Towards a neurodevelopmental model of bipolar disorder: a critical review of trait- and state-related functional neuroimaging in adolescents and young adults.

Neurodevelopmental mechanisms are increasingly implicated in bipolar disorder (BD), highlighting the importance of their study in young persons. Neuroimaging studies have demonstrated a central role for frontotemporal corticolimbic brain systems that subserve processing and regulation of emotions, and processing of reward in adults with BD. As adolescence and young adulthood (AYA) is a time when fully syndromal BD often emerges, and when these brain systems undergo dynamic maturational changes, the AYA epoch is implicated as a critical period in the neurodevelopment of BD. Functional magnetic resonance imaging (fMRI) studies can be especially informative in identifying the functional neuroanatomy in adolescents and young adults with BD (BDAYA) and at high risk for BD (HR-BDAYA) that is related to acute mood states and trait vulnerability to the disorder. The identification of early emerging brain differences, trait- and state-based, can contribute to the elucidation of the developmental neuropathophysiology of BD, and to the generation of treatment and prevention targets. In this critical review, fMRI studies of BDAYA and HR-BDAYA are discussed, and a preliminary neurodevelopmental model is presented based on a convergence of literature that suggests early emerging dysfunction in subcortical (e.g., amygdalar, striatal, thalamic) and caudal and ventral cortical regions, especially ventral prefrontal cortex (vPFC) and insula, and connections among them, persisting as trait-related features. More rostral and dorsal cortical alterations, and bilaterality progress later, with lateralization, and direction of functional imaging findings differing by mood state. Altered functioning of these brain regions, and regions they are strongly connected to, are implicated in the range of symptoms seen in BD, such as the insula in interoception, precentral gyrus in motor changes, and prefrontal cortex in cognition. Current limitations, and outlook on the future use of neuroimaging evidence to inform interventions and prevent the onset of mood episodes in BDAYA, are outlined.

Predicting depressed and elevated mood symptomatology in bipolar disorder using brain functional connectomes.

BACKGROUND: The study is aimed to identify brain functional connectomes predictive of depressed and elevated mood symptomatology in individuals with bipolar disorder (BD) using the machine learning approach Connectome-based Predictive Modeling (CPM). METHODS: Functional magnetic resonance imaging data were obtained from 81 adults with BD while they performed an emotion processing task. CPM with 5000 permutations of leave-one-out cross-validation was applied to identify functional connectomes predictive of depressed and elevated mood symptom scores on the Hamilton Depression and Young Mania rating scales. The predictive ability of the identified connectomes was tested in an independent sample of 43 adults with BD. RESULTS: CPM predicted the severity of depressed [concordance between actual and predicted values (r = 0.23, pperm (permutation test) = 0.031) and elevated (r = 0.27, pperm = 0.01) mood. Functional connectivity of left dorsolateral prefrontal cortex and supplementary motor area nodes, with inter- and intra-hemispheric connections to other anterior and posterior cortical, limbic, motor, and cerebellar regions, predicted depressed mood severity. Connectivity of left fusiform and right visual association area nodes with inter- and intra-hemispheric connections to the motor, insular, limbic, and posterior cortices predicted elevated mood severity. These networks were predictive of mood symptomatology in the independent sample (r ⩾ 0.45, p = 0.002). CONCLUSIONS: This study identified distributed functional connectomes predictive of depressed and elevated mood severity in BD. Connectomes subserving emotional, cognitive, and psychomotor control predicted depressed mood severity, while those subserving emotional and social perceptual functions predicted elevated mood severity. Identification of these connectome networks may help inform the development of targeted treatments for mood symptoms.

Elevated prenatal maternal sex hormones, but not placental aromatase, are associated with child neurodevelopment.

Fetal exposure to testosterone may contribute to vulnerability for autism spectrum disorder (ASD). It is hypothesized that placental aromatase prevents fetal exposure to maternal testosterone, however, this pathway and the implications for child neurodevelopment have not been fully explored. We examined the relationships between prenatal maternal testosterone and estradiol at 19.2 ± 1.3 weeks, cord blood testosterone and estradiol at birth, placental aromatase mRNA expression, and neurodevelopment using the Social Communication Questionnaire (SCQ), the Behavioral Assessment System for Children, 3rd Edition (BASC-3), and the Empathizing Quotient for Children (EQ-C) at 4.5-6.5 years of age in a sample of 270 Nulliparous-Mothers-to-be (nuMoM2b) study participants. Maternal testosterone levels were positively associated with SCQ scores, but the association was not significant after adjusting for maternal age at delivery, nor was there a significant interaction with sex. Maternal estradiol levels were negatively associated with BASC-3 Clinical Probability scores among males (n = 139). We report a significant interaction effect of cord blood testosterone and fetal sex on both total SCQ scores and t-scores on the Developmental Social Disorders subscale. Placental aromatase was not associated with any neurodevelopmental or hormone measure, but under conditions of low placental aromatase expression, high maternal testosterone was positively associated with SCQ scores in males (n = 46). No other associations between hormone levels and neurodevelopment were significant. Our findings provide a foundation for further investigation of the mechanisms through which maternal sex hormones and placental steroidogenesis may affect fetal hormone production and neurobehavior.

A graph theory-based whole brain approach to assess mood state differences in adolescents and young adults with bipolar disorder.

OBJECTIVES: Identifying hubs of brain dysfunction in adolescents and young adults with Bipolar I Disorder (BDAYA ) could provide targets for early detection, prevention, and treatment. Previous neuroimaging studies across mood states of BDAYA are scarce and often examined limited brain regions potentially prohibiting detection of other important regions. We used a data-driven whole-brain Intrinsic Connectivity Distribution (ICD) approach to investigate dysconnectivity hubs across mood states in BDAYA . METHODS: Functional magnetic resonance imaging whole-brain ICD data were investigated for differences across four groups: BDAYA -depressed (n = 22), BDAYA -euthymic (n = 45), BDAYA -elevated (n = 24), and healthy controls (HC, n = 111). Clusters of ICD differences were assessed for regional dysconnectivity and mood symptom relationships. Analyses were also performed for BDAYA overall (vs. HC) ICD differences persisting across mood states. RESULTS: ICD was higher in the BDAYA- depressed group than other groups in bilateral ventral/rostral/dorsal prefrontal cortex (PFC) and right lenticular nucleus (LN) (pcorrected  <0.05). In BDAYA -depressed, functional connectivity (FC) was increased between these regions with their contralateral homologues and PFC-medial temporal FC was more negative (p < 0.005). PFC-related findings correlated with depression scores (p < 0.05). The overall BDAYA group showed ICD increases in more ventral left PFC and right cerebellum, present across euthymia and acute mood states. CONCLUSIONS: This ICD approach supports a PFC hub of inter- and intra-hemispheric frontotemporal dysconnectivity in BDAYA with potential trait features and disturbances of higher magnitude during depression. Hubs were also revealed in LN and cerebellum, less common foci of BD research. The hubs are potential targets for early interventions to detect, prevent, and treat BD.

Telehealth Social Rhythm Therapy to Reduce Mood Symptoms and Suicide Risk Among Adolescents and Young Adults With Bipolar Disorder.

OBJECTIVE: Social rhythm irregularities are associated with increased bipolar disorder symptoms and suicide risk. This study was the first to examine the feasibility and acceptability of a 12-week social rhythm therapy (SRT) delivered predominantly via telehealth (three in-person sessions, nine via video teleconferencing) to adolescents and young adults with bipolar disorder. The primary aim was to determine the feasibility and acceptability of SRT delivered predominantly via telehealth. Secondary aims were to explore the intervention's impacts on social rhythm regularity, mood symptoms, and suicide propensity. METHODS: Thirteen adolescents and young adults with bipolar disorder received a modified SRT called Brain Emotion circuitry-targeted Self-Monitoring And Regulation Therapy for Daily Rhythms (BE-SMART-DR) administered mostly remotely, adjunctive to treatment as usual. Retention rates, client satisfaction, therapeutic alliance, and pre- to postintervention changes in social rhythm regularity, mood symptoms, and suicide propensity were assessed. RESULTS: BE-SMART-DR was associated with high retention rates (77%), high mean±SD scores on the Client Satisfaction Questionnaire (29.4±2.7), and high participant global scores on the Working Alliance Inventory (231.3±8.1), indicative of strong therapeutic alliance. Secondary outcome measures on social rhythm irregularities, mood symptoms, and suicide propensity decreased from pre- to posttherapy. Increased social rhythm regularity was associated with reduced suicide propensity after analyses were controlled for reductions in mood symptoms. CONCLUSIONS: These preliminary results indicate that SRT delivered largely by telemedicine is feasible and acceptable. The intervention appeared to reduce mood symptoms, and suicide propensity independent of mood symptoms, among adolescents and young adults with bipolar disorder.

Aging of the brain in bipolar disorder: Illness- and onset-related effects in cortical thickness and subcortical gray matter volume.

BACKGROUND: Older adults with bipolar disorder (BD) have received little study, although they often have severe symptoms, treatment resistance and high suicide risk. Furthermore, a subset develops cognitive dysfunction for unknown reasons. METHODS: Here, cortical thickness and subcortical gray matter volume were compared across individuals ages 40-79y: 103 with BD ("later-onset" at ages ≥25y, n = 21; "early-onset" < 25y, n = 82) and healthy controls (HCs, n = 98). RESULTS: Overall, those with BD showed lower prefrontal, cingulate, sensorimotor, parahippocampal, insula, temporal, parietal, and occipital cortical thickness (Cohen's d: 0.4 to 0.8) and hippocampal, amygdalar, thalamic, and striatal gray matter volume (d: 0.6 to 0.8). Later-onset BD showed negative relationships between age and parahippocampal, insular, temporal, parietal, and occipital cortical thickness, and hippocampal, thalamic and striatal volume (r: -0.7 to -0.4). Suicide attempt history was associated with lower dorsolateral prefrontal cortical thickness (d = 0.5). LIMITATIONS: The study used a cross-sectional design and the sample of those with a later-onset of BD was relatively modest. CONCLUSIONS: Results support widespread gray matter decreases in older adults with BD, and also suggest a separable later-onset phenotype characterized by age-related gray matter reductions in regions subserving cognitive, emotional and perceptual processes. Moreover, the results are the first to demonstrate structural brain differences associated with a history of suicide attempts in older adults with BD.

A graph theory neuroimaging approach to distinguish the depression of bipolar disorder from major depressive disorder in adolescents and young adults.

BACKGROUND: Markers to differentiate depressions of bipolar disorder (BD-Dep) from depressions of major depressive disorder (MDD-Dep), and for more targeted treatments, are critically needed to decrease current high rates of misdiagnosis that can lead to ineffective or potentially deleterious treatments. Distinguishing, and specifically treating the depressions, during the adolescent/young adult epoch is especially important to decrease illness progression and improve prognosis, and suicide, as it is the epoch when suicide thoughts and behaviors often emerge. With differences in functional connectivity patterns reported when BD-Dep and MDD-Dep have been studied separately, this study used a graph theory approach aimed to identify functional connectivity differences in their direct comparison. METHODS: Functional magnetic resonance imaging whole-brain functional connectivity (Intrinsic Connectivity Distribution, ICD) measures were compared across adolescents/young adults with BD-Dep (n = 28), MDD-Dep (n = 20) and HC (n = 111). Follow-up seed-based connectivity was conducted on regions of significant ICD differences. Relationships with demographic and clinical measures were assessed. RESULTS: Compared to the HC group, both the BD-Dep and MDD-Dep groups exhibited left-sided frontal, insular, and medial temporal ICD increases. The BD-Dep group had additional right-sided ICD increases in frontal, basal ganglia, and fusiform areas. In seed-based analyses, the BD-Dep group exhibited increased interhemispheric functional connectivity between frontal areas not seen in the MDD-Dep group. LIMITATIONS: Modest sample size; medications not studied systematically. CONCLUSIONS: This study supports bilateral and interhemispheric functional dysconnectivity as features of BD-Dep that may differentiate it from MDD-Dep in adolescents/young adults and serve as a target for early diagnosis and treatment strategies.

Toward a Digital Future in Bipolar Disorder Assessment: A Systematic Review of Disruptions in the Rest-Activity Cycle as Measured by Actigraphy.

Background: Disruptions in rest and activity patterns are core features of bipolar disorder (BD). However, previous methods have been limited in fully characterizing the patterns. There is still a need to capture dysfunction in daily activity as well as rest patterns in order to more holistically understand the nature of 24-h rhythms in BD. Recent developments in the standardization, processing, and analyses of wearable digital actigraphy devices are advancing longitudinal investigation of rest-activity patterns in real time. The current systematic review aimed to summarize the literature on actigraphy measures of rest-activity patterns in BD to inform the future use of this technology. Methods: A comprehensive systematic review using PRISMA guidelines was conducted through PubMed, MEDLINE, PsycINFO, and EMBASE databases, for papers published up to February 2021. Relevant articles utilizing actigraphy measures were extracted and summarized. These papers contributed to three research areas addressed, pertaining to the nature of rest-activity patterns in BD, and the effects of therapeutic interventions on these patterns. Results: Seventy articles were included. BD was associated with longer sleep onset latency and duration, particularly during depressive episodes and with predictive value for worsening of future manic symptoms. Lower overall daily activity was also associated with BD, especially during depressive episodes, while more variable activity patterns within a day were seen in mania. A small number of studies linked these disruptions with differential patterns of brain functioning and cognitive impairments, as well as more adverse outcomes including increased suicide risk. The stabilizing effect of therapeutic options, including pharmacotherapies and chronotherapies, on activity patterns was supported. Conclusion: The use of actigraphy provides valuable information about rest-activity patterns in BD. Although results suggest that variability in rhythms over time may be a specific feature of BD, definitive conclusions are limited by the small number of studies assessing longitudinal changes over days. Thus, there is an urgent need to extend this work to examine patterns of rhythmicity and regularity in BD. Actigraphy research holds great promise to identify a much-needed specific phenotypic marker for BD that will aid in the development of improved detection, treatment, and prevention options.

Gender-related association among childhood maltreatment, brain structure and clinical features in bipolar disorder.

Bipolar disorder (BD) and exposure to childhood maltreatment (CM), which is present at high rates in BD, are both associated with hippocampus and prefrontal cortex structural alterations thought to contribute to clinical features. Gender-related differences are implicated in BD for CM exposure, brain structure and clinical features. However, relationships among these factors in BD are understudied. This study aimed to investigate associations among gender, CM, hippocampus and prefrontal gray matter structure and clinical features in BD. Childhood trauma questionnaire, structured clinical assessments and 3 Tesla structural magnetic resonance imaging were obtained for 236 adults (18-63 years, 32.0 ± 12.6): 119 with BD (58.8% women) and 117 healthy controls (HCs, 50.4% women). Women with BD reported higher CM severity than men with BD and HCs (B=-14.34, 95% confidence intervals (CI)[-22.71,-5.97], p<.001). CM and gender showed a significant interaction for left hippocampus (B=-7.41, 95% CI[-14.10,-0.71], p<.05); CM severity was negatively associated with left hippocampus only in women with BD. In women with BD, CM was associated with post-traumatic stress disorder comorbidity (B = 25.68, 95% CI[15.11,36.25], p<.001). In men with BD, CM severity was associated with lower left frontal pole (B=-0.71, 95% CI[-1.14,-0.28], p<.05) and right superior frontal (B=-17.78, 95% CI[-30.66,-4.90], p<.05) surface area; the latter related to earlier age of first mood symptoms (B = 33.97, 95% CI[7.61, 60.33], p<.05). Findings support gender-related effects of CM on frontotemporal structure and clinical features of BD. The findings bring novel perspectives for gendered pathophysiological models of effects of CM in BD.

Hypertensive disorders during pregnancy and polycystic ovary syndrome are associated with child communication and social skills in a sex-specific and androgen-dependent manner.

Prenatal exposure to testosterone is implicated in the etiology of autism spectrum disorder (ASD). Hypertensive disorders of pregnancy and polycystic ovary syndrome are associated with both hyperandrogenism and increased risk for ASD. We examined whether increased maternal testosterone mediates the relationship between these hyperandrogenic disorders (HDs) during pregnancy and child communication and social skills. Maternal plasma was collected during the second trimester and parent-report measures of child communication and social skills were obtained at 4.5-6.5 years of age from 270 participants enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). Our retrospective frequency-matched cohort study design identified 58 mothers with one or both of the HDs and 58 matched controls. Women diagnosed with an HD who carried a female had higher testosterone levels compared to those carrying a male (t(56) = -2.70, p = 0.01). Compared to females controls, females born to women with an HD had significantly higher scores on the Social Communication Questionnaire (t(114) = -2.82, p =0.01). Maternal testosterone partially mediated the relationship between a diagnosis of an HD and SCQ scores among females. These findings point to sex-specific associations of two HDs - hypertensive disorders of pregnancy and polycystic ovary syndrome - on child communication and social skills and a mediating effect of maternal testosterone during pregnancy. Further research is needed to understand placental-mediated effects of maternal testosterone on child brain development and neurodevelopmental outcomes.

Rethinking "aggression" and impulsivity in bipolar disorder: Risk, clinical and brain circuitry features.

BACKGROUND: Elevated aggression and impulsivity are implicated in Bipolar Disorder (BD); however, relationships between these behavioral constructs have not been clarified, which can lead to misconceptions with negative consequences including stigma and adverse outcomes including suicide. The study aimed to clarify brain-based distinctions between the two constructs and their associations to risk factors, symptoms and suicide thoughts and behaviors. METHODS: Self-rated Brown-Goodwin Aggression (BGA) and Barratt Impulsiveness Scale (BIS) scores were compared between adults with BD (n = 38, 74% female) and healthy controls (HC, n = 29, 64% female). Relationships were examined between BGA and BIS with childhood trauma questionnaire (CTQ), mood, comorbidities, and magnetic resonance imaging gray matter volume (GMV) assessments. RESULTS: In BD, BGA and BIS total scores were both elevated and associated with childhood maltreatment (CM), particularly emotional CM, depression, substance use disorders (SUDs) and suicide attempts (SAs). BGA scores were increased by items corresponding to dysregulation of emotional and social behavior and associated with elevated mood states and suicide ideation and GMV decreases in bilateral orbitofrontal cortex and left posterior insula brain regions, previously associated with these behaviors and clinical features. BIS motor impulsiveness scores were associated with GMV decreases in anterior cingulate cortex implicated in mood and behavioral dyscontrol. LIMITATIONS: modest sample size, self-reports CONCLUSIONS: The findings suggest separable brain-based domains of dysfunction in BD of motor impulsiveness versus emotionally dysregulated feelings that are primarily self-directed. Both domains are associated with suicide behavior and modifiable risk factors of CM, depression and SUDs that could be targeted for prevention.

Graph theory analysis of whole brain functional connectivity to assess disturbances associated with suicide attempts in bipolar disorder.

Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph-theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD.

Brain grey and white matter structural associations with future suicidal ideation and behaviors in adolescent and young adult females with mood disorders.

Background: To reduce suicide in females with mood disorders, it is critical to understand brain substrates underlying their vulnerability to future suicidal ideation and behaviors (SIBs) in adolescence and young adulthood. In an international collaboration, grey and white matter structure was investigated in adolescent and young adult females with future suicidal behaviors (fSB) and ideation (fSI), and without SIBs (fnonSIB). Methods: Structural (n = 91) and diffusion-weighted (n = 88) magnetic resonance imaging scans at baseline and SIB measures at follow-up on average two years later (standard deviation, SD = 1 year) were assessed in 92 females [age(SD) = 16.1(2.6) years] with bipolar disorder (BD, 28.3%) or major depressive disorder (MDD, 71.7%). One-way analyses of covariance comparing baseline regional grey matter cortical surface area, thickness, subcortical grey volumes, or white matter tensor-based fractional anisotropy across fSB (n = 40, 43.5%), fSI (n = 33, 35.9%) and fnonSIB (n = 19, 20.6%) groups were followed by pairwise comparisons in significant regions (p < 0.05). Results: Compared to fnonSIBs, fSIs and fSBs showed significant decreases in cortical thickness of right inferior frontal gyrus pars orbitalis and middle temporal gyrus, fSIs of left inferior frontal gyrus, pars orbitalis. FSIs and fSBs showed lower fractional anisotropy in left uncinate fasciculus and corona radiata, and fSBs in right uncinate and superior fronto-occipital fasciculi. Conclusions: The study provides preliminary evidence of grey and white matter alterations in brain regions subserving emotional and behavioral regulation and perceptual processing in adolescent and young adult females with mood disorders with, versus without, future SIBs. Findings suggest potential targets to prevent SIBs in female adolescents and young adults.