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

섬유근육통에서 두개골 전기 자극의 효능 평가

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.

저자 스포트라이트: 만성 통증 관리 연구의 방법론과 발전

뇌 영상 바이오마커를 사용하여 섬유근육통 통증 및 신체 기능에 대한 두개골 전기 자극에 대한 무작위, 가짜 대조 시험

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.

두개골 전기 자극(CES) 시험을 위한 참가자 모집 및 기준선 MRI 스캔 방문

연구 참가자를 모집하려면 연구 모집 자료를 배포하고 승인된 방법을 사용하기 위한 기관 지침을 준수해야 합니다. 전화로 관심을 표명하는 사람을 선별하여 모든 포함 및 제외 기준을 충족하는지 확인합니다. 화면에 표시된 자격 기준에 따라 참가자를 포함하고 제외 기준이 충족되는 경우 개인을 제외합니다.각 기준선 방문 전에 각 참가자를 위해 두개골 전기 자극 또는 CES 장치를 준비합니다. 이렇게 하려면 먼저 화면이 켜질 때까지 상단 버튼을 약 2초 동안 눌러 장치를 켭니다. 장치가 작동하는지 확인한 후 화면이 꺼질 때까지 버튼을 약 2초 동안 눌러 꺼냅니다.각 케이스에 장치, 여분의 배터리, 끈, 작은 용액 애플리케이터 및 귀마개가 포함되어 있는지 확인하십시오. 그런 다음 참가자에게 제공할 각 가방에 하나의 장치 케이스를 넣고 각 가방에 전도성 용액 한 병, 소형 용액 애플리케이터를 채우기 위한 추가 캡 및 추가 귀 클립 전극 패드도 포함되어 있는지 확인합니다. 예정된 약속을 위해 자기 공명 영상 또는 MRI 스캐너 위치에서 동의서 사본 2부, CES 장치가 들어 있는 가방 및 기타 자료, 자격 시험 서류 및 설문지 패킷을 가지고 참가자를 만나십시오.자격이 있는 참가자와 함께 다음 단계로 진행하기 전에 동의하는 각 참가자와 함께 포함 테스트 서류를 작성하십시오. 장치 사용법을 설명하려면 케이스에서 장치를 제거하고 켜고 끄는 방법을 시연하십시오. 이어 클립 코드를 측면에 연결하는 방법을 보여줍니다.다음으로, 클립에 연결하는 접착제를 위로 당겨 귀 클립에서 오래된 전극 패드를 제거하는 방법을 보여줍니다. 그런 다음 패드의 구멍을 클립 중앙의 돌출된 부분에 맞추면서 단단히 눌러 부착합니다. 그런 다음 클립의 녹색 끝을 짜서 엽니다.귓불을 팁 사이에 놓고 클립을 부드럽게 닫아 귓불에 부착하는 방법을 보여줍니다. 참가자가 한 번 시도하도록 합니다. 작은 용액 어플리케이터에서 플라스틱 뚜껑을 제거하고 다른 뚜껑을 더 큰 용액 병의 상단에 부착하는 방법을 보여줍니다.그런 다음 작은 노즐을 위로 밀어 올려 작은 어플리케이터에 밀어 넣고 큰 병을 짜서 작은 어플리케이터를 채웁니다. 참가자에게 각 귀 클립 전극 패드에 용액을 약 1-2방울만 추가하도록 알립니다. 매일 장치를 사용할 때를 지시하십시오.참가자에게 빈 장치 로그를 제공하고 각 사용 중에 필요한 세부 정보를 기록하도록 요청합니다. 다음으로, 참가자에게 세 가지 간단한 신체 기능 테스트를 완료하도록 합니다. 먼저 참가자에게 완전히 서 있는 자세로 일어나도록 지시한 다음 등받이를 의자에 대고 다시 끝까지 앉습니다.참가자가 30초 동안 가능한 한 많이 이 작업을 수행하도록 합니다. 그런 다음 참가자에게 오른팔부터 시작하여 왼쪽으로 이동하면서 각 면당 30초 동안 덤벨로 팔 컬을 하도록 합니다. 그런 다음 참가자가 동력계에서 각 팔로 세 번의 악력 테스트를 수행하도록 합니다.동력계를 가능한 한 세게 쥐었다가 놓도록 요청하십시오. 다음으로, 참가자가 펜을 사용하여 설문지 패킷을 작성하고 패킷을 확인하여 모든 질문에 대한 답변이 이루어졌는지 확인하도록 합니다. 참가자를 MRI 스캐너로 데려간 후 MRI 기술자와 함께 선별 양식 을 검토하고 참가자가 모든 금속 액세서리를 제거했는지 확인합니다.MRI 기술자가 MRI 스캔 프로토콜을 관리하기 전에 참가자를 스캐너에 편안하게 넣을 수 있도록 도와줍니다.

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 ...

연구

의학

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

두개전기 자극(CES) 시험을 위한 MRI 스캔 프로토콜 설정