BACKGROUND:People with a familial history for bipolar I disorder are at substantially elevated risk for developing the disorder, but the mechanisms underlying this risk remain unclear. We examined whether familial risk is associated with distinct neurocognitive phenotypes and whether these phenotypes are related to behavioral approach (BAS) and inhibition (BIS). METHODS:Participants were 180 youth with and without familial risk for bipolar I disorder. Latent profile analysis identified neurocognitive phenotypes based on scores from Cambridge Neuropsychological Test Automated Battery tasks. Multinomial logistic regression examined associations between familial risk and cognitive phenotype membership. Linear regression tested associations among phenotypes and BIS/BAS scores. Mediation analysis assessed whether cognitive phenotypes mediated associations between familial risk and motivational ratings. RESULTS:Four cognitive profiles were identified: Resilient, Slowed Reaction Time, Lower Working Memory, and Global Lower Performance. In adjusted pairwise comparisons, individuals in the Resilient compared with the Global Lower Performance profile were significantly less likely to have familial risk for bipolar disorder (OR = 0.2, p = 0.02). Other profiles were also less likely to have familial risk for bipolar disorder, but the association was not significant (p = 0.08). Familial risk was associated with lower BAS Drive overall; however, its indirect effect through the Global Lower Performance profile was positive and approached significance, suggesting a potential suppression pattern. CONCLUSION:Familial risk for bipolar I disorder may be associated with a cognitive phenotype characterized by global neurocognitive underperformance. Findings suggest that familial risk may influence motivational processes through multiple liability pathways.

Objective:To quantify associations between childhood maltreatment and emerging major depressive disorder (MDD) in adolescents/young adults with and without a first-degree family history of bipolar I disorder. Method:A total of 116 youths 14 to 21 years old were classified into a high-risk group (n = 58) based on at least 1 first-degree relative diagnosed with bipolar I disorder and a low-risk group (n = 58) based on no first- or second-degree family history of bipolar disorder. Childhood maltreatment was assessed using the Childhood Trauma Questionnaire-Short Form (CTQ-SF). Psychiatric diagnoses were established with semistructured interviews. Logistic regression tested interactions between childhood maltreatment and familial risk, controlling for age and sex, as predictors of MDD. Results:Half of participants in the high-risk group exhibited current or past MDD compared with 24% of the low-risk group. Regression models showed that each 1-point increase in CTQ-SF total score was associated with a 7% increase in the odds of MDD (odds ratio [OR] = 1.07, 95% CI 1.01-1.17, p = .004). High-risk status conferred approximately 3 times greater odds of MDD vs low-risk status (OR = 3.04, 95% CI 1.14-8.43, p = .03). Each year of age increased risk of MDD by 34% (OR = 1.34, 95% CI 1.09-1.67, p = .01). The childhood maltreatment × familial risk interaction was not significant (p > .6). Conclusion:Childhood maltreatment and familial risk for bipolar I disorder independently increase the risk of MDD. Mitigating either risk factor independently could meaningfully reduce depression risk in at-risk youth. Diversity & Inclusion Statement:We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. 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. 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. 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.

Background: Although the occurrence of mania defines the onset of bipolar I disorder, affected individuals often report years of prodromal psychiatric symptoms, often including anxiety and anxiety-related disorders. Moreover, rates of childhood trauma are elevated and may contribute to these conditions as well as mood symptoms. This study aimed to better understand risk factors of prodromal anxiety among youth at familial risk for bipolar disorder. In addition to the impact of trauma, we examined potential mediating roles of two motivational systems – the Behavioral Approach System (BAS) associated with reward motivation and Behavioral Inhibition Systems (BIS) associated with threat avoidance. Methods: Participants were 181 youth, 14–21 years old, with and without familial risk for bipolar I disorder followed prospectively. Using linear mixed-effects models, we examined associations of childhood trauma and familial risk with BIS and BAS subscale scores (Reward Responsiveness, Drive, Fun Seeking), and anxiety measures. We examined BIS and BAS as potential mediators in the relationship between familial risk and trauma, and anxiety, followed over a one-year period. Results: Results showed a positive association of familial risk with BIS (b=0.3, p = 0.02) and a negative association of familial risk with BAS Drive (b=-0.3, p = 0.03). Familial risk (b=0.5, p < 0.01) and trauma (b=0.2, p < 0.01) were associated with higher anxiety measures. BIS scores mediated the effect of familial risk (indirect effect: b=0.1, p = 0.03, proportion mediated=20 %), but not trauma, on anxiety ratings. Conclusion: Threat avoidance may be an important mechanism through which familial risk for bipolar I disorder predisposes individuals for anxiety.

Background:Dysregulated ventral prefrontal-subcortical networks are implicated in bipolar disorder, although how connectivity changes within these networks during the emergence and resolution of affective episodes is unclear. To address this knowledge gap, in this post-hoc study, we investigated longitudinal changes in prefrontal-subcortical connectivity during remission from mania in individuals with bipolar I disorder. Methods:We followed 35 individuals with bipolar I disorder through eight weeks of treatment for a manic episode. Using mixed models, we compared changes in ventral prefrontal-subcortical connectivity between individuals who remitted (n = 16, Young Mania Rating Scale/Hamilton Depression Rating Scale < 10 by week eight) and those who did not (n = 19) during emotional distractor conditions of the continuous performance task (CPT-END), a cognitive attentional task with emotional and neutral distractors; at baseline, one and eight weeks of treatment covarying for age and sex. Results:During the eight-week trial, significant group-by-time interactions were found between medial prefrontal cortex and right inferior frontal gyrus pars triangularis. There was also a group-by-time interaction in connectivity between prefrontal cortex and left thalamus, bilateral amygdala, and pregenual anterior cingulate cortex. Conclusion:These results highlight distinct ventral prefrontal-subcortical connectivity patterns characterizing the remitted state in bipolar disorder during tasks requiring focused attention amid emotional distractions. In the context of previous research, remission was associated with more normative connectivity between medial prefrontal and both thalamus and ventrolateral prefrontal cortex. However, while ventral prefrontal-paralimbic/limbic connectivity may show improvement with symptom remission, it may not fully normalize, suggesting residual functional abnormalities despite clinical recovery.

Background: Response to pharmacotherapy varies considerably among youths with bipolar disorder (BD) and is poorly predicted by clinical or demographic features. It can take several weeks to determine whether medication for BD is clinically effective. Although neuroimaging biomarkers are promising predictors, few studies examined the predictive value of the brain connectomic topology. Methods: BD-I youth (N = 121) with no prior psychopharmacotherapy were randomized to 6-weeks of doubleblind quetiapine or lithium. Structural magnetic resonance imaging (MRI) was performed before medication and at one week after medication initiation. Brain structural connectome was established from the MRI scans, and topological metrics were calculated for each patient. Deep learning-based prediction model was built using baseline and one-week connectome topology to predict medication response at week 6. Results: Both baseline topological metrics and one-week topological changes could predict treatment response with significant accuracy (73.8 %- 86.8 %). A longitudinally joint model combining baseline and one-week topology provided the highest accuracy (91.3 %). The transferability between models for quetiapine and lithium was relatively poor. In addition, predictions for the two drugs were driven by similar baseline but distinct one-week salient topological patterns. Limitations: Independent replication is needed to validate our preliminary findings. Conclusion: Brain structural connectomic topology at baseline and its acute changes within the first week enable accurate BD medication response prediction. The most contributive brain regions differed between prediction models for quetiapine and lithium after one week. These findings provide preliminary evidence for the development of neuroimaging-based biomarkers for guiding therapeutic interventions in youth with BD.

Early emotional experiences preceding the onset of bipolar disorder and potentially contributing to core symptoms of emotional liability and dysregulation are not well understood. We hypothesized that individuals with a higher familial risk for bipolar disorder I (i.e., high-risk) would exhibit early differences in emotional experiences compared to youth without such a family history (i.e., low-risk).

The physiological performance of any sensory organ is determined by its anatomy and physical properties. Consequently, complex sensory structures with elaborate features have evolved to optimize stimulus detection. Understanding these structures and their physical nature forms the basis for mechanistic insights into sensory function. Despite its crucial role as a sensor for pheromones and other behaviorally instructive chemical cues, the vomeronasal organ (VNO) remains a poorly characterized mammalian sensory structure. Fundamental principles of its physico-mechanical function, including basic aspects of stimulus sampling, remain poorly explored. Here, we revisit the classical vasomotor pump hypothesis of vomeronasal stimulus uptake. Using advanced anatomical, histological, and physiological methods, we demonstrate that large parts of the lateral mouse VNO are composed of smooth muscle. Vomeronasal smooth muscle tissue comprises two subsets of fibers with distinct topography, structure, excitation-contraction coupling, and, ultimately, contractile properties. Specifically, contractions of a large population of noradrenaline-sensitive cells mediate both transverse and longitudinal lumen expansion, whereas cholinergic stimulation targets an adluminal group of smooth muscle fibers. The latter run parallel to the VNO's rostro-caudal axis and are ideally situated to mediate antagonistic longitudinal constriction of the lumen. This newly discovered arrangement implies a novel mode of function. Single-cell transcriptomics and pharmacological profiling reveal the receptor subtypes involved. Finally, 2D/3D tomography provides non-invasive insight into the intact VNO's anatomy and mechanics, enables measurement of luminal fluid volume, and allows an assessment of relative volume change upon noradrenergic stimulation. Together, we propose a revised conceptual framework for mouse vomeronasal pumping and, thus, stimulus sampling.

Individuals diagnosed with bipolar I disorder experience deficits in emotion recognition. This study investigates these potential deficits in adolescents (14-21) at familial risk for bipolar I disorder as defined by having a diagnosed biological parent.

In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex- / strain-selective raw chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animal's sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary secretome, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.

OBJECTIVES/GOALS: Cognitive dysfunction and/or depressionfollowing ischemic stroke results in loss of independence in daily functioning. The objective of this work is to assess neural correlates of post-stroke cognitive deficits and the effect of left frontal transcranial electrical stimulation on cognitive control and associated brain rhythms. METHODS/STUDY POPULATION: We recorded midfrontal scalp EEG from 15 healthy and 13 participants with stroke while they performed a multi-source interference task (MSIT). The stroke cohort also performed additional MSIT sessions where they received active and sham transcranial direct current stimulation (tDCS) on the left prefrontal cortex (PFC). The EEG was pre-processed to get rid of eye movement and other channel noise artifacts and filtered to retain 0.5-55 Hz components. A Morlet wavelet was used to estimate power in theta (4-8 Hz), alpha (8-15 Hz) and gamma (35-50 Hz) frequency bands over a period of 2 seconds following MSIT image presentation. A generalized linear mixed effects model was used to find effect of group on behavior and EEG oscillations. A GLME was also used to find effects of active tDCS on behavior and EEG. RESULTS/ANTICIPATED RESULTS: We found Group (healthy v stroke) as a significant predictor of both response time (behavior) and conflict evoked theta power in the frontal channels (F1-Fz, F2-Fz). We also found that active tDCS significantly improved MSIT performance as compared to sham, after accounting for cognitive load. Active tDCS also induced low frequency oscillations in frontal EEG channels compared to sham. Preliminary results indicate that mid-frontal theta oscillations are a potential neural correlate of post-stroke cognitive deficit and tDCS of the left PFC might be a promising therapeutic intervention to ameliorate this. DISCUSSION/SIGNIFICANCE: Current therapeutic approaches often do not alleviate post stroke executive dysfunction, hence a better understanding of the brain network changes underlying such deficit can elucidate neural correlates of post stroke cognitive deficit to inform the development of neuromodulation interventions.

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed a disruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone.

Background: In order to identify biomarkers of prodromal mood disorders, we examined functional brain acti-vation in children and adolescent at familial risk for bipolar disorder.Methods: Offspring of parents with bipolar I disorder (at-risk youth; N = 115, mean +/- SD age: 13.6 +/- 2.7; 54 % girls) and group-matched offspring of healthy parents (healthy controls; N = 58, mean +/- SD age: 14.2 +/- 3.0; 53 % girls) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. At baseline, at-risk youth had no history of mood episodes or psychotic disorders. Subjects were followed longitudinally until developing their first mood episode or being lost to follow-up. Standard event-related region-of-interest (ROI) analyses were performed to compare brain activation at baseline between groups and in survival analyses.Results: At baseline, at-risk youth exhibited reduced activation to emotional distracters in the right ventrolateral prefrontal cortex (VLPFC) (p = 0.04). Activation was not significantly altered in additional ROIs, including left VLPFC, bilateral amygdala, caudate, or putamen. In those at-risk youth who developed their first mood episode during follow-up (n = 17), baseline increased activation in right VLPFC, right caudate, and right putamen activation predicted the development of a mood episode. Limitations: Sample size of converters, loss to follow-up, and number of statistical comparisons. Conclusions: We found preliminary evidence that a reduced activation in right VLPFC might be a marker of risk for or resilience to mood disorders in at-risk youth. Conversely, an increased activation in the right VLPFC, caudate, and putamen might indicate an increased risk for the later development of their first mood episode.

Introduction While pain self-management programs can significantly improve patient outcomes, poor adherence is common and the need for research on predictors of adherence has been noted. A potential, but commonly overlooked, predictor is cognitive function. Our aim, then, was to examine the relative influence of various cognitive functional domains on engagement with an online pain self-management program.Method A secondary analysis of a randomized controlled trial testing the impact of E-health (a 4-month subscription to the online Goalistics Chronic Pain Management Program) plus treatment as usual, relative to treatment as usual alone, on pain and opioid dose outcomes in adults receiving long-term opioid therapy of morphine equivalence dose ≥20 mg; 165 E-health participants who completed an on-line neurocognitive battery were included in this sub-analysis. A variety of demographic, clinical, and symptom rating scales were also examined. We hypothesized that better processing speed and executive functions at baseline would predict engagement with the 4-month E-health subscription.Results Ten functional cognitive domains were identified using exploratory factor analysis and the resultant factor scores applied for hypothesis testing. The strongest predictors of E-health engagement were selective attention, and response inhibition and speed domains. An explainable machine learning algorithm improved classification accuracy, sensitivity, and specificity.Conclusions The results suggest that cognition, especially selective attention, inhibitory control, and processing speed, is predictive of online chronic pain self-management program engagement. Future research to replicate and extend these findings seems warranted.ClinicalTrials.gov Registration Number NCT03309188

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent among youth with or at familial risk for bipolar-I disorder (BD-I), and ADHD symptoms commonly precede and may increase the risk for BD-I; however, associated neuropathophysiological mechanisms are not known. In this cross-sectional study, we sought to investigate brain structural network topology among youth with ADHD, with and without familial risk of BD-I.METHODS:We recruited 3 groups of psychostimulant-free youth (aged 10-18 yr), namely youth with ADHD and at least 1 biological parent or sibling with BD-I (high-risk group), youth with ADHD who did not have a first- or second-degree relative with a mood or psychotic disorder (low-risk group) and healthy controls. We used graph-based network analysis of structural magnetic resonance imaging data to investigate topological properties of brain networks. We also evaluated relationships between topological metrics and mood and ADHD symptom ratings.RESULTS:A total of 149 youth were included in the analysis (49 healthy controls, 50 low-risk youth, 50 high-risk youth). Low-risk and high-risk ADHD groups exhibited similar differences from healthy controls, mainly in the default mode network and central executive network. We found topological alterations in the salience network of the high-risk group, relative to both low-risk and control groups. We found significant abnormalities in global network properties in the high-risk group only, compared with healthy controls. Among both low-risk and high-risk ADHD groups, nodal metrics in the right triangular inferior frontal gyrus correlated positively with ADHD total and hyperactivity/impulsivity subscale scores.LIMITATIONS:The cross-sectional design of this study could not determine the relevance of these findings to BD-I risk progression.CONCLUSION:Youth with ADHD, with and without familial risk for BD-I, exhibit common regional abnormalities in the brain connectome compared with healthy youth, whereas alterations in the salience network distinguish these groups and may represent a prodromal feature relevant to BD-I risk.