Combined EEG and in silico modeling to investigate the mechanisms of ketamine's sustained antidepressant effect in patients

结合脑电图和计算机建模研究氯胺酮对患者持续抗抑郁作用的机制

• 批准号: 10218406
• 负责人: PATRICK David SKOSNIK
• 金额: $ 16.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-23 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218406
• 关键词: Affect; Anesthesia procedures; Anesthetics; Animal Model; Antidepressive Agents; Apical; Auditory; Auditory area; Biological Markers; Biophysics; Brain; Brain-Derived Neurotrophic Factor; Chemosensitization; Clinic; Computer Models; Connecticut; Data; Decision Making; Development; Diagnosis; Disease remission; Distal; Dose; Electroencephalography; FDA approved; Frequencies; Glutamatergic Agents; Glutamates; Hospitals; Human; Infusion procedures; Isomerism; Ketamine; Knowledge; Lead; Long-Term Potentiation; Measures; Medial; Memory; Mental Depression; Methods; Modeling; Monitor; Moods; Neocortex; Neuronal Plasticity; Patients; Pharmaceutical Preparations; Photic Stimulation; Prefrontal Cortex; Publishing; Research; Rodent Model; Role; Sensory; Signal Transduction; Somatosensory Evoked Potentials; Synapses; Synaptic plasticity; System; Techniques; Therapeutic; Therapeutic Effect; Time; United States; Vertebral column; Work; antidepressant effect; density; depression model; depressive symptoms; design; disability; enantiomer; improved; in silico; insight; mortality; neocortical; neuromechanism; novel; public health relevance; recruit; relating to nervous system; response; translational model; translational study; treatment effect; treatment response; treatment-resistant depression

ABSTRACT Depression affects around ten percent of people in the United States. Two-thirds of these patients do not respond to traditional antidepressants and are diagnosed with treatment-resistant depression (TRD). Also, conventional antidepressants take approximately three to four weeks to show effects. Ketamine, a drug that has been traditionally used as an anesthetic agent, represents a promising hope. At doses lower than those utilized for anesthesia, ketamine has been found to improve depressive symptoms in more than half of the patients diagnosed with TRD. Recently, an isomer of ketamine, esketamine, has been approved by the FDA for the treatment of TRD. Repeated dosing of ketamine and esketamine augment their antidepressant effect, prolonging the therapeutic benefit from a few days to up to a few weeks and increasing response and remission rates. Animal models of depression have shown that a single dose of ketamine works by increasing neuroplasticity, the ability of the brain to change and adapt. However, how repeated ketamine treatments augment the antidepressant effect is not known. Understanding the underlying mechanism of augmented therapeutic effect in humans would make it possible to a) prolong ketamine’s antidepressant effect beyond a few weeks, b) increase response and remission rates, and c) develop novel molecules with better response and remission rates. Therefore, we are proposing to combine two techniques to understand the brain changes associated with the augmented improvements in patients. The first technique is electroencephalography (EEG), which monitors the electrical activity of the neocortex, the part of the brain involved in memory, decision making, and mood, features that are affected in depression. Using an EEG task that measures neuroplasticity, we will probe the neocortex to identify changes in neuroplasticity associated with the sustained antidepressant effects in patients diagnosed with TRD treated with repeated ketamine dosing. They will undergo the EEG task before they begin their treatment, after their first treatment, and then again after they finish all their treatments. The second technique is computer modeling of the neocortex using a computer model that has been developed to understand the brain mechanisms generating EEG, called the Human Neocortical Neurosolver (HNN). We will use HNN to make mechanistic interpretations of the neocortical mechanisms underlying the EEG changes associated with the sustained antidepressant effect. This will identify the neocortical changes responsible for the sustained therapeutic response, which may allow for better treatment targeting.

抽象的 抑郁症影响美国约百分之十。这些患者中有三分之二 对传统抗抑郁药的反应未反应，被诊断出患有耐药性抑郁症（TRD）。还， 常规的抗抑郁药大约需要三到四个星期才能显示出作用。氯胺酮，一种药物 传统上被用作麻醉剂，代表了希望的希望。低于那些剂量 氯胺酮用于麻醉，可改善超过一半以上的抑郁症状 被诊断为TRD的患者。最近，氯胺酮的异构体Esketamine已被FDA批准 用于治疗TRD。 氯胺酮和埃斯京胺的反复给药增强其抗抑郁作用，延长了 几天到几周的治疗益处，并提高了响应和缓解率。动物 抑郁模型表明，单剂量氯胺酮通过增加神经可塑性，即 大脑改变和适应的能力。但是，氯胺酮治疗如何增加 抗抑郁作用尚不清楚。了解增强治疗作用的潜在机制 在人类中，a）延长氯胺酮的抗抑郁作用以至几周，b） 提高响应和缓解速率，c）发展具有更好响应和缓解的新分子 费率。因此，我们提议结合两种技术以了解相关的大脑变化 随着患者的增强改善。 第一种技术是脑电图（EEG），它可以监视 NeoCortex是记忆，决策和情绪所涉及的大脑的一部分，这些特征受到影响 沮丧。使用测量神经可塑性的脑电图任务，我们将探测新皮层以识别变化 在与被诊断为TRD治疗的患者中持续的抗抑郁作用相关的神经可塑性 重复的氯胺酮给药。他们将在开始治疗之前接受脑电图任务 首次治疗，然后在他们完成所有治疗后再次治疗。 第二种技术是使用已经过去的计算机模型对新皮层进行计算机建模 开发的是了解产生脑电图的大脑机制，称为人类新皮质神经溶剂剂 （HNN）。我们将使用HNN对新皮质机制进行机械解释 脑电图变化与持续的抗抑郁作用相关。这将确定新皮质的变化 负责持续的治疗反应，这可能允许更好的治疗靶向。