits signal detection; cross-sectional design. CONCLUSION: This study reveals that higher AVR is associated with higher regional CBF in adolescents with BD. Present findings advance understanding of potential neurofunctional mechanisms linking retinal vascular caliber with psychiatric diagnoses. This proof-of-concept study was designed to generate initial insights to guide future studies focusing on the vascular-brain connection in youth and in psychiatry.

Comorbid Eating Disorders in a Sample of Youth With Bipolar Disorder: Elevated Burden of Dimensional and Categorical Psychopathology.

Objective: There is growing recognition of the importance of comorbid eating disorders (ED) among individuals with bipolar disorder (BD). However, most studies on this topic have focused on adult samples, and little is known regarding comorbid ED among youth with BD.Methods: The sample included 197 youth with DSM-IV BD (BD-I, BD-II, or BD-NOS [not otherwise specified]), aged 13-20 years and recruited from a subspecialized clinic within a tertiary academic health sciences center from 2009 to 2017. Univariate analyses examined demographic and clinical variables among participants with versus without lifetime DSM-IV ED. Variables significant at P < .10 were entered into a backward stepwise regression.Results: Fifty-six participants (28.4%) had lifetime DSM-IV ED (3.6% anorexia nervosa, 8.1% bulimia nervosa, 16.8% ED not otherwise specified). Significant correlates of lifetime ED were female sex (P < .001), BD-II subtype (P = .03), suicidal ideation (P = .006), suicide attempts (P = .004), non-suicidal self-injury (P < .001), sexual abuse (P = .02), cigarette smoking (P = .001), anxiety disorders (P = .004), posttraumatic stress disorder (P = .004), substance use disorders (P = .006), history of individual therapy (P = .01), and family history of anxiety (P = .01). Significant correlates of no lifetime ED were BD-I subtype (P < .001) and lifetime lithium use (P = .01). The ED group had significantly more severe lifetime depression (P < .001) and significantly more self-reported affective lability (P < .001) and borderline personality traits (P < .001). In multivariate analysis, the most robust predictors of lifetime ED were female sex (odds ratio [OR] = 4.61, P = .004), BD-I subtype (OR = 0.21, P = .03), cigarette smoking (OR = 2.78, P = .02), individual therapy (OR = 3.92, P = .03), family history of anxiety (OR = 2.86, P = .02), and borderline personality traits (OR = 1.01, P = .009).Conclusions: ED are common among youth with BD and associated with adverse clinical characteristics, many of which converge with prior adult literature. Future studies evaluating specific ED subtypes are warranted, as are treatment studies targeting comorbid ED in youth with BD.

Editorial: Embedding Functional Neuroimaging Within Clinical Trials for Mania: Toward Answering the Questions, Who, How, and When?

Neurocognitive deficits are common in bipolar disorder (BD) across the life span, and functional neuroimaging studies have elucidated anomalous neural circuitry underlying these deficits. Nonetheless, the literature regarding changes in neural circuitry in the context of clinical trials in BD remains sparse. In this issue, Li and Lei et al.1 report results of a randomized, double-blind, controlled trial comparing treatment effects of lithium and quetiapine on functional neural circuitry during a continuous performance task probing vigilance and working memory. Participants completed the continuous performance task while undergoing functional magnetic resonance imaging (MRI) to determine functional connectivity. This method uses functional MRI data to examine temporal synchrony in activation of spatially distinct brain regions' coordinated activation, which is thought to reflect flow of neural information between brain regions. At baseline, compared with controls, youth with BD experiencing a manic episode exhibited relative deficits in connectivity within regions relevant to sensory processing, affective reactivity, and cognitive control. After 1 week of treatment, functional connectivity among youth with BD treated with quetiapine, but not lithium, became similar to controls. After 6 weeks of treatment, functional connectivity deficits were normalized in both treatment groups, with no significant differences between treatment groups. Youth with the greatest changes in manic symptoms and functional connectivity were older, but similar in terms of other baseline clinical characteristics. This study underscores the benefits of including functional neuroimaging in clinical trials, offering unique insights into differential effects of antimanic treatments on key brain processes thought to underlie symptoms and symptomatic improvement in youth with BD.