Acute modulation of neural circuitry regulating immune function in depression

调节抑郁症免疫功能的神经回路的急性调节

• 批准号: 9752678
• 负责人: Jonathan Savitz
• 金额: $ 25.76万
• 依托单位: LAUREATE INSTITUTE FOR BRAIN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752678
• 关键词: Acute; Address; Affect; Agonist; Amygdaloid structure; Anti-inflammatory; Behavior Therapy; Biological Markers; Brain; Chronic; Clinical Trials; Cognitive; Communication; Depressed mood; Development; Down-Regulation; Emotional; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutamates; Hamilton Rating Scale for Depression; Hippocampus (Brain); Hour; Immune; Immune response; Immune system; Immunity; Immunologic Markers; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; Intervention; Investigation; Knowledge; Kynurenic Acid; Kynurenine; Left; Life Expectancy; Link; Measures; Medial; Mediating; Medical; Memory; Mental Depression; Modeling; Molecular; Molecular Target; Monitor; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; National Institute of Mental Health; Neuronal Plasticity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Play; Premature Mortality; Process; Prognostic Marker; Public Health; Quinolinic Acid; Randomized; Recovery; Relapse; Research; Research Priority; Risk; Role; Sampling; Serum; Severities; Shapes; Synaptic plasticity; Temporal Lobe; Testing; Therapeutic; Time; Training; Treatment Efficacy; Visit; Work; blood-based biomarker; chronic depression; cytokine; depressed patient; depressive symptoms; design; hemodynamics; immune function; immunoregulation; indexing; memory recall; mood regulation; neural circuit; neurofeedback; neuroregulation; neurotoxic; new therapeutic target; novel; novel therapeutics; outcome forecast; personalized medicine; placebo group; pre-clinical; precision medicine; preclinical study; predictive marker; prognostic; reduce symptoms; relating to nervous system; response; restoration; societal costs; specific biomarkers; therapy development; treatment response

PROJECT SUMMARY The pathophysiology of depression remains poorly understood, perhaps explaining why half of depressed patients do not adequately respond to available treatments, leading to chronic depression with its associated morbidity, premature mortality, and societal costs. Inflammation in the body is communicated to the brain, leading to depression in some individuals. But the brain also regulates the immune system and yet little is known about how depression-linked neural abnormalities affect systemic immunity. Without more detailed knowledge, intervening therapeutically in the dynamic, homeostatic interplay between the brain and immune system is challenging. We use real-time neurofeedback (NF) to experimentally modulate a key neural node (i.e. amygdala and hippocampus of the medial temporal lobe, MTL) that has been shown to regulate immune function pre-clinically. By comparing depressed subjects who can versus those who cannot regain plasticity or function of the MTL due to NF modulation, we take a step towards identifying immune markers of treatment response and prognosis (aim 1). Conversely, by characterizing the immune changes that occur in subjects who are able to regain MTL plasticity/function, biomarkers of therapeutic brain changes can be identified (aim 2). Moreover, if this NF-induced change in immunity plays a mechanistic role in recovery from depression, then medications can be developed to augment this therapeutic immune response. The NF paradigm used here is focused on the amygdala. In two clinical trials, we showed that training depressed subjects to upregulate their left amygdala activity while recalling positive autobiographical memories significantly reduced symptoms and increased fMRI functional connectivity of the amygdala and hippocampus relative to depressed subjects in the sham group. Here, the main hypotheses are that: (1) baseline levels of inflammatory cytokines and neurotoxic kynurenine metabolites will be higher in subjects who are unable to effectively upregulate their amygdala (non- responders) compared with subjects who effectively upregulate their amygdala (responders). (2) Compared with non-responders, responders to NF will show increases in anti-inflammatory cytokines and neuroprotective kynurenines post-NF training. To test these hypotheses, we will measure depressive symptoms, circuits (amygdala activity and changes in MTL connectivity), and molecules (cytokines and kynurenines) using a within-subjects design. Unmedicated subjects with depression (PHQ-9 score ≥10, n=32) will complete two, one hour-long sessions (V1-V2) of NF (no sham). V1 and V2 will be held two weeks apart and will incorporate both training and evaluative components. Serum will be obtained at V1 and V2 and at a third visit without fMRI at week 4 (V3). This research is highly impactful because we need to understand the mechanisms underpinning the bidirectional relationship between inflammation and depression in order to facilitate development of new pharmacological or behavioral therapies, and identify predictive, prognostic, and monitoring biomarkers.

项目概要 抑郁症的病理生理学仍然知之甚少，这也许可以解释为什么一半的抑郁症 患者对现有治疗没有充分反应，导致慢性抑郁症及其相关疾病 发病率、过早死亡和社会成本身体的炎症会传递到大脑， 导致某些人抑郁，但大脑也调节免疫系统，但作用甚微。 已知与抑郁相关的神经异常如何影响系统免疫力，但没有更详细的信息。 知识，对大脑和免疫之间的动态、稳态相互作用进行治疗干预 系统具有挑战性。我们使用实时神经反馈（NF）来实验性地调节关键神经节点。 （即内侧颞叶的杏仁核和海马体，MTL）已被证明可以调节免疫 通过比较能够恢复可塑性或无法恢复的抑郁受试者。 由于 NF 调节而影响 MTL 的功能，我们向识别治疗的免疫标志物迈出了一步 离线反应和预后（目标 1），通过表征受试者中发生的免疫变化。 能够恢复 MTL 可塑性/功能，可以识别治疗性大脑变化的生物标志物（目标 2）。 此外，如果这种 NF 诱导的免疫变化在抑郁症的恢复中发挥机械作用，那么 可以开发药物来增强这种治疗性免疫反应，这里使用的 NF 范式是。 在两项临床试验中，我们发现训练抑郁症受试者可以上调他们的杏仁核。 回忆积极的自传体记忆时，左侧杏仁核活动显着减轻症状 与抑郁症受试者相比，杏仁核和海马体的功能磁共振成像功能连接性增强 假手术组的主要假设是：（1）炎症细胞因子和神经毒性的基线水平。 在无法有效上调杏仁核（非- (2) 与有效上调杏仁核的受试者（反应者）相比。 与无反应者相比，NF 反应者的抗炎细胞因子和神经保护作用会增加 为了测试这些假设，我们将测量抑郁症状、神经回路。 （杏仁核活动和 MTL 连接的变化）和分子（细胞因子和犬尿氨酸） 受试者内设计。未接受药物治疗的抑郁症受试者（PHQ-9 得分≥10，n=32）将完成两项、一项。 为期一小时的 NF 会议（V1-V2）（无假）将相隔两周举行，并将两者结合在一起。 训练和评估成分将在 V1 和 V2 以及第三次访视时获得，无需 fMRI。 第 4 周（V3）这项研究非常有影响力，因为我们需要了解支撑机制。 炎症和抑郁之间的双向关系，以促进新的开发 药物或行为疗法，并确定预测、预后和监测生物标志物。