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 大约百分之十的美国人患有抑郁症，其中三分之二的人患有抑郁症。 对传统抗抑郁药没有反应并被诊断为难治性抑郁症 (TRD)。 传统的抗抑郁药大约需要三到四个星期才能发挥作用。 传统上用作麻醉剂，在低于这些剂量的情况下代表了有希望的希望。 氯胺酮用于麻醉，已被发现可以改善一半以上的抑郁症状 最近，氯胺酮的异构体艾氯胺酮已获得 FDA 批准。 用于治疗TRD。 重复服用氯胺酮和艾氯胺酮可增强其抗抑郁作用，延长持续时间 治疗效果从几天到几周不等，并提高动物的反应率和缓解率。 抑郁症模型表明，单剂量氯胺酮通过增加神经可塑性发挥作用， 然而，重复的氯胺酮治疗如何增强大脑的改变和适应能力。 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，可以a）将氯胺酮的抗抑郁效果延长几周以上，b） 提高反应和缓解率，以及 c) 开发具有更好反应和缓解的新型分子 因此，我们建议结合两种技术来了解相关的大脑变化。 随着患者病情的进一步改善。 第一种技术是脑电图（EEG），它监测大脑的电活动。 新皮质是大脑中与记忆、决策和情绪有关的部分，其特征受到影响 使用测量神经可塑性的脑电图任务，我们将探测新皮质以识别变化。 神经可塑性与 TRD 患者持续抗抑郁作用相关 重复服用氯胺酮，他们将在开始治疗之前和治疗之后接受脑电图任务。 第一次治疗，然后在完成所有治疗后再次治疗。 第二种技术是使用已被研究过的计算机模型对新皮质进行计算机建模。 开发用于理解产生脑电图的大脑机制，称为人类新皮质神经解算器 （HNN）。我们将使用 HNN 对新皮质机制进行机械解释。 与持续抗抑郁作用相关的脑电图变化这将识别新皮质的变化。 负责持续的治疗反应，这可能有助于更好的治疗目标。