Name: В центре внимания автора: Методологии и достижения в исследованиях в области лечения хронической боли
Uploaded: 2024-01-05T14:00:00
Description: Read this Scientific Article Protocol about Author Spotlight: Towards Biomarker Development Using Neuroimaging as a Tool to Enhance the Understanding of the Neural Basis of Pain at JoVE.com

Авторы выражают признательность исследователям из Центра визуальной и нейрокогнитивной реабилитации, в том числе доктору Брюсу Кроссону и доктору Лизе Кришнамурти, за их вклад в работу. Авторы также благодарят Грейс Ингхэм за неоценимую помощь в съемочном процессе. Эта работа была частично поддержана премией Министерства по делам ветеранов США за исследования и развитие карьеры IK2 RX003227 (Анна Вудбери) и грантом Центра 5I50RX002358. Спонсор не играет никакой роли в планировании исследования, сборе данных, управлении, анализе, интерпретации или составлении отчетности.

Исследование проводилось с одобрения Университета Эмори (IRB 112768) и Институциональных наблюдательных советов Атланты VA (1585632-2; Внутренний справочный номер: 003), а также в Комитет по исследованиям и разработкам штата Атланта (регистрационный номер Совета директоров: 3881). Все испытуемые дал...

Оценка эффективности электростимуляции черепа при фибромиалгии

Методы настоящего исследования обеспечивают не только возможность высокоэффективного метода лечения фибромиалгии, но и возможность улучшить процесс диагностики фибромиалгии с первого момента ее болевого симптоматического профиля. Использование как активной CES, так и фиктивной CES, с ...

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>3T Siemens MAGNETOM Prisma Scanner</td>
			<td>Siemens Healthineers</td>
			<td>N/A</td>
			<td>From Emory&#39;s website: &#34;The Siemens Magnetom Prisma 3T whole-body MR system is equipped with: a state-of-the art gradient system with a maximum (per axis) strength of 80 mT/m and slew rate of 200 T/m/sec 
			64 independent RF receiver channels capable of 204 receiver connections 
			a 2-channel RF transmitter. Multiple coils are available, including: a 64-channel head/neck coil with 52 channels for imaging of the head region 
			a 32-channel head-only coil 
			a 20-channel head/neck coil with 16 channels for head 
			spine array coil 
			flexible chest coil 
			large and small flexible coil for extremity imaging.</td>
		</tr>
		<tr>
			<td>Alpha-Stim AID Kit</td>
			<td>Electromedical Products International Inc.</td>
			<td>SKU: 500KIT</td>
			<td>A total of 50 devices ordered for research purposes. 
			From the site: &#34;A prescription or order from a licensed healthcare professional is required to purchase this device (within the USA). FDA cleared for anxiety, insomnia and pain only, with approval for depression outside of the United States.&#34;</td>
		</tr>
		<tr>
			<td>CONN Toolbox v21a16 (RRID:SCR_009550)&#160;</td>
			<td>Whitfield-Gabrieli and Nieto-Castanon</td>
			<td>Version v21a16 (RRID:SCR_009550)</td>
			<td>CONN is an open-source SPM-based cross-platform software for the computation, display, and analysis of functional connectivity Magnetic Resonance Imaging (fcMRI). CONN is used to analyze resting state data (rsfMRI) as well as task-related designs.&#160;</td>
		</tr>
		<tr>
			<td>DSI Studio&#160;(RRID:SCR_009557)&#160;</td>
			<td>Fang-Cheng (Frank) Yeh</td>
			<td>RRID:SCR_009557</td>
			<td>DSI Studio is a tractography software tool that maps brain connections and correlates findings with neuropsychological disorders. It is a collective implementation of several diffusion MRI methods, including diffusion tensor imaging (DTI), generalized q-sampling imaging (GQI), q-space diffeomorphic reconstruction (QSDR), diffusion MRI connectometry, and generalized deterministic fiber tracking.</td>
		</tr>
		<tr>
			<td>fMRIPrep 20.2.5 (RRID:SCR_016216)&#160;</td>
			<td>NiPreps (NeuroImaging PREProcessing tools)</td>
			<td>Version 20.2.5. (RRID:SCR_016216)</td>
			<td>A functional magnetic resonance imaging (fMRI) data preprocessing pipeline that is designed to provide an easily accessible, state-of-the-art interface that is robust to variations in scan acquisition protocols and that requires minimal user input, while providing easily interpretable and comprehensive error and output reporting. It performs basic processing steps (coregistration, normalization, unwarping, noise component extraction, segmentation, skull-stripping, etc.) providing outputs that can be easily submitted to a variety of group level analyses, including task-based or resting-state fMRI, graph theory measures, and surface or volume-based statistics.</td>
		</tr>
		<tr>
			<td>MRIQC&#160;</td>
			<td>NiPreps (NeuroImaging PREProcessing tools)</td>
			<td></td>
			<td>MRIQC extracts no-reference IQMs (image quality metrics) from structural (T1w and T2w) and functional MRI (magnetic resonance imaging) data. (not directly used for analyses)</td>
		</tr>
		<tr>
			<td>Sammons Preston Jamar Hydraulic Hand Dynamometer</td>
			<td>Alpha Med Inc.</td>
			<td>SKU SAMP5030J1</td>
			<td>From the website: Ideal for routine screening of grip strength and initial and ongoing evaluation of clients with hand trauma and dysfunction. 
			Unit comes with carrying/storage case, certificate of calibration and complete instructions. Warranted for one full year. The warranty does not cover calibration. Latex free.</td>
		</tr>
		<tr>
			<td>SPRI 5-Pound Vinyl-Coated Weight</td>
			<td>SPRI | Amazon</td>
			<td>N/A</td>
			<td>Color: (E) Dark Blue | 5-Pound. Appears on Amazon: Dumbbells Hand Weights Set of 2 - Vinyl Coated Exercise &#38; Fitness Dumbbell for Home Gym Equipment Workouts Strength Training Free Weights for Women, Men (1-10 Pound, 12, 15, 18, 20 lb), https://www.amazon.com/stores/SPRI/Weights/page/9D10835A-CFAB-4DA1-BEE9-AE993C6B5BC1</td>
		</tr>
		<tr>
			<td>SPRI 8-Pound Vinyl-Coated Weight</td>
			<td>SPRI | Amazon</td>
			<td>N/A</td>
			<td>Color: (H) Black |8-Pound. Appears on Amazon: Dumbbells Hand Weights Set of 2 - Vinyl Coated Exercise &#38; Fitness Dumbbell for Home Gym Equipment Workouts Strength Training Free Weights for Women, Men (1-10 Pound, 12, 15, 18, 20 lb), https://www.amazon.com/stores/SPRI/Weights/page/9D10835A-CFAB-4DA1-BEE9-AE993C6B5BC1</td>
		</tr>
	</tbody>
</table>

a randomized, sham-controlled trial of cranial electrical stimulation for fibromyalgia pain and physical function, using brain imaging biomarkers

Фибромиалгия — это хронический болевой синдром, который проявляется совокупностью широких симптомов, включая снижение физической функции, усталость, когнитивные нарушения и другие соматические жалобы. Доступные методы лечения часто недостаточны для лечения симптомов, при этом недостаточный контроль боли обычно приводит к использованию опиоидов для попыток лечения. Черепная электростимуляция (CES) является многообещающим нефармакологическим вариантом лечения болевых состояний, в котором используется импульсная стимуляция электрическим током для изменения функции мозга с помощью чрескожных электродов. Эти нейронные механизмы и применение CES для облегчения симптомов фибромиалгии требуют дальнейшего изучения.
В общей сложности 50 участников из Системы здравоохранения по делам ветеранов Атланты (VAHCS) с диагнозом фибромиалгия были включены в группу, а затем были рандомизированы в группу плацебо плюс стандартная терапия или активную группу CES плюс стандартная терапия. Исходные оценки были получены до начала лечения. Оба вмешательства проводились в течение 12 недель, а участники оценивались через 6 недель и 12 недель после начала лечения. Первичный исход заключался в том, наблюдались ли боль и функциональные улучшения при применении КЭИ. Кроме того, исходная и последующая магнитно-резонансная томография в состоянии покоя (rs-fcMRI) были получены в 6-недельном и 12-недельном временных точках для оценки клинического применения биомаркеров нейронных связей и лежащих в их основе нейронных ассоциаций, связанных с эффектами лечения.
Это рандомизированное плацебо-контролируемое исследование для определения эффективности КЭИ для уменьшения боли и функции при фибромиалгии и дальнейшей разработки рс-фМРТ в качестве клинического инструмента для оценки нейронных коррелятов и механизмов хронической боли и анальгетической реакции.

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.

В центре внимания автора: Методологии и достижения в исследованиях в области лечения хронической боли

Рандомизированное фиктивно контролируемое исследование черепной электростимуляции боли и физической функции при фибромиалгии с использованием биомаркеров визуализации мозга

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.

Что касается результатов набора, то участники в основном набирались путем рассылки писем о наборе и последующих телефонных звонков в соответствии с изложенными правилами системы здравоохранения штата Атланта. Исследовательская группа набрала в общей сложности 50 уч?...

Read this Scientific Article Protocol about Author Spotlight: Towards Biomarker Development Using Neuroimaging as a Tool to Enhance the Understanding of the Neural Basis of Pain at JoVE.com

Настоящее исследование представляет собой рандомизированное плацебо-контролируемое исследование для определения эффективности краниальной электростимуляции (CES) для уменьшения боли и функции при фибромиалгии и дальнейшей разработки магнитно-резонансной томографии с функциональными связями покоя (rs-fcMRI) в качестве клинического инструмента для оценки нейронных коррелятов и механизмов хронической боли и обезболивающей реакции.

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

Мы пытаемся решить две основные проблемы, связанные с исследованием боли. Во-первых, это потребность в неинвазивных, нефармакологических методах лечения, которые могут быть эффективно назначены людям, страдающим от хронической боли. Во-вторых, это разработка надежных биомаркеров, таких как нейровизуализация, которую мы используем для оценки боли при фибромиалгии и ответа на лечение.Разработка и доступ к многочисленным пакетам нейропрограммного обеспечения с открытым исходным кодом позволяет оптимизировать использование анализа данных нейровизуализации. Многие из этих инструментов, такие как fMRIPrep, позволяют исследователям, которые не знакомы с методами нейровизуализации, выполнять критически важные этапы предварительной обработки. Чтобы сохранить ослепление, мы не можем титровать эффект с помощью устройства, как это было бы в клинических условиях.Стимуляция, как правило, ниже порога восприятия, но мы можем недодозировать пациентов в группе нашего исследования, что приводит к меньшему размеру эффекта и разнице между группами. Электрическая стимуляция черепа является неинвазивной. Это низкий риск, и он достаточно доступен, чтобы участники могли самостоятельно управлять им в своих домашних условиях.Мы также можем извлечь показатели использования каждого из исследуемых устройств, чтобы правильно оценить соблюдение режима лечения. А МРТ функциональной связности в состоянии покоя позволяет нам оценить изменения в мозге, которые могут произойти в результате нашего лечения. Мы ожидаем, что наше исследование будет способствовать дальнейшему развитию биомаркеров с использованием нейровизуализации в качестве инструмента.Это способствует лучшему пониманию нейронной основы боли, и мы надеемся, что эти методы в конечном итоге будут использоваться для руководства клинической диагностикой и принятия решений для людей, страдающих от боли.

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Research

JoVE Journal

Medicine

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 disturbances, and other somatic complaints. Available therapies are often insufficient in treating symptoms, with inadequate pain control commonly leading to opioid usage for attempted management. Cranial electrical stimulation (CES) is a promising non-pharmacologic treatment option for pain conditions that uses pulsed electrical current stimulation to modify&#160;brain function via transcutaneous electrodes. These neural mechanisms and the applications of CES in fibromyalgia symptom relief require further exploration.
A total of 50 participants from the Atlanta Veterans Affairs Healthcare System (VAHCS) diagnosed with fibromyalgia were enrolled and then block-randomized into either a placebo plus standard therapy or active CES plus standard therapy group. Baseline assessments were obtained prior to the start of treatment. Both interventions occurred over 12 weeks, and participants were assessed at 6 weeks and 12 weeks after treatment initiation. The primary outcome investigated whether pain and functional improvements occur with the application of CES. Additionally, baseline and follow-up resting state functional connectivity magnetic resonance imaging (rs-fcMRI) were obtained at the 6-week and 12-week time points to assess for clinical applications of neural connectivity biomarkers and the underlying neural associations related to treatment effects.
This is a randomized, placebo-controlled trial to determine the efficacy of CES for improving pain and function in fibromyalgia and further develop rs-fcMRI as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

The current study is a randomized, placebo-controlled trial to determine the efficacy of cranial electrical stimulation (CES) for improving pain and function in fibromyalgia and further develop resting functional connectivity magnetic resonance imaging (rs-fcMRI) as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.