participant recruitment and baseline mri scan visit for the cranial electrical stimulation (ces) trial

评估颅脑电刺激对纤维肌痛的疗效

Of the many existing states of chronic pain, one of the most notoriously difficult diseases to diagnose, clinically assess, and treat is fibromyalgia. Fibromyalgia is a debilitating chronic pain syndrome that involves chronic widespread pain, decreased physical function, fatigue, psycho-emotional and sleep disturbances, and various somatic complaints affecting approximately 2-3% of the general population in the Americas (about 8 million people in the U.S.)1. Diagnosis of the disease is heavily reliant on a patient&#39;s understanding of their own symptom profile and pain experience, and without that proper understanding by both clinician and patient of the disease, methods of treatment lose considerable efficacy2. A better definition of fibromyalgia&#39;s origins and impact as well as a reliable clinical biomarker to guide fibromyalgia diagnosis and treatment&#160;are necessary to best serve all patients.
Even with a confirmed diagnosis, difficulties with the treatment process only grow. As a whole, chronic pain affects more individuals than heart disease, diabetes, and cancer combined. The subjective nature of its assessment places it as a primary driver for the opioid epidemic, especially given the difficulty in discerning incompletely treated physical pain from substance use disorder and drug-seeking behavior3. In 2020, 91,799 drug overdose deaths occurred in the United States (a 30% increase from 2019), and opioids were found to be the main cause of these deaths (74.8% of all 2020 drug overdose deaths)4. Thus, non-pharmacologic alternatives are needed for chronic pain and fibromyalgia treatment to slow the opioid epidemic, which is particularly important in the veteran population where the risk of suicide and opioid use disorder is higher5. Non-pharmacologic and complementary therapies are therefore often used as first-line treatments6.
The search for novel, efficacious fibromyalgia interventions has led many researchers and clinicians to methods of noninvasive brain stimulation, including cranial stimulation. Even though the pathophysiologic mechanisms that result in the development of the disease have not been definitively determined, existing evidence supports the idea that fibromyalgia is a disorder of autonomic nervous system dysfunction and central (i.e., brain and spinal cord) pain processing mechanisms7,8. Stimulation of certain areas of the brain could lead to improved function in those areas of processing. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been correlated with reductions in pain but have also been associated with activation site scalp irritation, headaches, and inaccessibility outside of treatment facilities9. Noninvasive vagus nerve stimulation (nVNS), which can provide neuromodulation through stimulation over the skin at the neck or at the level of the ear, has the potential for the treatment of chronic pain, and invasive vagus nerve stimulation (VNS) has been shown to improve chronic pain symptoms10. However, neither invasive nor noninvasive VNS have been sufficiently explored in the literature or fully validated for use in fibromyalgia treatment11,12,13,14.
Cranial electrical stimulation (CES) is a non-pharmacological, noninvasive brain stimulation treatment that consists of pulsed, alternating microcurrent (less than 0.5 mA) applied via transcutaneous electrodes placed on the earlobes15. It is remarkably accessible and can be delivered through portable devices used by patients within their own living spaces. In comparison to other cranial stimulation methods, the noninvasive nature and the convenience of patient self-application at home increases the potential of CES as a beneficial option for widespread fibromyalgia treatment use and self-management of pain. It has been cleared by the U.S. Food and Drug Administration (FDA) as a treatment for insomnia, depression, anxiety, and pain15.
The current study evaluates the efficacy of CES as a fibromyalgia treatment modality by comparing active CES (administered by a true study device) versus sham CES (administered by a sham study device). There is some preliminary evidence to support the use of CES in the treatment of pain conditions such as fibromyalgia16,17. A 2001 study of 60 participants randomized to active or sham CES for 3 weeks of daily 60 min sessions revealed a 28% improvement in tender point scores, 27% improvement in general pain scores, and no placebo effect18. CES has not been evaluated in a veteran population, nor has it been adequately evaluated in males with fibromyalgia. A Veterans Affairs (VA)-funded systematic review of CES published in 2018 concluded that evidence is insufficient for CES to have clinically important effects on fibromyalgia, given that most trials had small sample sizes, short durations, and a high risk of bias due to inadequate blinding. However, the review suggests that CES does not cause serious side effects, and there is low-strength evidence to suggest modest benefits in patients with anxiety and depression19. Therefore, further research is warranted regarding the use of this FDA-cleared, low-risk device, particularly in fibromyalgia.
In order to fully evaluate the efficacy, researchers assessed physical fitness alongside neural biomarkers and pain experience. The purpose of treating chronic pain states is to improve physical function. Fibromyalgia is consistently correlated with negative effects on both physical function and patients&#39; perception of their own physical abilities20. Previous studies have utilized simple physical fitness assessments to determine stamina and mobility, such as the 6 Minute Walk Test (6MWT)20,21, Five Time Sit to Stand (5TSTS)20, and various measures of carrying capacity and strength in the context of daily activities22. To account for standard measures while also mitigating the amount of strenuous activity required right before an MRI scan, the study team used the 30-Second Chair Sit Stand Test as a measure of stamina and mobility and both bicep curls and a hand grip test as measures of strength23. The movements required in each of these assessments are very common in everyday activities, so it is a clear measure of how people are physically functioning in their day-to-day lives, both with and without treatment.
Even with subjective pain assessments and physical function measures of efficacy, the mechanisms of CES are not fully understood. Prior neuroimaging studies have sought a better understanding by exploring the direct effect of CES on network connectivity in the brain. Feusner et al.24 found that CES is associated with cortical deactivation for 0.5 Hz and 100 &#181;A stimulation of bilateral frontal, parietal, and posterior midline regions and postulated that frequency of stimulation may have more of an effect than current intensity in relation to cortical deactivation. Their group found significant effects on some but not all nodes of the default mode network (DMN). The authors suggest that based on this data, CES may affect resting state functional connectivity. Fibromyalgia and other chronic pain states have been shown to affect intrinsic brain connectivity in regions associated with pain and perception25,26, so treatments that alter functional connectivity in response could prove to be both beneficial and effective. Further exploration of the longer-term effects of daily treatment in relation to clinical improvement, as well as how deceased activation in the brain relates to previously observed decreases in electroencephalogram frequencies, is needed to further understand the therapeutic mechanism of action27.
Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) is the neuroimaging method that allows for the observation of these functional connectivity changes. Longitudinal resting state fMRI allows clinicians and researchers to establish a baseline of resting state connectivity and track alterations over time in response to CES treatment methods. It also helps to determine how changes in functional connectivity are correlated to differences in the experience of pain. Initial studies of neuroimaging for fibromyalgia used positron emission tomography (PET) and single-photon-emission computed tomography (SPECT) to examine the brain, but there are issues with both techniques in this regard: SPECT has a lower resolution than PET, and PET scans are invasive, which is not preferable for patients experiencing chronic pain. Functional magnetic resonance imaging (fMRI) scans have greater resolution than SPECT, but they examine brain activity in response to patients&#39; specific actions or perceptions of stimuli28. It is rs-fcMRI scans that can outline functional connectivity between regions of the brain and may be able to determine where and how fibromyalgia exists as well as the best methods of treatment28.
Evaluating the efficacy of non-pharmacologic treatments for pain conditions such as fibromyalgia is of utmost importance both in the current setting of the opioid epidemic and in examining chronic pain as a risk factor for suicide29,30, which is substantially increased among the veteran population. Additionally, the lack of adequate clinical biomarkers for pain is a recognized knowledge gap. Using a combination of behavioral measures and neuroimaging at multiple timepoints to assess treatment response is a novel approach to fibromyalgia evaluation, as is the utilization of auricular CES as a treatment.
The protocol aims to address the gap in fibromyalgia research by investigating the effects of CES on pain and physical function outcomes and evaluating neuroimaging as a tool for predictive and response biomarkers related to the clinical outcomes of CES therapy31.

作者聚焦：慢性疼痛管理研究的方法和进展

一项使用脑成像生物标志物进行颅脑电刺激治疗纤维肌痛疼痛和身体功能的随机、假对照试验

We are trying to address two main issues with regards to pain research. The first is the need for non-invasive, non-pharmacologic therapies that can be effectively administered to individuals suffering from chronic pain. The second is the development of reliable biomarkers, such as the neuroimaging that we're using for the purposes of assessing both fibromyalgia pain and treatment response.The development and access of multiple open source neuro software packages allows for the streamlined use of neuroimaging data analysis. Many of these tools such as fMRIPrep allow researchers who are not familiar with the neuroimaging practices to complete critical pre-processing steps. To maintain blinding, we're unable to titrate for effect using the device as we would in a clinical setting.The stimulation is typically below the perceptual threshold, but we may be underdosing individuals in our study's treatment group, which causes a smaller effect size and difference between the groups. Cranial electrical stimulation is non-invasive. It's low risk, and it's accessible enough to be self-administered by participants in their own home settings.We can also extract usage rates from each of the research devices to properly evaluate compliance with the treatment. And resting state functional connectivity MRI allows us to assess changes in the brain that may occur as a result of our treatment. We anticipate that our research will further guide biomarker development using neuroimaging as a tool.This contributes to a better understanding of the neural basis of pain, and our hope is that these techniques will eventually be used to guide clinical diagnosis and decision making for individuals suffering from pain.

颅脑电刺激 （CES） 试验的参与者招募和基线 MRI 扫描访问

要招募研究参与者，请遵守分发研究招募材料和采用经批准的方法的机构指南。对通过电话表达兴趣的人进行筛选，以确保他们符合所有纳入和排除标准。按照屏幕上显示的资格标准将参与者包括在内，如果满足任何排除标准，则将个人排除在外。在每次基线访视之前，为每个参与者准备颅脑电刺激或 CES 设备。为此，首先按住顶部按钮约两秒钟，直到屏幕亮起，以打开设备。确保设备正常工作后，按住按钮约两秒钟，直到屏幕变为空白以将其关闭。确保每个箱子都包含设备、备用电池、挂绳、一个小溶液涂抹器和耳夹。然后，在每个袋子中放置一个设备盒，以提供给参与者，并确保每个袋子还包含一瓶导电溶液、一个用于填充小型溶液涂抹器的额外盖子和额外的耳夹电极垫。在磁共振成像或 MRI 扫描仪位置与参与者会面，以便进行预定的约会，携带两份同意书副本、装有 CES 设备的袋子和其他材料、资格测试文件和问卷包。与每个同意的参与者一起完成包含性测试文书工作，然后再与符合条件的参与者进行下一步。要向他们解释设备的使用情况，请从外壳中取出设备，并演示如何打开和关闭它。演示如何将耳夹线连接到侧面。接下来，展示如何通过拉起将其连接到耳夹的粘合剂从耳夹中取下旧电极垫。然后，将新垫子上的孔与夹子中心的凸起区域对齐，同时用力按下它来连接新垫子。之后，挤压夹子的绿色尖端以打开它。演示如何将耳垂放置在耳垂之间，并轻轻合上夹子以将其连接到耳垂。让参与者尝试一次。向他们展示如何从小型溶液涂抹器上取下塑料顶部，并将备用瓶盖连接到较大溶液瓶的顶部。然后，向上推小喷嘴，将其滑入小涂抹器中，然后挤压大瓶子以填充小涂抹器。告诉参与者只向每个耳夹电极垫中加入大约一到两滴溶液。指示每天何时使用该设备。给参与者一个空白的设备日志，并要求在每次使用期间记录必要的详细信息。接下来，让参与者完成三个简短的身体机能测试。首先，指导参与者上升到完全站立的姿势，然后一直坐下，同时保持背部靠在椅子上。让参与者在 30 秒内尽可能多地执行此操作。然后让参与者用哑铃在每侧做手臂卷曲，每侧 30 秒，首先从右臂开始，然后向左移动。之后，让参与者在测力计上对每只手臂进行三次握力试验。要求尽可能用力挤压测力计，然后松开它。接下来，让参与者用笔完成问卷包，并检查问卷包以确保所有问题都得到回答。将参与者带到 MRI 扫描仪前后，与 MRI 技术人员一起查看筛查表，并确保参与者已移除所有金属配件。在执行 MRI 扫描协议之前，帮助 MRI 技术人员将参与者舒适地放入扫描仪中。

Research

JoVE Journal

Medicine

Participant Recruitment and Baseline MRI Scan Visit for the Cranial Electrical Stimulation (CES) Trial

A Randomized, Sham-Controlled Trial of Cranial Electrical Stimulation for Fibromyalgia Pain and Physical Function, Using Brain Imaging Biomarkers

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive ...

科研

医学

Setting up an MRI Scan Protocol for the Cranial Electrical Stimulation (CES) Trial

为颅脑电刺激 （CES） 试验设置 MRI 扫描协议

颅脑电刺激 （CES） 试验的参与者招募和基线 MRI 扫描访问

颅脑电刺激（CES）试验的参与者招募和基线 MRI 扫描访问