Importance Mania/hypomania is the pathognomonic feature of bipolar disorder (BD). Established, reliable neural markers denoting mania/hypomania risk to help with early risk detection and diagnosis and guide the targeting of pathophysiologically informed interventions are lacking. Objective To identify patterns of neural responses associated with lifetime mania/hypomania risk, the specificity of such neural responses to mania/hypomania risk vs depression risk, and the extent of replication of findings in 2 independent test samples. Design, Setting, and Participants This cross-sectional study included 3 independent samples of young adults aged 18 to 30 years without BD or active substance use disorder within the past 3 months who were recruited from the community through advertising. Of 603 approached, 299 were ultimately included and underwent functional magnetic resonance imaging at the University of Pittsburgh, Pittsburgh, Pennsylvania, from July 2014 to May 2023. Main Outcomes and Measures Activity and functional connectivity to approach-related emotions were examined using a region-of-interest mask supporting emotion processing and emotional regulation. The Mood Spectrum Self-Report assessed lifetime mania/hypomania risk and depression risk. In the discovery sample, elastic net regression models identified neural variables associated with mania/hypomania and depression risk; multivariable regression models identified the extent to which selected variables were significantly associated with each risk measure. Multivariable regression models then determined whether associations in the discovery sample replicated in both test samples. Results A total of 299 participants were included. The discovery sample included 114 individuals (mean [SD] age, 21.60 [1.91] years; 80 female and 34 male); test sample 1, 103 individuals (mean [SD] age, 21.57 [2.09] years; 30 male and 73 female); and test sample 2, 82 individuals (mean [SD] age, 23.43 [2.86] years; 48 female, 29 male, and 5 nonbinary). Associations between neuroimaging variables and Mood Spectrum Self-Report measures were consistent across all 3 samples. Bilateral amygdala-left amygdala functional connectivity and bilateral ventrolateral prefrontal cortex-right dorsolateral prefrontal cortex functional connectivity were positively associated with mania/hypomania risk: discovery omnibus χ2 = 1671.7 (P < .001); test sample 1 omnibus χ2 = 1790.6 (P < .001); test sample 2 omnibus χ2 = 632.7 (P < .001). Bilateral amygdala-left amygdala functional connectivity and right caudate activity were positively associated and negatively associated with depression risk, respectively: discovery omnibus χ2 = 2566.2 (P < .001); test sample 1 omnibus χ2 = 2935.9 (P < .001); test sample 2 omnibus χ2 = 1004.5 (P < .001). Conclusions and Relevance In this study of young adults, greater interamygdala functional connectivity was associated with greater risk of both mania/hypomania and depression. By contrast, greater functional connectivity between ventral attention or salience and central executive networks and greater caudate deactivation were reliably associated with greater risk of mania/hypomania and depression, respectively. These replicated findings indicate promising neural markers distinguishing mania/hypomania-specific risk from depression-specific risk and may provide neural targets to guide and monitor interventions for mania/hypomania and depression in at-risk individuals.

中文翻译：

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3 个独立年轻人样本中与躁狂/轻躁狂和抑郁风险相关的神经网络功能连接模式。

重要性 躁狂/轻躁狂是双相情感障碍 (BD) 的典型特征。缺乏既定的、可靠的神经标记物来表示躁狂/轻躁狂风险，以帮助早期风险检测和诊断，并指导病理生理学干预措施的针对性。目的 确定与终生躁狂/轻躁狂风险相关的神经反应模式、这种神经反应对躁狂/轻躁狂风险与抑郁风险的特异性，以及在 2 个独立测试样本中研究结果的重复程度。设计、背景和参与者 这项横断面研究包括 3 个独立样本，这些样本是通过广告从社区招募的，过去 3 个月内没有 BD 或活性物质使用障碍，年龄在 18 至 30 岁之间。2014 年 7 月至 2023 年 5 月，在 603 名接近者中，最终纳入了 299 名，并在宾夕法尼亚州匹兹堡的匹兹堡大学接受了功能性磁共振成像。主要结果和措施使用区域检查了与接近相关情绪的活动和功能连接支持情绪处理和情绪调节的兴趣掩模。情绪谱自我报告评估了终生躁狂/轻躁狂风险和抑郁风险。在发现样本中，弹性网络回归模型识别了与躁狂/轻躁狂和抑郁风险相关的神经变量；多变量回归模型确定了所选变量与每个风险度量显着相关的程度。然后，多变量回归模型确定发现样本中的关联是否在两个测试样本中复制。结果 共有 299 名参与者被纳入。发现样本包括 114 名个体（平均 [SD] 年龄，21.60 [1.91] 岁；80 名女性和 34 名男性）；测试样本1，103人（平均[SD]年龄，21.57[2.09]岁；30名男性和73名女性）；测试样本 2，82 人（平均 [SD] 年龄，23.43 [2.86] 岁；48 名女性，29 名男性，5 名非二元性别）。神经影像变量与情绪谱自我报告测量之间的关联在所有 3 个样本中都是一致的。双侧杏仁核-左杏仁核功能连接和双侧腹外侧前额叶皮层-右背外侧前额叶皮层功能连接与躁狂/轻躁狂风险呈正相关：发现综合 χ2 = 1671.7 (P < .001)；测试样本 1 综合 χ2 = 1790.6 (P < .001)；测试样本 2 综合 χ2 = 632.7 (P < .001)。双侧杏仁核-左杏仁核功能连接和右尾状核活动分别与抑郁风险呈正相关和负相关：发现综合 χ2 = 2566.2 (P < .001)；测试样本 1 综合 χ2 = 2935.9 (P < .001)；测试样本 2 综合 χ2 = 1004.5 (P < .001)。结论和相关性 在这项针对年轻人的研究中，杏仁核间功能连接性越大，躁狂/轻躁狂和抑郁的风险越大。相比之下，腹侧注意力或显着性与中央执行网络之间更大的功能连接以及更大的尾状核失活分别与躁狂/轻躁狂和抑郁的风险更大相关。这些重复的研究结果表明有希望区分躁狂/轻躁狂特定风险和抑郁症特定风险的神经标记，并可能提供神经目标来指导和监测高危个体的躁狂/轻躁狂和抑郁干预措施。