Adolescence and young adulthood are critical periods for the emergence of bipolar disorder (BD). Instability in sleep and rest-activity rhythms is associated with elevated risk for BD, yet little is known about the neural correlates of this vulnerability. White matter organization in fronto-limbic pathways, which support mood regulation and show sensitivity to sleep/rest-activity rhythm disruption, offers a promising avenue for investigation. Participants (16-24y;N = 112) recruited across a spectrum of mania vulnerability (MOODS-SRL) completed 14 days of actigraphy followed by a neuroimaging assessment. Diffusion MRI was used to derive Neurite Orientation Dispersion and Density Imaging, focusing on the Orientation Dispersion Index (ODI) of the cingulum bundle, uncinate fasciculus, and forceps minor. Clinician-rated symptoms of mania and depression were assessed at baseline and 6-months follow-up. We evaluated whether the links between actigraphy-derived sleep duration variability, sleep onset variability, and Circadian Function Index (CFI; index of circadian rhythm robustness) and white matter ODI were moderated by baseline mania vulnerability, and tested whether baseline ODI predicted 6-month mood symptoms. At higher levels of mania vulnerability, lower CFI (greater rest-activity instability) associated with higher ODI (greater white matter disorganization) in the cingulum bundle (β=-0.22;P = 0.029) and uncinate fasciculus (β = -0.22;P = 0.020). Moreover, higher uncinate fasciculus ODI predicted greater mania symptoms at 6-month follow-up and fully mediated the CFI-mania symptom association (β = -0.10;95 %CI[-0.14,-0.02]). Rest-activity instability may disrupt fronto-limbic white matter, increasing risk to mania in those at elevated vulnerability for BD. Stabilizing rest-activity rhythms in at-risk individuals may help preserve white matter integrity and mitigate BD risk.
Background Adolescence is a critical window for autonomic and limbic development and a period of elevated risk for depression. Although autonomic and limbic system function have, independently, been linked to depression, they are coupled and both influenced by early life stress (ELS). We do not yet know, however, whether the association of autonomic activity and limbic connectivity with depressive symptoms differs across dimensions of ELS. Methods Participants were 93 youth (Mage = 12.3) who completed the Trier Social Stress Test (TSST) with continuous electrocardiogram (ECG) recording. ECG-derived high-frequency heart rate variability (RespHRV) was assessed across the baseline, reactivity, and recovery phases of the TSST. Hippocampal-amygdala connectivity was estimated from resting-state data acquired just before the TSST using the Tian atlas. We tested whether RespHRV recovery and connectivity were jointly associated with depressive symptoms and whether ELS dimensions of threat, unpredictability, and deprivation moderated this association. Results Greater RespHRV during recovery was associated with more negative right hippocampal tail-left lateral amygdala connectivity (β = −0.42, q = 0.002). In a joint model, threat (β = −0.34, p = .007) and deprivation (β = −0.36, p = .009 independently moderated this association. Specifically, more negative connectivity predicted fewer symptoms when paired with weaker RespHRV recovery in high-ELS youth, but with stronger RespHRV recovery in low-ELS youth. Conclusions Whether autonomic-limbic coupling buffers or confers risk for depression depends on the early environment in which it developed.
Eugenia Giampetruzzi, C. Antonacci, Jean Rachel Bahk et al.· Neurobiology of Stress· 0 citations
BACKGROUND
Identifying reproducible neural markers of bipolar disorder(BD) risk is critical for early detection and differentiation from unipolar/major depression. We previously demonstrated that inter-amygdala functional connectivity(FC) and bilateral-ventrolateral-right-dorsolateral-prefrontal-cortex(vlPFC-dlPFC)-FC were positively associated with both mania/hypomania and depression risk and mania/hypomania risk, respectively, as measured by the Mood Spectrum Self-Report(MOODS-SR) 'mood' subdomains, replicated in three independent samples. We tested whether these neural markers also generalized to the MOODS-SR 'cognition' and 'energy' subdomains and whether they are elevated in individuals with BD versus those at-risk.
METHODS
Three independent young adult samples without BD(n=299/ages 18-30) completed an fMRI approach emotion-processing task(Discovery n=114/age=21.60±1.91; Test sample-1 n=103/21.57±2.09; Test sample-2 n=82/23.43±2.86), and a fourth sample with BD(n=32/25.11±3.73) completed the same protocol. Poisson loglinear models tested whether previously identified neural markers of MOODS-SR mood subdomains were also associated with manic and depressive cognition and energy subdomains. One-way ANOVAs compared neural variables showing significant relationships with subdomain scores between low-risk, high-risk, and BD groups.
RESULTS
Across all risk samples, inter-amygdala-FC was positively associated with manic and depressive mood and cognition subdomains(qFDRs<0.001-0.01); vlPFC-dlPFC-FC was positively associated with manic mood and cognition subdomains(qFDRs<0.001-0.048). Inter-amygdala-FC differed significantly across groups(F2,328=3.56, P=0.03) and was higher in BD versus low-risk and in high-risk versus low-risk groups(Ps=0.033).
CONCLUSIONS
Inter-amygdala-FC emerged as a robust, cross-dimensional correlate of BD risk, linking subsyndromal risk to syndromal BD, whereas vlPFC-dlPFC-FC was specific to mania risk. Findings support a multidimensional, circuit-based model of BD risk supporting early identification and prevention.
Maya C. Schumer, M. Bertocci, S. Iyengar et al.· Biological Psychiatry: Cogni...· 0 citations
Introduction: Cognitive impairment and disturbed rest-activity patterns often persist between episodes of major depressive disorder (MDD) and bipolar disorder (BD). Whether these deficits are disorder-specific or transdiagnostic remains unclear, as does the existence of a link between rest-activity phenotypes and cognitive performance. Methods: Using the All of Us Research Program, we derived normative deviation scores across four cognitive domains (sustained attention, inhibitory control, reward-based impulsivity, social cognition) from non-clinical controls (NCC), then compared deviations in MDD and BD. MDD was adequately powered to regress deviation scores on four 90-day Fitbit-derived phenotypes (step count, sleep duration, wakefulness after sleep onset, sleep timing variability); the same analysis was run on NCC as a sensitivity check. Results: Samples were substantially larger than prior works (MDD 5,087-6,536; BD 545-739; NCC 40,589-51,491). Relative to NCC, MDD and BD exhibited worse sustained attention (Delta Glass = -0.081 vs. -0.187) and higher impulsivity (Delta Glass = 0.092 vs. 0.240), with deficits more pronounced in BD. No wearable phenotype was significantly associated with cognitive performance in MDD (R2< 0.01); NCC associations, though significant, were of negligible magnitude (R2 <= 1.2%). Discussion: Inter-episode cognitive impairment was domain-selective rather than global, with a gradient BD > MDD. Despite adequate power, wearable rest-activity phenotypes were not associated with cognition in MDD. Whether this extends to BD, where deficits were largest, could not be tested due to limited power. Community-dwelling samples likely underestimate impairment relative to clinical cohorts.
F. Corponi, M. Kalfas, M. Reami et al.· medRxiv· 0 citations
Background. Bipolar disorder (BD) is characterized by circadian rhythm disruptions, contributing to mood instability and recurrence. These rhythms are regulated by clock genes in the suprachiasmatic nucleus, including the CLOCK 3111T/C (rs1801260) polymorphism that has been linked to delayed sleep phase, insomnia, and altered circadian expression. Both circadian disruption and adverse childhood experiences (ACEs) correlate with white matter (WM) abnormalities. We hypothesized that rs1801260 moderates ACE effects on WM microstructure in BD. Methods. We enrolled 137 BD patients in depressive episodes. Participants underwent 3T MRI, rs1801260 genotyping and completed the Childhood Trauma Questionnaire. Moderation (PROCESS) tested genotype–ACE interactions on whole-brain fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) values; voxel-wise TBSS (FSL Randomize) localized effects, with sex-stratified and GLZ analyses for genotype–sex interactions. Results. Significant rs1801260 × ACE interactions emerged for FA and RD across physical abuse, physical neglect, and emotional neglect. Higher ACEs were associated with lower FA/higher RD only in CLOCK rs1801260*C carriers, mainly females. TBSS showed physical abuse × rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse × sex × rs1801260 interactions on FA/RD, with effects specific to female CLOCK rs1801260*C carriers but genotype-independent in males. Conclusions. rs1801260 moderates the impact of early-life stress on WM integrity in BD, particularly in emotion-regulation tracts, with CLOCK rs1801260*C carriers showing greater vulnerability. Effects are genotype-specific in females but genotype-independent in males, possibly reflecting sex-dimorphic neurodevelopment driven by estrogen–androgen modulation of clock genes, HPA axis, and myelination.
F. Nozza, B. Bravi, L. Fortaner-Uyá et al.· Genes· 0 citations
BACKGROUND
Alcohol use disorder (AUD) is frequently comorbid with sleep disturbances, yet the neural mechanisms through which sleep and AUD jointly shape brain organization remain unclear. Conventional resting-state analyses describe connectivity but not the energetic cost of transitions between large-scale network states.
METHODS
Resting-state fMRI data from 93 individuals with AUD and 91 demographically matched healthy controls (HC) from the Human Connectome Project were analyzed. Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI). Static inter-network transition energies were computed across eight canonical networks using network control theory. Group × PSQI interactions were tested for directed transitions, with Bonferroni correction. Exploratory ROI analyses examined limbic-to-subcortical ROI pairs.
RESULTS
Individuals with AUD showed greater sleep impairment than HC, particularly in sleep latency, efficiency, and nocturnal disturbances. A significant Group × PSQI interaction was observed for limbic-to-subcortical transition energy (Bonferroni-corrected p = 0.020). In HC, poorer sleep was associated with lower transition energy; this coupling was absent in AUD. Uncorrected effects converged on transitions targeting the subcortical network. Eleven ROI pairs survived correction, linking parahippocampal, amygdalar, and temporal regions to thalamic subnuclei.
CONCLUSION
Comorbid sleep disturbance in AUD may reflect disrupted energetic regulation of limbic-subcortical state transitions. Network control energy provides a mechanistic framework for understanding sleep-brain interactions in addiction.
Ningning Zeng, Mubing Ding, Min Wang et al.· Addictive Behaviours· 0 citations
Associations between patterns of brain connectivity and brain structural features have transdiagnostic relevance to psychopathology. There is considerable evidence for disruptions to the hippocampus and temporoparietal brain systems in psychotic disorders. The present study examines structure–function relationships—specifically, the relation of hippocampal volume with patterns of temporoparietal effective connectivity—in youth at clinical high-risk for psychosis (CHR-P) and healthy controls (HCs). Participants at CHR-P and HCs completed clinical symptom measures and magnetic resonance imaging at baseline (n = 388, 42.5% female, age = 19.8 ± 4.2) in the second cohort of the North American Prodrome Longitudinal Study. Group Iterative Multiple Model Estimation established a common functional network of temporoparietal effective connectivity in the full sample. Next, supervised (assuming the CHR-P and HC groups represent classes) and unsupervised (data-driven) clustering procedures interrogated effective connectivity parameters relevant to subsamples. Mean difference tests by unsupervised cluster membership determined whether clusters formed based on temporoparietal effective connectivity differed in hippocampal volume. Clusters were also compared on representation of CHR-P and positive and negative symptom totals to determine whether unsupervised clustering recovered clinical features. Unsupervised clustering generated two clusters that differed significantly in right hippocampal volume and attenuated positive and negative symptoms with small-to-medium effect sizes. The cluster demonstrating reduced right hippocampal volume reported greater symptoms. Unsupervised clustering did not recover diagnostic groups. Findings are consistent with literature indicating the transdiagnostic relevance of hippocampal volume to organizational properties of brain functional networks and patterns of temporoparietal connectivity.
K. Aberizk, B. Ku, Hengyi Cao et al.· Brain Structure and Function· 0 citations