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

Bewertung der Wirksamkeit der kranialen elektrischen Stimulation bei Fibromyalgie

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.

Autor im Rampenlicht: Methoden und Fortschritte der Forschung zur Behandlung chronischer Schmerzen

Eine randomisierte, scheinkontrollierte Studie zur kranialen elektrischen Stimulation bei Fibromyalgie-Schmerzen und körperlicher Funktion unter Verwendung von bildgebenden Biomarkern des Gehirns

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.

Rekrutierung der Teilnehmer und Besuch des MRT-Scans zu Studienbeginn für die Studie zur kranialen Elektrostimulation (CES)

Halten Sie sich bei der Rekrutierung von Studienteilnehmern an die institutionellen Richtlinien für die Verteilung von Studienrekrutierungsmaterialien und die Anwendung zugelassener Methoden. Überprüfen Sie die Personen, die telefonisch Interesse bekunden, um sicherzustellen, dass sie alle Ein- und Ausschlusskriterien erfüllen. Befolgen Sie die auf dem Bildschirm angezeigten Zulassungskriterien, um Teilnehmer einzuschließen und Einzelpersonen auszuschließen, wenn Ausschlusskriterien erfüllt sind.Bereiten Sie vor jedem Baseline-Besuch die kraniale Elektrostimulation oder das CES-Gerät für jeden Teilnehmer vor. Schalten Sie dazu zunächst das Gerät ein, indem Sie die obere Taste etwa zwei Sekunden lang drücken, bis der Bildschirm aufleuchtet. Nachdem Sie sichergestellt haben, dass das Gerät funktioniert, drücken Sie die Taste etwa zwei Sekunden lang, bis der Bildschirm leer wird, um es auszuschalten.Stellen Sie sicher, dass jede Hülle das Gerät, zusätzliche Batterien, ein Schlüsselband, einen kleinen Lösungsapplikator und Ohrclips enthält. Legen Sie dann eine Gerätehülle in jede Tasche, die den Teilnehmern gegeben werden soll, und stellen Sie sicher, dass jede Tasche auch eine Flasche mit leitender Lösung, eine zusätzliche Kappe zum Befüllen des kleinen Lösungsapplikators und zusätzliche Ohrclip-Elektrodenpads enthält. Treffen Sie den Teilnehmer am Standort des Magnetresonanztomographie- oder MRT-Scanners für den geplanten Termin mit zwei Kopien der Einverständniserklärung, der Tasche mit dem CES-Gerät und anderen Materialien, Unterlagen für die Eignungsprüfung und einem Fragebogenpaket.Füllen Sie die Unterlagen für die Inklusionstests mit jedem zustimmenden Teilnehmer aus, bevor Sie mit den berechtigten Teilnehmern zum nächsten Schritt übergehen. Um ihnen die Geräteverwendung zu erklären, nehmen Sie das Gerät aus der Hülle und demonstrieren Sie, wie Sie es ein- und ausschalten. Zeigen Sie, wie Sie das Ohrclip-Kabel an der Seite befestigen.Zeige als Nächstes, wie du die alten Elektrodenpads von der Ohrklammer entfernst, indem du den Klebstoff hochziehst, der sie mit der Klammer verbindet. Befestigen Sie dann das neue Pad, indem Sie das Loch darin mit dem erhabenen Bereich in der Mitte des Clips ausrichten, während Sie es fest nach unten drücken. Drücken Sie danach die grünen Spitzen des Clips zusammen, um ihn zu öffnen.Demonstrieren Sie, wie Sie das Ohrläppchen zwischen den Spitzen positionieren und den Clip vorsichtig schließen, um ihn am Ohrläppchen zu befestigen. Lassen Sie den Teilnehmer es einmal versuchen. Zeigen Sie ihnen, wie sie den Plastikdeckel vom kleinen Lösungsapplikator entfernen und die alternative Kappe oben an der größeren Lösungsflasche befestigen.Schieben Sie dann die kleine Düse nach oben, schieben Sie sie in den kleinen Applikator und drücken Sie die große Flasche zusammen, um den kleinen Applikator zu füllen. Weisen Sie den Teilnehmer darauf hin, dass er nur etwa ein bis zwei Tropfen der Lösung auf jedes Ohrclip-Elektrodenpad geben soll. Geben Sie an, wann das Gerät jeden Tag verwendet werden soll.Geben Sie dem Teilnehmer ein leeres Geräteprotokoll und bitten Sie ihn, die erforderlichen Details bei jeder Nutzung zu protokollieren. Lassen Sie den Teilnehmer als Nächstes drei kurze körperliche Funktionstests absolvieren. Weisen Sie den Teilnehmer zunächst an, sich in eine volle stehende Position zu erheben und sich dann ganz nach unten zu setzen, während Sie den Rücken gegen den Stuhl drücken.Lassen Sie den Teilnehmer dies so oft wie möglich in 30 Sekunden tun. Lassen Sie den Teilnehmer dann 30 Sekunden lang pro Seite Armbeuger mit einer Hantel auf jeder Seite machen, beginnend mit dem rechten Arm und dann nach links. Lassen Sie den Teilnehmer danach drei Griffkrafttests mit jedem Arm auf einem Prüfstand durchführen.Bitten Sie darum, den Prüfstand so fest wie möglich zusammenzudrücken und dann loszulassen. Lassen Sie den Teilnehmer als Nächstes das Fragebogenpaket mit einem Stift ausfüllen und überprüfen Sie das Paket, um sicherzustellen, dass alle Fragen beantwortet wurden. Nachdem Sie den Teilnehmer zum MRT-Scanner geführt haben, überprüfen Sie das Screening-Formular mit den MRT-Technikern und stellen Sie sicher, dass der Teilnehmer alle Metallteile entfernt hat.Helfen Sie MRT-Technikern, den Teilnehmer bequem in den Scanner zu bringen, bevor Sie das MRT-Scanprotokoll durchführen.

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 ...

Forschung

Medizin

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

Einrichten eines MRT-Scan-Protokolls für die Studie zur kranialen Elektrostimulation (CES)