Passive Electrical Neurofeedback Treatment of mTBI: MEG and Behavioral Outcomes
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 66
- 试验地点
- 2
- 主要终点
- Rivermead Post Concussion Symptom Questionnaire
研究概览
简要总结
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 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 EEG monitoring. Nexalin is another tES technique , with FDA approvals for treating insomnia, depression, and anxiety. 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 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, the investigators will study changes in abnormal MEG slow-waves before and after IASIS treatment (relative to a 'sham' treatment group) in Veterans with mTBI. For a subset of participants who may have remaining TBI symptoms at the end of all IASIS treatment sessions, MEG slow-wave changes will be recorded before and after additional Nexalin treatment. In addition, the investigators will examine treatment-related changes in PCS, PTSD symptoms, neuropsychological test performances, and their association with changes in MEG slow-waves. The investigators 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.
详细描述
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. Furthermore, a substantial number of studies have shown higher (nearly double) rates of comorbid PTSD in individuals with mTBI, observed in military and civilian settings. IASIS is among a class of passive neurofeedback treatments that combine low-intensity pulses for transcranial electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring. Nexalin is another tES technique , with FDA approvals for treating insomnia, depression, and anxiety. LIP-tES techniques have shown promising results in alleviating PCS in 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 as a non-invasive imaging marker for neuronal abnormalities in mTBI. Using region of interest (ROI) and voxel-wise approaches, the investigators demonstrated that MEG slowwave source imaging detects abnormal slow-waves (delta-band, 1-4 Hz) with ~85% sensitivity in chronic and sub-acute mTBI patients with persistent PCS. 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, the investigators will study changes in abnormal MEG slowwaves before and after IASIS treatment (relative to a 'sham' treatment group), and for a subset, before and after additional Nexalin treatment, in Veterans with mTBI. In addition, the investigators will examine treatment-related changes in PCS, PTSD symptoms, neuropsychological test performances, and their association with changes in MEG slow-waves. Pre-treatment baseline and posttreatment rs-MEG exams, symptoms assessments, and neuropsychological tests will be performed. The investigators 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: To detect the loci of injury in Veterans with mTBI and assess the mechanisms underlying functional neuroimaging changes related to IASIS treatment, and for a subset of Veterans with remaining symptoms, additional Nexalin treatment, using rs-MEG slow-wave source imaging. The investigators' voxel-wise rs-MEG source-imaging technique will be used to identify abnormal slow-wave generation (delta band) in the baseline and post-treatment MEG exams to assess treatment-related changes on a single-subject basis. Healthy control (HC) Veterans, matched for combat exposure, will be used to establish an MEG normative database. Test-retest reliability of MEG slow-wave source imaging for mTBI will also be examined.
Hypothesis 1: Veterans with mTBI will generate abnormal MEG slow-waves during the baseline MEG exam. Voxel-wise MEG slow-wave source imaging will show significantly higher sensitivity than conventional MRI in identifying the loci of injury on a single-subject basis. The test-retest reliability of MEG slow-wave source imaging is expected to be high, with intra-class correlation coefficient (ICC) 0.75 between two sequential MEG exams.
Hypothesis 2: In wakefulness, slow-wave generation is a signature of ongoing neural rearrangement/ healing, rather than a negative consequence of neuronal injury. IASIS treatment will enhance neural rearrangement/healing by initially potentiating slow-wave generation immediately after each treatment session.
Hypothesis 3: 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. In Veterans with mTBI who finish IASIS treatment, but not in the sham group, MEG source imaging will show a significant decrease in abnormal slow-waves at post-treatment exam. Such significant decreases will also be evident in both the voxel-wise and overall abnormal MEG slow-wave measures.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
盲法说明
Sham treatment, double-blind design: During the sham treatment, we will prep and preplace the electrodes for common reference, A-, B-, plus the set of electrodes on the scalp of the participant following the 10-20 EEG configuration for A+ and A-, just like the procedure for real TES treatment. However, no LIP-tES pulses will be sent from the system during sham treatment, based a code entered to the system. A staff member (SRA #1) will assign a mTBI Veteran to either the mTBI-TES or the mTBI Sham group, with an attached code from an existing code bank. Then, the TES treatment operator (SRA #2) who is blind to the group assignment will enter the code to the TES system during treatments. Based on the code, the system automatically loads the protocol for either TES or Sham treatment. Only at the end of the study (after V16), the group assignment is revealed. Therefore, both the participant and TES treatment operator (SRA #2) are blind to the group assignment during the study.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Inclusion of Veterans for the mTBI groups:
- •All symptomatic mTBI patients will be evaluated in a clinical interview to document the nature of the injuries and ongoing PCS.
- •The diagnosis of mTBI patients is based on standard VA/DOD diagnostic criteria.
- •Inclusion in the mTBI patient group requires a TBI that meets the following criteria:
- •a loss of consciousness (LOC) < 30 minutes or transient confusion, disorientation, or impaired consciousness immediately after the trauma
- •post-traumatic amnesia (PTA) < 24 hours
- •an initial Glasgow Coma Scale (GCS) [90] between 13-15 (if available)
- •Since the GCS assessment is often not available in theater, Veterans with missing GCS, but who meet other inclusion criteria will also be recruited.
- •Each patient must have at least 3 items of persistent PCS at the beginning of the study.
- •Inclusion of Healthy Control (HC) group:
- •Veterans that qualify as HCs will be age, education, combat exposure, and socioeconomically matched to the mTBI groups.
- •In addition to exclusion criteria listed above, HC subjects must not have been diagnosed with head injury, affective disorder, or PTSD (CAPS-5 < 8) throughout life.
排除标准
- •Exclusion criteria for study participations include:
- •history of other neurological, developmental, or psychiatric disorders (based on the DSM-5 (MINI-7) [86] structured interview), e.g.,:
- •brain tumor
- •Alzheimer's disease
- •schizophrenia
- •bipolar disorder
- •or other chronic neurovascular diseases such as hypertension and diabetes
- •substance or alcohol use disorders according to DSM-5 [87] criteria within the six months prior to the study
- •history of metabolic or other diseases known to affect the central nervous system (see [88] for similar criteria)
- •Metal objects (e.g., shrapnel or metal fragments) that fail MRI screening, or extensive metal dental hardware, e.g.,:
- •braces and large metal dentures
- •fillings are acceptable
- •other metal objects in the head
- •neck, or face areas that cause non-removable artifacts in the MEG data
- •Potential subjects will be administered the Beck Depression Inventory (BDI-II) to evaluate level of depressive symptoms, and suicidal ideation
- •any participant who reports a "2" or "3" on the BDI-II: item 9 (suicidal thoughts or wishes) will also be excluded.
- •However, depression following mTBI or traumatic event of PTSD is common [89]: therefore, in two mTBI groups, the investigators will include and match patients with depression symptoms reported after their injury/event, and will co-vary BDI-II score in data analyses.
结局指标
主要结局
Rivermead Post Concussion Symptom Questionnaire
时间窗: Baseline through end of treatment, an average of 6 weeks
The Rivermead Post Concussion Symptom Questionnaire (RPQ) total score was used to assess change in post-concussion symptoms due to TES. Our focus in this analysis was the difference score in RPQ total score pre- vs post-treatment measures. The questionnaire has 16 items and uses scale of 0 - 4, with 0 as "not experienced at all" and 4 as "a severe problem." Value range: 0 - 64, where the higher scores mean a worse outcome. For this measure, we focused on the difference score: total score from prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.
Change in Abnormal Magnetoencephalography (MEG) Slow-Waves (1-4 Hz) Activity
时间窗: Baseline through end of treatment, an average of 6 weeks
We will develop a voxel-wise whole brain MEG source imaging approach for detecting abnormal Magnetoencephalography (MEG) slow-waves (1-4 Hz) in mTBI Veterans. The unit of the abnormal MEG source activity was measured in pico Ampere-meter (or pA-m which is 10\^(-12) A-m). Natural logarithm transformation (i.e., e-based) was used. So, the unit of the MEG source imaging was log(pA-m). The range of the voxel-wise MEG source activity scale is 0-10. High amplitude of the MEG source activity suggests more serious injury. In the present study, we measured the Difference score in MEG exam pre- vs post the transcranial electrical stimulation (TES) treatment. Our primary measure is the reduction of the abnormal MEG source activity for slow waves (1-4 Hz), defined as the MEG activity at the pre-TES exam minus that at the post-TES exam. So, the higher this difference score is, the better outcomes due to the TES treatment in reducing the abnormal MEG signal.
Neurobehavioral Symptoms Inventory
时间窗: Baseline through end of treatment, an average of 6 weeks
The Neurobehavioral Symptoms Inventory (NSI) total score was used to assess the changes of post-concussion symptoms due to TES. Our focus in this analysis was the difference score in NSI total score pre- vs post-treatment measures. The NSI has 22 items and uses a response scale of 0 - 4, with 0 as "none" and 4 as "very severe." Value range: 0 - 88, where the higher scores mean a worse outcome/more severe post-concussive symptoms. For this measure, we focused on the difference score: total score from prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.
次要结局
- The McGill Pain Questionnaire (MGPQ)(Baseline through end of treatment, an average of 6 weeks)
- Post-Concussion Check List (PCL-5)(Up to 6 weeks)
- California Verbal Learning Test-2nd Edition - Free Recall Total Correct T-score(Up to 6 weeks)
- Delis-Kaplan Executive Function System (DKEFS) - Trail Number/Letter Switching Scaled(Up to 6 weeks)
- Connors Continuous Performance Task II (CPT-II) - Inattention Omissions T-Score(Up to 6 weeks)
- Clinician-Administered PTSD Scale (CAPS-5)(Up to 6 weeks)
- Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) Processing Speed Index(Up to 6 weeks)
- Barratt Impulsivity Scale(Up to 6 weeks)
- Frontal Systems Behavior Scale(Baseline through end of treatment, an average of 6 weeks)