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.

摘要 抑郁症影响着美国大约10%的人。三分之二的病人 对传统的抗抑郁药没有反应，并被诊断患有难治性抑郁症（TRD）。还有， 传统的抗抑郁药需要大约三到四周才能显示效果。克他命，一种 传统上被用作麻醉剂，代表了一个有希望的希望。剂量低于 用于麻醉，氯胺酮已被发现可以改善一半以上的抑郁症状， 诊断为TRD的患者。最近，氯胺酮的一种异构体艾司氯胺酮已被FDA批准 用于治疗TRD。 氯胺酮和艾司氯胺酮的重复给药增强了其抗抑郁作用， 从几天到几周的治疗益处以及增加的响应和缓解率。动物 抑郁症模型表明，单剂量氯胺酮通过增加神经可塑性起作用， 大脑改变和适应的能力。然而，重复氯胺酮治疗如何增加 抗抑郁作用尚不清楚。了解增强治疗效果的潜在机制 在人类中，将有可能a）延长氯胺酮的抗抑郁作用超过几周，B） 增加反应和缓解率，和c）开发具有更好反应和缓解的新分子 rates.因此，我们建议将联合收割机两种技术结合起来，以了解大脑的变化相关 随着患者病情的改善。 第一种技术是脑电图（EEG），它监测大脑皮层的电活动。 新皮层，大脑中与记忆、决策和情绪有关的部分， 萧条使用脑电图任务，测量神经可塑性，我们将探测新皮层， 在经治疗的TRD患者中，与持续抗抑郁作用相关的神经可塑性 反复服用氯胺酮他们将在开始治疗前、治疗后接受EEG任务。 第一次治疗，然后在他们完成所有治疗后再进行一次。 第二种技术是使用计算机模型对新皮层进行计算机建模， 为了了解产生EEG的大脑机制而开发的，称为人类新皮层神经求解器 （HNN）。我们将使用HNN对大脑皮层的机制进行机械解释， EEG变化与持续抗抑郁作用相关。这将确定新皮层的变化 负责持续的治疗反应，这可以允许更好的治疗靶向。