Identifying tripartite relationship among cortical thickness, neuroticism, and mood and anxiety disorders.

The number of young adults seeking help for emotional distress, subsyndromal-syndromal mood/anxiety symptoms, including those associated with neuroticism, is rising and can be an early manifestation of mood/anxiety disorders. Identification of gray matter (GM) thickness alterations and their relationship with neuroticism and mood/anxiety symptoms can aid in earlier diagnosis and prevention of risk for future mood and anxiety disorders. In a transdiagnostic sample of young adults (n = 252;177 females; age 21.7 ± 2), Hypothesis (H) 1:regularized regression followed by multiple regression examined relationships among GM cortical thickness and clinician-rated depression, anxiety, and mania/hypomania; H2:the neuroticism factor and its subfactors as measured by NEO Personality Inventory (NEO-PI-R) were tested as mediators. Analyses revealed positive relationships between left parsopercularis thickness and depression (B = 4.87, p = 0.002), anxiety (B = 4.68, p = 0.002), mania/hypomania (B = 6.08, p ≤ 0.001); negative relationships between left inferior temporal gyrus (ITG) thickness and depression (B = - 5.64, p ≤ 0.001), anxiety (B = - 6.77, p ≤ 0.001), mania/hypomania (B = - 6.47, p ≤ 0.001); and positive relationships between left isthmus cingulate thickness (B = 2.84, p = 0.011), and anxiety. NEO anger/hostility mediated the relationship between left ITG thickness and mania/hypomania; NEO vulnerability mediated the relationship between left ITG thickness and depression. Examining the interrelationships among cortical thickness, neuroticism and mood and anxiety symptoms enriches the potential for identifying markers conferring risk for mood and anxiety disorders and can provide targets for personalized intervention strategies for these disorders.

Neural markers of mania that distinguish inpatient adolescents with bipolar disorder from those with other psychopathology.

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD.

Prefrontal, parietal, and limbic condition-dependent differences in bipolar disorder: a large-scale meta-analysis of functional neuroimaging studies.

BACKGROUND: Over the past few decades, neuroimaging research in Bipolar Disorder (BD) has identified neural differences underlying cognitive and emotional processing. However, substantial clinical and methodological heterogeneity present across neuroimaging experiments potentially hinders the identification of consistent neural biomarkers of BD. This meta-analysis aims to comprehensively reassess brain activation and connectivity in BD in order to identify replicable differences that converge across and within resting-state, cognitive, and emotional neuroimaging experiments. METHODS: Neuroimaging experiments (using fMRI, PET, or arterial spin labeling) reporting whole-brain results in adults with BD and controls published from December 1999-June 18, 2019 were identified via PubMed search. Coordinates showing significant activation and/or connectivity differences between BD participants and controls during resting-state, emotional, or cognitive tasks were extracted. Four parallel, independent meta-analyses were calculated using the revised activation likelihood estimation algorithm: all experiment types, all resting-state experiments, all cognitive experiments, and all emotional experiments. To confirm reliability of identified clusters, two different meta-analytic significance tests were employed. RESULTS: 205 published studies yielding 506 individual neuroimaging experiments (150 resting-state, 134 cognitive, 222 emotional) comprising 5745 BD and 8023 control participants were included. Five regions survived both significance tests. Individuals with BD showed functional differences in the right posterior cingulate cortex during resting-state experiments, the left amygdala during emotional experiments, including those using a mixed (positive/negative) valence manipulation, and the left superior and right inferior parietal lobules during cognitive experiments, while hyperactivating the left medial orbitofrontal cortex during cognitive experiments. Across all experiments, there was convergence in the right caudate extending to the ventral striatum, surviving only one significance test. CONCLUSIONS: Our findings indicate reproducible localization of prefrontal, parietal, and limbic differences distinguishing BD from control participants that are condition-dependent, despite heterogeneity, and point towards a framework for identifying reproducible differences in BD that may guide diagnosis and treatment.

Altered patterns of central executive, default mode and salience network activity and connectivity are associated with current and future depression risk in two independent young adult samples.

Neural markers of pathophysiological processes underlying the dimension of subsyndromal-syndromal-level depression severity can provide objective, biologically informed targets for novel interventions to help prevent the onset of depressive and other affective disorders in individuals with subsyndromal symptoms, and prevent worsening symptom severity in those with these disorders. Greater functional connectivity (FC) among the central executive network (CEN), supporting emotional regulation (ER) subcomponent processes such as working memory (WM), the default mode network (DMN), supporting self-related information processing, and the salience network (SN), is thought to interfere with cognitive functioning and predispose to depressive disorders. We examined in young adults (1) relationships among activity and FC in these networks and current depression severity, using a paradigm designed to examine WM and ER capacity in n = 90, age = 21.7 (2.0); (2) the extent to which these relationships were specific to depression versus mania/hypomania; (3) whether findings in a first, "discovery" sample could be replicated in a second, independent, "test" sample of young adults n = 96, age = 21.6 (2.1); and (4) whether such relationships also predicted depression at up to 12 months post scan and/or mania/hypomania severity in (n = 61, including participants from both samples, age = 21.6 (2.1)). We also examined the extent to which there were common depression- and anxiety-related findings, given that depression and anxiety are highly comorbid. In the discovery sample, current depression severity was robustly predicted by greater activity and greater positive functional connectivity among the CEN, DMN, and SN during working memory and emotional regulation tasks (all ps < 0.05 qFDR). These findings were specific to depression, replicated in the independent sample, and predicted future depression severity. Similar neural marker-anxiety relationships were shown, with robust DMN-SN FC relationships. These data help provide objective, neural marker targets to better guide and monitor early interventions in young adults at risk for, or those with established, depressive and other affective disorders.

Differentiating white matter measures that protect against vs. predispose to bipolar disorder and other psychopathology in at-risk youth.

Bipolar disorder (BD) is highly heritable. Identifying objective biomarkers reflecting pathophysiological processes predisposing to, versus protecting against BD, can help identify BD risk in offspring of BD parents. We recruited 21 BD participants with a first-degree relative with BD, 25 offspring of BD parents, 27 offspring of comparison parents with non-BD psychiatric disorders, and 32 healthy offspring of healthy parents. In at-risk groups, 23 had non-BD diagnoses and 29, no Axis-I diagnoses(healthy). Five at-risk offspring who developed BD post scan(Converters) were included. Diffusion imaging(dMRI) analysis with tract segmentation identified between-group differences in the microstructure of prefrontal tracts supporting emotional regulation relevant to BD: forceps minor, anterior thalamic radiation(ATR), cingulum bundle(CB), and uncinate fasciculus(UF). BD participants showed lower fractional anisotropy (FA) in the right CB (anterior portion) than other groups (q < 0.05); and in bilateral ATR (posterior portion) versus at-risk groups (q < 0.001). Healthy, but not non-BD, at-risk participants showed significantly higher FA in bilateral ATR clusters than healthy controls (qs < 0.05). At-risk groups showed higher FA in these clusters than BD participants (qs < 0.05). Non-BD versus healthy at-risk participants, and Converters versus offspring of BD parents, showed lower FA in the right ATR cluster (qs < 0.05). Low anterior right CB FA in BD participants versus other groups might result from having BD. High bilateral ATR FA in at-risk groups, and in healthy at-risk participants, versus healthy controls might protect against BD/other psychiatric disorders. Absence of elevated right ATR FA in non-BD versus healthy at-risk participants, and in Converters versus non-converter offspring of BD parents, might lower protection against BD in at-risk groups.