Passive electrical neurofeedback treatment of mTBI: MEG and Behavioral Outcomes

轻度创伤性脑损伤（mTBI）是持续的身体、认知、情感和精神损伤的主要原因。 OEF/OIF/OND退伍军人和公众的行为缺陷。然而，潜在的病理生理学 脑震荡后的症状（PCS）尚不完全清楚，也没有有效的治疗方法。在 此外，PCS和创伤后应激障碍（PTSD）症状之间存在大量重叠， mTBI。IASIS是一类被动神经反馈治疗，其结合联合收割机低强度脉冲， 经颅电刺激（LIP-tES）与脑电图（EEG）监测。LIP-tES技术 在缓解患有TBI的PCS个体方面显示出有希望的结果。然而，神经机制 由于缺乏神经影像学检查，LIP-tES治疗TBI的潜在效果尚不清楚 对这种治疗干预的研究。传统的神经成像技术，如MRI和CT 在检测由mTBI引起的生理异常或评估 mTBI治疗。在急性期和慢性期，CT和MRI通常是阴性的，即使在具有以下特征的mTBI患者中也是如此。 持续性PCS。相反，越来越多的证据支持静息态脑磁图（rs- MEG）慢波源成像（δ波段，1-4 Hz）作为神经元的非侵入性成像标记物 mTBI异常。本申请的主要目标是使用rs-MEG来识别神经系统的异常。 在患有mTBI的退伍军人中与IASIS治疗相关的行为变化的基础。使用双- 采用安慰剂对照的盲法设计，我们将研究IASIS前后异常MEG慢波的变化 治疗（相对于“假”治疗组）。此外，我们将研究治疗- PCS、PTSD症状、神经心理测试表现的相关变化，以及它们与 脑磁图慢波的变化我们将第一次讨论一个关于机制的基本问题 慢波在脑损伤中的作用，即清醒时慢波的产生是否仅仅是一个负面的影响。 如果它是神经元损伤的结果，或者如果它是正在进行的神经元重排和愈合的标志， 发生在受伤的部位。具体目标1将检测mTBI退伍军人的损伤位点，并评估 与使用rs-MEG慢波的IASIS治疗相关的功能性神经影像学变化的潜在机制 源成像。我们假设MEG慢波源成像将显示出显著更高的灵敏度 在单个受试者的基础上识别损伤部位方面，我们还假设， 清醒时，慢波产生是正在进行的神经重排/愈合的标志，而不是一个 神经元损伤的负面后果。此外，我们假设IASIS最终将减少异常 在治疗过程结束时，由于完成了以下工作， 神经重排/愈合。具体目标2将检查PCS和PTSD的治疗相关变化 mTBI退伍军人的症状。我们假设与假手术组相比， IASIS治疗组将显示PCS和PTSD症状的显著更大减少， 基线和治疗后评估。具体目标3将研究IASIS治疗之间的关系- mTBI退伍军人rs-MEG慢波成像、PCS和神经心理学测量的相关变化。 我们假设MEG慢波生成减少与PCS总分降低相关， 个体PCS分数（例如，睡眠障碍、创伤后头痛、恐惧症和记忆问题 症状），并改善IASIS后和基线检查之间的神经心理学检查评分。的 这项研究的成功将首次证实， 清醒导致mTBI的显著治疗益处，包括异常慢- 波伴随PCS和认知功能的改善。

Mild traumatic brain injury (mTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral deficits in OEF/OIF/OND Veterans and the general public. However, the underlying pathophysiology is not completely understood, and there are few effective treatments for post-concussive symptoms (PCS). In addition, there are substantial overlaps between PCS and post-traumatic stress disorder (PTSD) symptoms in mTBI. IASIS is among a class of passive neurofeedback treatments that combine low-intensity pulses for transcranial electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring. LIP-tES techniques have shown promising results in alleviating PCS individuals with TBI. However, the neural mechanisms underlying the effects of LIP-tES treatment in TBI are unknown, owing to the dearth of neuroimaging investigations of this therapeutic intervention. Conventional neuroimaging techniques such as MRI and CT have limited sensitivity in detecting physiological abnormalities caused by mTBI, or in assessing the efficacy of mTBI treatments. In acute and chronic phases, CT and MRI are typically negative even in mTBI patients with persistent PCS. In contrast, evidence is mounting in support of resting-state magnetoencephalography (rs- MEG) slow-wave source imaging (delta-band, 1-4 Hz) as a noninvasive imaging marker for neuronal abnormalities in mTBI. The primary goal of the present application is to use rs-MEG to identify the neural underpinnings of behavioral changes associated with IASIS treatment in Veterans with mTBI. Using a double- blind placebo controlled design, we will study changes in abnormal MEG slow-waves before and after IASIS treatment (relative to a ‘sham’ treatment group) in Veterans with mTBI. In addition, we will examine treatment- related changes in PCS, PTSD symptoms, neuropsychological test performances, and their association with changes in MEG slow-waves. We for the first time will address a fundamental question about the mechanism of slow-waves in brain injury, namely whether slow-wave generation in wakefulness is merely a negative consequence of neuronal injury or if it is a signature of ongoing neuronal rearrangement and healing that occurs at the site of the injury. Specific Aim 1 will detect the loci of injury in Veterans with mTBI and assess the mechanisms underlying functional neuroimaging changes related to IASIS treatment using rs-MEG slow-wave source imaging. We hypothesize that MEG slow-wave source imaging will show significantly higher sensitivity than conventional MRI in identifying the loci of injury on a single-subject basis. We also hypothesize that in wakefulness, slow-wave generation is a signature of ongoing neural rearrangement / healing, rather than a negative consequence of neuronal injury. Furthermore, we hypothesize IASIS will ultimately reduce abnormal MEG slow-wave generation in mTBI by the end of the treatment course, owing to the accomplishment of neural rearrangement / healing. Specific Aim 2 will examine treatment-related changes in PCS and PTSD symptoms in Veterans with mTBI. We hypothesize that compared with the sham group, mTBI Veterans in the IASIS treatment group will show significantly greater decreases in PCS and PTSD symptoms between baseline and post-treatment assessments. Specific Aim 3 will study the relationship among IASIS treatment- related changes in rs-MEG slow-wave imaging, PCS, and neuropsychological measures in Veterans with mTBI. We hypothesize that Reduced MEG slow-wave generation will correlate with reduced total PCS score, individual PCS scores (e.g., sleep disturbance, post-traumatic headache, photophobia, and memory problem symptoms), and improved neuropsychological exam scores between post-IASIS and baseline exams. The success of the proposed research will for the first time confirm that potentiation of slow-wave generation in wakefulness leads to significant therapeutic benefits in mTBI, including an ultimate reduction of abnormal slow- waves accompanied by an improvement in PCS and cognitive functioning.