[Dynamic alterations in regional brain activity associated with bipolar disorder and smoking status]

Patients with bipolar disorder (BD) have a high prevalence of smoking. Smoking status may interact with disease-related brain functional abnormalities and jointly influence resting-state brain activity. This study aims to investigate the independent and interactive effects of BD diagnosis and smoking status on the dynamic instability of regional brain activity. Based on resting-state functional magnetic resonance imaging (fMRI) data, dynamic amplitude of low-frequency fluctuation (dALFF), dynamic fractional amplitude of low-frequency fluctuation (dfALFF), and dynamic regional homogeneity (dReHo) were integrated to evaluate fluctuations in regional brain activity. Furthermore, associations between abnormal brain regions, clinical symptoms, and daily cigarette consumption were analyzed.

From July 2022 to November 2025, a total of 113 participants were recruited at the Second Xiangya Hospital of Central South University, including 25 smoking patients with BD (BDsm group), 33 non-smoking patients with BD (BDnsm group), 23 smoking healthy controls (HCsm group), and 32 non-smoking healthy controls (HCnsm group). The BDsm and BDnsm groups were combined as the BD group, while the HCsm and HCnsm groups were combined as the healthy control (HC) group. Resting-state fMRI data were collected and preprocessed, followed by calculation of dALFF, dfALFF, and dReHo using a sliding-window approach. The 3 dynamic indices were standardized and subjected to principal component analysis, with the first principal component extracted as a composite measure of dynamic regional brain activity. Whole-brain two-way analysis of covariance (ANCOVA) was performed to examine the interaction effects and main effects of BD diagnosis and smoking status, with age, sex, years of education, and dataset source included as covariates. Brain regions showing significant effects were further analyzed using post hoc comparisons and Pearson correlation analyses.

Whole-brain analysis revealed a significant interaction effect between BD diagnosis and smoking status in the right thalamus. Post hoc analyses showed that dynamic activity instability in the right thalamus was significantly higher in the BDsm group than in the HCsm group (t=3.955, P<0.001) and the BDnsm group (t=5.987, P<0.001). The BDnsm group exhibited lower right thalamic dynamic activity instability than the HCnsm group (t=-6.681, P<0.001), and the HCsm group showed lower instability than the HCnsm group (t=-4.530, P<0.001). After controlling for dataset source, the interaction effect remained significant, and the results were replicated only in the male subgroup. A main effect of BD diagnosis was identified in the ventromedial prefrontal cortex and left dorsolateral prefrontal cortex. Post hoc analyses showed that dynamic activity instability in the ventromedial prefrontal cortex and left dorsolateral prefrontal cortex was significantly higher in the BDsm group than in the HCsm group (ventromedial prefrontal cortex: t=5.046, P<0.001; left dorsolateral prefrontal cortex: t=3.152, P=0.003). Similarly, the BDnsm group exhibited significantly higher dynamic activity instability in these regions than the HCnsm group (ventromedial prefrontal cortex: t=3.440, P=0.001; left dorsolateral prefrontal cortex: t=4.684, P<0.001). No significant main effect of smoking status was observed. Among all smokers, daily cigarette consumption was positively correlated with dynamic activity instability in the right thalamus (r=0.335, P=0.026). Among smoking patients with BD, dynamic activity instability in the left dorsolateral prefrontal cortex was positively correlated with anxiety symptoms (r=0.451, P=0.031).

BD diagnosis and smoking status exert interactive effects on dynamic activity in the right thalamus. Under non-smoking conditions, patients with BD exhibited reduced thalamic dynamic activity instability; however, this BD-associated reduction was attenuated among smokers and showed an association with smoking exposure intensity. Patients with BD demonstrated increased dynamic activity instability in prefrontal regions, suggesting abnormalities in brain regions involved in emotional regulation and cognitive control.