Liu Xiaobo, Wan Bin, Zhang Xi-Han, Cui Ruifang, Long Siyu, Ge Ruiyang, Liu Lang, Xiao Jinming, Liu Zhen-Qi, Yan Jiadong, Xie Ke, Yao Meng, Wen Xin, Wang Sanwang, Gao Yujun
Department of Psychiatry, Wuhan Wuchang Hospital, Wuhan University of Science and Technology, Wuhan, China.
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
BMC Med. 2025 Aug 5;23(1):457. doi: 10.1186/s12916-025-04277-7.
Bipolar disorder (BD) is a heterogeneous psychiatric condition characterized by distinct episodes: manic (BipM), depressive (BipD), mixed (mBD), and remission (rBD). Current evidence indicates alterations in brain functional connectivity in BD, yet a comprehensive understanding across all episodes remains incomplete.
Here, to investigate how different BD episodes alter brain functional organization, we calculated the sensory-association axis using diffusion map embedding on the functional connectome matrix and compared this axis between the four BD groups and neurotypical controls. Then, we employed regression dynamic causal modeling to investigate the directional information flow along the reorganized sensory-association axis across different BD episodes. Furthermore, we applied Nested Spectral Partitioning to decode functional integration and segregation along the same axis. Finally, we compared the reorganization patterns with normative maps of clinical symptomatology, cellular composition, and receptor distribution to elucidate symptom-related and molecular-level associations.
Compared to healthy controls, we observed sensory region expansion and association region compression in BipM, BipD, and rBD. The mBD showed expanded visual and prefrontal regions but compressed motor and precuneus regions. Analyzing neural information flow revealed reduced connectivity in association regions for BipM and BipD, indicating association dominance in functional reorganization. Conversely, mBD exhibited heightened bidirectional signal flow between sensory and association regions, emphasizing increased integrative processing. Network analyses further revealed increased integration and decreased segregation across unipolar episodes, with the highest integration in mBD. Clinical correlations highlighted that emotional fluctuations primarily related to association region reorganization, suggesting potential biomarkers for mood episode detection. Moreover, these functional reorganizations spatially correlated with serotonin transporter, gamma-aminobutyric acid type A receptor, alpha-4-beta-4 nicotinic acetylcholine receptor, and specific cortical neuron layers (layer 4 and layer 5 excitatory neurons).
Our findings propose functional reorganization as both a biomarker and a simplified neural phenotype framework for systematically quantifying BD-related neural abnormalities.
双相情感障碍（BD）是一种异质性精神疾病，其特征为不同的发作类型：躁狂发作（BipM）、抑郁发作（BipD）、混合发作（mBD）和缓解期（rBD）。目前的证据表明BD患者脑功能连接存在改变，但对所有发作类型的全面理解仍不完整。
在此，为了研究不同的BD发作类型如何改变脑功能组织，我们使用扩散映射嵌入功能连接组矩阵来计算感觉-联合轴，并比较了四个BD组与神经典型对照组之间的该轴。然后，我们采用回归动态因果模型来研究不同BD发作类型沿重组后的感觉-联合轴的定向信息流。此外，我们应用嵌套谱划分来解码沿同一轴的功能整合和分离。最后，我们将重组模式与临床症状学、细胞组成和受体分布的规范图谱进行比较，以阐明症状相关和分子水平的关联。
与健康对照组相比，我们在BipM、BipD和rBD中观察到感觉区域扩张和联合区域压缩。mBD表现为视觉和前额叶区域扩张，但运动和楔前叶区域压缩。对神经信息流的分析显示，BipM和BipD的联合区域连接减少，表明在功能重组中联合占主导。相反，mBD在感觉和联合区域之间表现出增强的双向信号流，强调整合处理增加。网络分析进一步显示，单相发作期间整合增加而分离减少，mBD的整合程度最高。临床相关性突出表明，情绪波动主要与联合区域重组有关，提示可能存在用于情绪发作检测的生物标志物。此外，这些功能重组在空间上与5-羟色胺转运体、A型γ-氨基丁酸受体、α-4-β-4烟碱型乙酰胆碱受体以及特定的皮质神经元层（第4层和第5层兴奋性神经元）相关。
我们的研究结果提出功能重组既是一种生物标志物，也是一个简化的神经表型框架，用于系统地量化与BD相关的神经异常。
