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.

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.

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.

Endothelial Function in Youth With Bipolar Disorder: Preliminary Evidence for Mood Polarity Differences.

Background: Bipolar disorder (BD) confers risk for accelerated atherosclerosis and early cardiovascular disease (CVD). In adults, mood symptom burden is associated with CVD. Here we examine endothelial dysfunction, considered an early predictor of CVD, in relation to mood states and symptoms among youth with BD.Methods: Participants were 209 youth, aged 13-20 years, including 114 with BD and 95 healthy controls (HC) recruited between 2012 and 2020. Diagnoses and mood symptoms were ascertained using validated, semi-structured interviews based on DSM-IV-TR criteria. Reactive hyperemia index (RHI), a measure of endothelial function, was assessed non-invasively via pulse amplitude tonometry (PAT). RHI was compared across 4 groups: BD-euthymic (n = 34), BD-depressed (n = 36), BD-hypomanic/mixed (n = 44), and HC (n = 95) controlling for age, sex, and obesity. Analyses also examined for RHI-mood associations in the overall BD group.Results: RHI was significantly different between groups (F3,202 = 4.47, P = .005, ηp2 = 0.06). Specifically, RHI was lower in the BD-depressed group compared to HC (P = .04, d = 0.4). Additionally, the BD-hypomanic/mixed group had higher RHI compared to the BD-euthymic (P = .02, d = 0.55), BD-depressed (P < .001, d = 0.79), and HC (P = .04, d = 0.55) groups. Lastly, within the BD group, higher RHI was associated with higher mania scores (P = .006, ß = 0.26), but not depression scores. All analyses remained significant in sensitivity analyses further controlling for cardiovascular risk factors and for current lithium, second-generation antipsychotic, and any medication use.Conclusions: We found that symptomatic youth with BD have anomalous RHI, which varies according to mood polarity. Future studies in larger samples, with prospective repeated measures, should investigate whether endothelial dysfunction partially subserves the psychiatric symptoms and cardiovascular risk observed in BD.

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.

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.

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.

Association of Lithium and Second-Generation Antipsychotics with Neurocognition in Youth with Bipolar Disorder.

Objective: Numerous studies have examined the association of antimanic medications with neurocognition in adults with bipolar disorder (BD). However, few studies have examined this topic in youth. Thus, we aimed to examine the association of lithium and second-generation antipsychotics (SGAs), the first-line antimanic medications for youth with BD, with neurocognition in a relatively large sample of youth with BD. Methods: Participants included 91 youth with BD-I, -II, or -Not Otherwise Specified, aged 13-20 years (n = 14 current lithium use, n = 51 current SGA use). We examined four tests from the Cambridge Neuropsychological Test Automated Battery: Intra/Extra Dimensional Set-Shifting Task (IED), Rapid Visual Information Processing Task (RVP), Stockings of Cambridge Test (SOC), and Affective Go/No-Go (AGN). Within-sample Z-scores were computed, and a global neurocognitive composite score and g factor derived from these tests comprised the primary outcomes. Multivariable analyses controlled for age, sex, and IQ. Results: Current lithium use was significantly associated with poorer cognitive flexibility/set-shifting (IED). After further controlling for lifetime comorbid attention-deficit/hyperactivity disorder and current depression symptoms in sensitivity analyses, the lithium finding was no longer significant. Current SGA use was significantly associated with greater affective processing bias (AGN). No significant findings survived correction for multiple comparisons. All other cognitive outcomes were not significantly associated with current lithium use, current SGA use, or total number of current medications. Conclusions: Treatment with lithium or SGAs was associated with minimal neurocognitive impairments, with small effect sizes in primary multivariable analyses. This study adds to the limited body of literature examining medication use in relation to neurocognition in youth with BD. While the current study cannot rule out associations of smaller effect size, present findings suggest that leading mood-stabilizing medications are not associated with frank neurocognitive impairments in youth with BD.

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

Cannabis use and resting state functional connectivity in adolescent bipolar disorder.

BACKGROUND: Adolescents with bipolar disorder have high rates of cannabis use, and cannabis use is associated with increased symptom severity and treatment resistance in bipolar disorder. Studies have identified anomalous resting-state functional connectivity among reward networks in bipolar disorder and cannabis use independently, but have yet to examine their convergence. METHODS: Participants included 134 adolescents, aged 13 to 20 years: 40 with bipolar disorder and lifetime cannabis use, 31 with bipolar disorder and no history of cannabis use, and 63 healthy controls without lifetime cannabis use. We used a seed-to-voxel analysis to assess the restingstate functional connectivity of the amygdala, the nucleus accumbens and the orbitofrontal cortex, regions implicated in bipolar disorder and cannabis use. We used a generalized linear model to explore bivariate correlations for each seed, controlling for age and sex. RESULTS: We found 3 significant clusters. Resting-state functional connectivity between the left nucleus accumbens seed and the left superior parietal lobe was negative in adolescents with bipolar disorder and no history of cannabis use, and positive in healthy controls. Resting-state functional connectivity between the right orbitofrontal cortex seed and the right lateral occipital cortex was positive in adolescents with bipolar disorder and lifetime cannabis use, and negative in healthy controls and adolescents with bipolar disorder and no history of cannabis use. Resting-state functional connectivity between the right orbitofrontal cortex seed and right occipital pole was positive in adolescents with bipolar disorder and lifetime cannabis use, and negative in adolescents with bipolar disorder and no history of cannabis use. LIMITATIONS: The study did not include a cannabis-using control group. CONCLUSION: This study provides preliminary evidence of cannabis-related differences in functional reward circuits in adolescents with bipolar disorder. Further studies are necessary to evaluate whether the present findings reflect consequences of or predisposition to cannabis use.

Clinical and neurostructural characteristics among youth with familial and non-familial bipolar disorder: Family history and youth bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is highly heritable and often severe, particularly when illness onset occurs early in life. There is limited knowledge regarding the clinical and neurostructural correlates of family history of BD among youth with BD. METHODS: Clinical characteristics were evaluated in 197 youth with BD, ages 13-20 years, including 87 with familial BD and 110 with non-familial BD. Structural neuroimaging was examined in a subsample of familial BD (n=39), non-familial BD (n=42), and healthy control (HC, n=58) youth. Region of interest (ROI) analyses of anterior cingulate cortex (ACC), inferior frontal gyrus (IFG), and amygdala were complemented by whole-brain vertex-wise analyses. RESULTS: Youth with familial BD had more family history of other psychiatric disorders, less severe worst manic episode, and less treatment with lithium, selective serotonin reuptake inhibitor (SSRI) antidepressants, and any lifetime psychiatric medications. None of these findings survived after correction for multiple comparisons. There were no significant between-group differences in ROI analyses. In whole-brain analyses, significant differences in cortical thickness were as follows: familial and non-familial BD < HC in left precentral gyrus and right inferior parietal lobe; familial BD < HC in left superior frontal gyrus; non-familial BD < HC in right precentral gyrus. LIMITATIONS: Relatives did not complete full diagnostic interviews. CONCLUSIONS: There were relatively few differences in clinical and neurostructural correlates related to family history of BD in youth with BD. Current findings suggest that family history of BD is not a strong contributor to the clinical or neuroimaging phenotypes in youth with BD.

Neurostructural correlates of retinal microvascular caliber in adolescent bipolar disorder.

Objectives: Vascular-brain associations are well established in adults but neglected in youth and psychiatric populations, who are at greater cardiovascular risk. We therefore examined the association of retinal vascular caliber with regional brain structure in adolescents with and without bipolar disorder (BD). Methods: One hundred and three adolescents (n = 51 BD, n = 52 healthy control [HC]) completed retinal fundus imaging, yielding arteriolar and venular diameters, followed by T1-weighted 3-Tesla MRI. Region of interest (ROI) analyses examined ventrolateral prefrontal cortex (vlPFC) and ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, and hippocampus, complemented by vertex-wise analyses. Linear regression assessed the association between retinal measures and brain structure, adjusting for covariates including age, sex, BMI, and intracranial volume (ICV). Results: In the overall sample, arteriolar caliber was negatively associated with ACC volume (ß = -0.20, p uncorrected = .046) and surface area (ß = -0.19, p uncorrected = .049). There were no other significant ROI findings. Vertex-wise analyses detected several significant positive bilateral associations of arteriovenous ratio (AVR) with volume and surface area in regions including rostral middle frontal gyrus (left p = .001; right p = .006), isthmus cingulate cortex (left and right p < .001), and left precuneus (p < .001). Significant negative associations were also observed for AVR (p = .03) and arteriolar caliber (p = .01), including a cluster encompassing the left rostral middle frontal gyrus and orbitofrontal cortical thickness. In the sole retinal-by-diagnosis interaction, greater AVR was more strongly associated with lower volume in the left middle temporal and fusiform gyri in BD versus HC (p = .004). Conclusion: This study provides evidence that vascular-brain associations are already evident in adolescence, suggesting that optimizing cardiovascular health may benefit the brain. This may be particularly relevant in BD and other brain disorders. Future research focusing on subpopulations where vascular-brain associations may be especially strong, for whom vascular-related interventions may be most indicated, is warranted.

Neurostructural Correlates of Cannabis Use in Adolescent Bipolar Disorder.

BACKGROUND: Little is known regarding the association of cannabis use with brain structure in adolescents with bipolar disorder (BD). This subject is timely, given expanded availability of cannabis contemporaneously with increased social acceptance and diminished societal constraints to access. Therefore, we set out to examine this topic in a sample of adolescents with BD and healthy control (HC) adolescents. METHODS: Participants included 144 adolescents (47 BD with cannabis use [BDCB+; including 13 with cannabis use disorder], 34 BD without cannabis use [BDCB-], 63 HC without cannabis use) ages 13-20 years. FreeSurfer-processed 3T MRI with T1-weighted contrast yielded measures of cortical thickness, surface area (SA), and volume. Region of interest (amygdala, hippocampus, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) analyses and exploratory vertex-wise analysis were undertaken. A general linear model tested for between-group differences, accounting for age, sex, and intracranial volume. RESULTS: Vertex-wise analysis revealed significant group effects in frontal and parietal regions. In post-hoc analyses, BDCB+ exhibited larger volume and SA in parietal regions, and smaller thickness in frontal regions, relative to HC and BDCB-. BDCB- had smaller volume, SA, and thickness in parietal and frontal regions relative to HC. There were no significant region of interest findings after correcting for multiple comparisons. CONCLUSION: This study found that cannabis use is associated with differences in regional brain structure among adolescents with BD. Future prospective studies are necessary to determine the direction of the observed association and to assess for dose effects.

Peripheral biomarkers of mitochondrial dysfunction in adolescents with bipolar disorder.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of bipolar disorder (BD). Impediment of mitochondrial oxidative phosphorylation results in a shift toward anaerobic respiration and lactate production. Elevated CNS lactate levels in adults with BD inform the need to evaluate lactate in peripheral samples and early in the course of BD. Furthermore, there exists a recent surge of investigations looking at circulating cell-free mitochondrial DNA (ccf-mtDNA) as a potential biomarker as they are released from cells under physiological stress, apoptosis, or bioenergetic compromise. OBJECTIVES: To compare lactate and ccf-mtDNA, two different ways in assessing the mitochondrial health and function, in adolescents with BD versus healthy control adolescents (HC). METHODS: One-hundred and five adolescents (n = 64 BD, n = 41 HC) were included. Serum lactate level was measured using a commercially available colorimetric kit. Serum ccf-mtDNA concentration was measured using quantitative polymerase chain reaction from ccfDNA purified by commercially available spin columns. Diagnosis and mood symptoms were evaluated using semi-structured interviews. RESULTS: There is an increase in serum lactate level of adolescents with BD (1.319 ± 0.444 nmol/uL) versus HC (1.168 ± 0.353 nmol/uL; p = 0.043), but not ccf-mtDNA. Among BD adolescents, depression symptoms were negatively correlated with ccf-mtDNA levels (ρ = -0.289; p = 0.038) but loses significance when corrected for multiple comparison. Lactate was positively correlated with ccf-mtDNA in the overall sample (ρ = 0.201; p = 0.043). When examined by diagnosis, this association remained in BD (ρ = 0.273; p = 0.032), but not HC. CONCLUSION: These preliminary results indicate that elevated lactate is observed even among adolescents early in their course of BD, that the association between lactate and ccf-mtDNA appears to be specific to BD, and that ccf-mtDNA is potentially associated with depression symptoms in adolescent BD. In addition, the effect of psychotropic medications used in the treatment of BD on peripheral lactate and ccf-mtDNA requires further investigation.