Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany.
Mol Psychiatry. 2024 Nov;29(11):3527-3536. doi: 10.1038/s41380-024-02612-7. Epub 2024 May 27.
Interoceptive fear, which is shaped by associative threat learning and memory processes, plays a central role in abnormal interoception and psychiatric comorbidity in conditions of the gut-brain axis. Although animal and human studies support that acute inflammation induces brain alterations in the central fear network, mechanistic knowledge in patients with chronic inflammatory conditions remains sparse. We implemented a translational fear conditioning paradigm to elucidate central fear network reactivity in patients with quiescent inflammatory bowel disease (IBD), compared to patients with irritable bowel syndrome (IBS) and healthy controls (HC). Using functional magnetic resonance imaging, conditioned differential neural responses within regions of the fear network were analyzed during acquisition and extinction learning. In contrast to HC and IBS, IBD patients demonstrated distinctly altered engagement of key regions of the central fear network, including amygdala and hippocampus, during differential interoceptive fear learning, with more pronounced responses to conditioned safety relative to pain-predictive cues. Aberrant hippocampal responses correlated with chronic stress exclusively in IBD. During extinction, differential engagement was observed in IBD compared to IBS patients within amygdala, ventral anterior insula, and thalamus. No group differences were found in changes of cue valence as a behavioral measure of fear acquisition and extinction. Together, the disease-specific alterations in neural responses during interoceptive fear conditioning in quiescent IBD suggest persisting effects of recurring intestinal inflammation on central fear network reactivity. Given the crucial role of interoceptive fear in abnormal interoception, these findings point towards inflammation-related brain alterations as one trajectory to bodily symptom chronicity and psychiatric comorbidity. Patients with inflammatory conditions of the gut-brain axis may benefit from tailored treatment approaches targeting maladaptive interoceptive fear.
内感受恐惧是由联想性威胁学习和记忆过程塑造的，在肠道-大脑轴相关疾病中异常的内感受和精神共病中起着核心作用。尽管动物和人类研究支持急性炎症会引起大脑中央恐惧网络的改变，但慢性炎症患者的机制知识仍然很少。我们实施了一个转化恐惧条件反射范式，以阐明处于静止炎症性肠病（IBD）状态下的患者的中央恐惧网络反应性，与肠易激综合征（IBS）患者和健康对照（HC）进行比较。使用功能磁共振成像，在获得和消退学习期间分析了中央恐惧网络内的条件性差异神经反应。与 HC 和 IBS 患者不同，IBD 患者在差异内感受恐惧学习期间表现出中央恐惧网络关键区域的明显改变的参与，与疼痛预测线索相比，对条件性安全线索的反应更为明显。异常的海马体反应与 IBD 患者的慢性应激相关，而与 IBS 患者无关。在消退期间，与 IBS 患者相比，IBD 患者在杏仁核、前腹侧岛叶和丘脑内观察到差异参与。在作为恐惧获得和消退的行为测量的线索效价变化方面，没有发现组间差异。总之，在静止 IBD 期间进行内感受恐惧条件反射时，神经反应的疾病特异性改变表明反复肠道炎症对中央恐惧网络反应性的持续影响。鉴于内感受恐惧在异常内感受中的关键作用，这些发现表明炎症相关的大脑改变是躯体症状慢性化和精神共病的一种轨迹。患有肠道-大脑轴炎症性疾病的患者可能受益于针对适应性内感受恐惧的定制治疗方法。
