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.

项目摘要 抑郁症的病理生理学仍然知之甚少，也许可以解释为什么一半的抑郁症患者 患者对现有的治疗没有充分的反应，导致慢性抑郁症及其相关的 发病率、过早死亡率和社会成本。体内的炎症会传递到大脑， 导致一些人抑郁。但大脑也调节免疫系统，但几乎没有 了解抑郁症相关的神经异常如何影响全身免疫力。如果没有更详细的 知识，在大脑和免疫系统之间的动态，稳态相互作用的治疗干预 制度具有挑战性。我们使用实时神经反馈（NF）来实验性地调节一个关键的神经节点 (i.e.杏仁核和内侧颞叶的海马，MTL），已被证明可以调节免疫 临床前功能。通过比较那些能够与那些不能恢复可塑性的抑郁症患者， 由于NF调节MTL的功能，我们朝着鉴定治疗的免疫标志物迈出了一步。 反应和预后（目标1）。相反，通过描述受试者的免疫变化， 能够重新获得MTL可塑性/功能，可以鉴定治疗性脑变化的生物标志物（目的2）。 此外，如果这种NF诱导的免疫变化在抑郁症的恢复中起着机械作用，那么 可以开发药物来增强这种治疗性免疫应答。这里使用的NF范式是 集中在杏仁核上在两项临床试验中，我们发现，训练抑郁症患者上调他们的 左杏仁核活动，而回忆积极的自传体记忆显着减少症状， 杏仁核和海马体的fMRI功能连接相对于抑郁症受试者增加， 假手术组。在这里，主要假设是：（1）基线水平的炎症细胞因子和神经毒性 犬尿氨酸代谢物在不能有效地上调其杏仁核（非 与有效上调其杏仁核的受试者（应答者）相比。(2)相比 对于无应答者，NF应答者将显示抗炎细胞因子和神经保护因子的增加。 NF训练后的犬尿氨酸。为了验证这些假设，我们将测量抑郁症状， （杏仁核活性和MTL连接性的变化）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评分≥10，n=32）将完成两项，一项 1小时的NF疗程（V1-V2）（无假手术）。V1和V2将相隔两周举行， 培训和评价部分。将在V1和V2以及第三次访视时（无fMRI）采集血清， 第4周（V3）。这项研究非常有影响力，因为我们需要了解其背后的机制 炎症和抑郁症之间的双向关系，以促进新的 药理学或行为疗法，并鉴定预测性、预后性和监测性生物标志物。