Name: Forfatter Spotlight: Metoder og fremskridt inden for forskning i kronisk smertebehandling
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

Forfatterne vil gerne anerkende støtten fra forskere ved Center for Visual and Neurocognitive Rehabilitation, herunder Dr. Bruce Crosson og Dr. Lisa Krishnamurthy, for deres input til arbejdet. Forfatterne takker også Grace Ingham for hendes uvurderlige hjælp i filmprocessen. Dette arbejde blev delvist støttet af United States Department of Veterans Affairs, Rehabilitation Research and Development Service Career Development Award IK2 RX003227 (Anna Woodbury) og Center Grant 5I50RX002358. Finansieringsyderen har ingen rolle i undersøgelsesdesign, dataindsamling, styring, analyse, fortolkning eller rapportering.

Undersøgelsen blev udført under godkendelse af Emory University (IRB 112768) og Atlanta VA Institutional Review Boards (1585632-2; Internt referencenummer: 003) samt Atlanta VA R&D COMMITTEE (BESTYRELSESREFERENCENUMMER: 3881). Alle forsøgspersoner gav deres informerede samtykke til inklusion, før de deltog i denne undersøgelse. For en visuel repræsentation af undersøgelsesprotokollens tidslinje, se figur 1).
<img alt="Figure...

Vurdering af effektiviteten af kraniel elektrisk stimulering ved fibromyalgi

Metoderne i den aktuelle undersøgelse giver ikke kun mulighed for en yderst effektiv behandlingsmodalitet for fibromyalgi, men også muligheden for at forbedre den diagnostiske proces for fibromyalgi fra det første tilfælde af dens smertesymptomprofil. Brug af både aktiv CES og falsk CES, hvor opdagelsen af typen af hvert enkelt udstyr var afhængig af serienumre og en separat nøgle, gjorde det muligt at blinde både forsøgspersoner og forskere indtil afslutningen af deltagelsen, hvorved den interne validitet blev ...

Af de mange eksisterende tilstande af kroniske smerter er fibromyalgi en af de mest notorisk vanskelige sygdomme at diagnosticere, klinisk vurdere og behandle. Fibromyalgi er et invaliderende kronisk smertesyndrom, der involverer kroniske udbredte smerter, nedsat fysisk funktion, træthed, psyko-emotionelle og søvnforstyrrelser og forskellige somatiske klager, der påvirker ca. 2-3% af den generelle befolkning i Amerika (ca. 8 millioner mennesker i USA) 1. Diagnosticering af sygdommen er stærkt afhængig af en patients forståelse af deres egen symptomprofil og smerteoplevelse, og uden den rette forståelse af sygdommen hos både kliniker og patient mister behandlingsmetoder betydelig effekt2. En bedre definition af fibromyalgiens oprindelse og indvirkning samt en pålidelig klinisk biomarkør til at vejlede fibromyalgidiagnose og behandling er nødvendig for bedst at betjene alle patienter.
Selv med en bekræftet diagnose vokser vanskelighederne med behandlingsprocessen kun. Som helhed påvirker kroniske smerter flere individer end hjertesygdomme, diabetes og kræft tilsammen. Den subjektive karakter af dens vurdering placerer den som en primær drivkraft for opioidepidemien, især i betragtning af vanskeligheden ved at skelne ufuldstændigt behandlet fysisk smerte fra stofmisbrug og stofsøgende adfærd3. I 2020 var der 91.799 dødsfald som følge af overdosis i USA (en stigning på 30 % i forhold til 2019), og opioider viste sig at være hovedårsagen til disse dødsfald (74,8 % af alle dødsfald som følge af overdosis i 2020)4. Der er således behov for ikke-farmakologiske alternativer til behandling af kroniske smerter og fibromyalgi for at bremse opioidepidemien, hvilket er særligt vigtigt i veteranbefolkningen, hvor risikoen for selvmord og opioidmisbrug er højere5. Ikke-farmakologiske og komplementære terapier anvendes derfor ofte som førstevalgsbehandlinger6.
Søgningen efter nye, effektive fibromyalgi-interventioner har ført mange forskere og klinikere til metoder til ikke-invasiv hjernestimulering, herunder kraniestimulering. Selvom de patofysiologiske mekanismer, der resulterer i udviklingen af sygdommen, ikke er endeligt bestemt, understøtter eksisterende beviser ideen om, at fibromyalgi er en lidelse i det autonome nervesystem dysfunktion og centrale (dvs. hjerne og rygmarv) smertebehandlingsmekanismer 7,8. Stimulering af visse områder af hjernen kan føre til forbedret funktion i disse områder af behandlingen. Gentagen transkraniel magnetisk stimulering (rTMS) og transkraniel jævnstrømsstimulering (tDCS) er blevet korreleret med reduktion af smerte, men er også blevet forbundet med irritation af hovedbunden, hovedpine og utilgængelighed uden for behandlingsfaciliteter9. Ikke-invasiv vagusnervestimulering (nVNS), som kan give neuromodulation gennem stimulering over huden i nakken eller på niveau med øret, har potentiale til behandling af kroniske smerter, og invasiv vagusnervestimulering (VNS) har vist sig at forbedre kroniske smertesymptomer10. Imidlertid er hverken invasiv eller ikke-invasiv VNS blevet tilstrækkeligt undersøgt i litteraturen eller fuldt valideret til brug i fibromyalgibehandling 11,12,13,14.
Kranial elektrisk stimulation (CES) er en ikke-farmakologisk, ikke-invasiv hjernestimuleringsbehandling, der består af pulserende, vekselstrøm (mindre end 0,5 mA) påført via transkutane elektroder placeret på øreflipperne15. Det er bemærkelsesværdigt tilgængeligt og kan leveres via bærbare enheder, der bruges af patienter i deres egne opholdsrum. I sammenligning med andre kraniestimuleringsmetoder øger den ikke-invasive karakter og bekvemmeligheden ved patientens selvanvendelse derhjemme potentialet for CES som en gavnlig mulighed for udbredt fibromyalgi-behandlingsbrug og selvbehandling af smerter. Det er blevet godkendt af US Food and Drug Administration (FDA) som en behandling for søvnløshed, depression, angst og smerte15.
Den aktuelle undersøgelse evaluerer effektiviteten af CES som en fibromyalgi-behandlingsmodalitet ved at sammenligne aktiv CES (administreret af en ægte undersøgelsesenhed) versus falsk CES (administreret af en falsk undersøgelsesenhed). Der er nogle foreløbige beviser, der understøtter brugen af CES til behandling af smertetilstande som fibromyalgi16,17. En undersøgelse fra 2001 af 60 deltagere, der var randomiseret til aktiv eller falsk CES i 3 ugers daglige 60 minutters sessioner, afslørede en 28% forbedring i tender point-score, 27% forbedring i generelle smertescore og ingen placeboeffekt18. CES er ikke blevet evalueret i en veteranpopulation, og det er heller ikke blevet tilstrækkeligt evalueret hos mænd med fibromyalgi. En Veterans Affairs (VA)-finansieret systematisk gennemgang af CES offentliggjort i 2018 konkluderede, at beviser er utilstrækkelige til, at CES kan have klinisk vigtige virkninger på fibromyalgi, da de fleste forsøg havde små stikprøvestørrelser, korte varigheder og en høj risiko for bias på grund af utilstrækkelig blinding. Gennemgangen tyder dog på, at CES ikke forårsager alvorlige bivirkninger, og der er lav styrke beviser, der tyder på beskedne fordele hos patienter med angst og depression19. Derfor er yderligere forskning berettiget vedrørende brugen af denne FDA-godkendte lavrisikoenhed, især ved fibromyalgi.
For fuldt ud at evaluere effektiviteten vurderede forskerne fysisk kondition sammen med neurale biomarkører og smerteoplevelse. Formålet med behandling af kroniske smertetilstande er at forbedre den fysiske funktion. Fibromyalgi er konsekvent korreleret med negative effekter på både fysisk funktion og patienters opfattelse af egne fysiske evner20. Tidligere undersøgelser har brugt simple fysiske konditionsvurderinger til at bestemme udholdenhed og mobilitet, såsom 6 Minute Walk Test (6MWT)20,21, Five Time Sit to Stand (5TSTS)20 og forskellige målinger af bæreevne og styrke i forbindelse med daglige aktiviteter22. For at tage højde for standardforanstaltninger og samtidig afbøde mængden af anstrengende aktivitet, der kræves lige før en MR-scanning, brugte undersøgelsesholdet 30-sekunders stolesædetest som et mål for udholdenhed og mobilitet og både bicepscurls og en håndgrebstest som mål for styrke23. De bevægelser, der kræves i hver af disse vurderinger, er meget almindelige i hverdagsaktiviteter, så det er et klart mål for, hvordan folk fungerer fysisk i deres daglige liv, både med og uden behandling.
Selv med subjektive smertevurderinger og fysiske funktionsmålinger af effektivitet er mekanismerne i CES ikke fuldt ud forstået. Tidligere neuroimaging-undersøgelser har søgt en bedre forståelse ved at udforske den direkte effekt af CES på netværksforbindelse i hjernen. Feusner et al.24 fandt, at CES er forbundet med kortikal deaktivering for 0,5 Hz og 100 μA stimulering af bilaterale frontale, parietale og posteriore midtlinjeregioner og postulerede, at stimuleringsfrekvensen kan have mere effekt end nuværende intensitet i forhold til kortikal deaktivering. Deres gruppe fandt betydelige effekter på nogle, men ikke alle noder i standardtilstandsnetværket (DMN). Forfatterne foreslår, at baseret på disse data kan CES påvirke hviletilstandens funktionelle forbindelse. Fibromyalgi og andre kroniske smertetilstande har vist sig at påvirke iboende hjerneforbindelse i regioner forbundet med smerte og opfattelse25,26, så behandlinger, der ændrer funktionel forbindelse som reaktion, kan vise sig at være både gavnlige og effektive. Yderligere udforskning af de langsigtede virkninger af daglig behandling i forhold til klinisk forbedring, samt hvordan afdød aktivering i hjernen relaterer til tidligere observerede fald i elektroencefalogramfrekvenser, er nødvendig for yderligere at forstå den terapeutiske virkningsmekanisme27.
Hviletilstand funktionel forbindelse magnetisk resonansbilleddannelse (rs-fcMRI) er den neuroimaging-metode, der giver mulighed for observation af disse funktionelle forbindelsesændringer. Longitudinel hviletilstand fMRI giver klinikere og forskere mulighed for at etablere en baseline for hviletilstandsforbindelse og spore ændringer over tid som reaktion på CES-behandlingsmetoder. Det hjælper også med at bestemme, hvordan ændringer i funktionel forbindelse er korreleret med forskelle i oplevelsen af smerte. Indledende undersøgelser af neuroimaging for fibromyalgi brugte positronemissionstomografi (PET) og enkeltfotonemission computertomografi (SPECT) til at undersøge hjernen, men der er problemer med begge teknikker i denne henseende: SPECT har en lavere opløsning end PET, og PET-scanninger er invasive, hvilket ikke er at foretrække for patienter, der oplever kroniske smerter. Funktionelle magnetisk resonansbilleddannelse (fMRI) scanninger har større opløsning end SPECT, men de undersøger hjerneaktivitet som reaktion på patienternes specifikke handlinger eller opfattelser af stimuli28. Det er rs-fcMRI-scanninger, der kan skitsere funktionel forbindelse mellem områder af hjernen og muligvis være i stand til at bestemme, hvor og hvordan fibromyalgi eksisterer samt de bedste behandlingsmetoder28.
Evaluering af effektiviteten af ikke-farmakologiske behandlinger for smertetilstande som fibromyalgi er af største betydning både i den nuværende situation for opioidepidemien og for at undersøge kroniske smerter som en risikofaktor for selvmord29,30, hvilket er væsentligt øget blandt veteranbefolkningen. Derudover er manglen på tilstrækkelige kliniske biomarkører for smerte et anerkendt videnshul. Brug af en kombination af adfærdsmæssige målinger og neuroimaging på flere tidspunkter til at vurdere behandlingsrespons er en ny tilgang til fibromyalgievaluering, ligesom brugen af aurikulær CES som behandling.
Protokollen har til formål at afhjælpe hullet i fibromyalgiforskning ved at undersøge virkningerne af CES på smerte og fysiske funktionsresultater og evaluere neuroimaging som et værktøj til prædiktive og responsbiomarkører relateret til de kliniske resultater af CES-terapi31.

<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

Fibromyalgi er et kronisk smertesyndrom, der præsenterer sig med en konstellation af brede symptomer, herunder nedsat fysisk funktion, træthed, kognitive forstyrrelser og andre somatiske klager. Tilgængelige behandlinger er ofte utilstrækkelige til behandling af symptomer, hvor utilstrækkelig smertekontrol ofte fører til opioidbrug til forsøg på behandling. Kranial elektrisk stimulering (CES) er en lovende ikke-farmakologisk behandlingsmulighed for smertetilstande, der bruger pulserende elektrisk strømstimulering til at ændre hjernens funktion via transkutane elektroder. Disse neurale mekanismer og anvendelserne af CES i fibromyalgi-symptomlindring kræver yderligere udforskning.
I alt 50 deltagere fra Atlanta Veterans Affairs Healthcare System (VAHCS) diagnosticeret med fibromyalgi blev tilmeldt og derefter blokrandomiseret til enten placebo plus standardterapi eller aktiv CES plus standardterapigruppe. Baseline-vurderinger blev foretaget før behandlingsstart. Begge interventioner fandt sted over 12 uger, og deltagerne blev vurderet 6 uger og 12 uger efter behandlingsstart. Det primære resultat undersøgte, om der opstår smerter og funktionelle forbedringer ved anvendelse af CES. Derudover blev baseline og opfølgning hviletilstand funktionel forbindelse magnetisk resonansbilleddannelse (rs-fcMRI) opnået ved 6-ugers og 12-ugers tidspunkterne for at vurdere for kliniske anvendelser af neurale forbindelsesbiomarkører og de underliggende neurale associationer relateret til behandlingseffekter.
Dette er et randomiseret, placebokontrolleret forsøg for at bestemme effektiviteten af CES til forbedring af smerte og funktion ved fibromyalgi og videreudvikle rs-fcMRI som et klinisk værktøj til at vurdere de neurale korrelater og mekanismer for kronisk smerte og smertestillende respons.

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.

Forfatter Spotlight: Metoder og fremskridt inden for forskning i kronisk smertebehandling

Et randomiseret, sham-kontrolleret forsøg med kraniel elektrisk stimulering til fibromyalgismerter og fysisk funktion ved hjælp af hjernebilleddannelsesbiomarkører

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.

Med hensyn til rekrutteringsresultater blev deltagerne primært rekrutteret via mailing af rekrutteringsbreve og opfølgende telefonopkald baseret på de skitserede regler for Atlanta VA Healthcare System. Undersøgelsesholdet rekrutterede i alt 50 deltagere, hvilket beviser effektiviteten af de metoder, der blev brugt til at nå rekrutteringsmålet (se figur 2). Brugen af de nye diagnostiske kriterier for klinisk fibromyalgi gjorde det muligt for undersøgel...

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

Den aktuelle undersøgelse er et randomiseret, placebokontrolleret forsøg for at bestemme effektiviteten af kraniel elektrisk stimulering (CES) til forbedring af smerte og funktion ved fibromyalgi og videreudvikle hvilefunktionel forbindelse magnetisk resonansbilleddannelse (rs-fcMRI) som et klinisk værktøj til at vurdere de neurale korrelater og mekanismer for kronisk smerte og smertestillende respons.

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

Vi forsøger at løse to hovedproblemer med hensyn til smerteforskning. Den første er behovet for ikke-invasive, ikke-farmakologiske terapier, der effektivt kan administreres til personer, der lider af kroniske smerter. Den anden er udviklingen af pålidelige biomarkører, såsom neuroimaging, som vi bruger med henblik på at vurdere både fibromyalgismerter og behandlingsrespons.Udviklingen og adgangen til flere open source neuro-softwarepakker giver mulighed for strømlinet brug af neuroimaging-dataanalyse. Mange af disse værktøjer, såsom fMRIPrep, giver forskere, der ikke er bekendt med neuroimaging-praksis, mulighed for at gennemføre kritiske forbehandlingstrin. For at opretholde blinding er vi ikke i stand til at titrere for effekt ved hjælp af enheden, som vi ville gøre i kliniske omgivelser.Stimulationen er typisk under den perceptuelle tærskel, men vi kan underdosere individer i vores studies behandlingsgruppe, hvilket medfører en mindre effektstørrelse og forskel mellem grupperne. Kraniel elektrisk stimulering er ikke-invasiv. Det er lav risiko, og det er tilgængeligt nok til at blive selvadministreret af deltagerne i deres egne hjemmemiljøer.Vi kan også udtrække brugshastigheder fra hver af forskningsenhederne for korrekt at evaluere overholdelsen af behandlingen. Og hviletilstandens funktionelle forbindelse MR giver os mulighed for at vurdere ændringer i hjernen, der kan opstå som følge af vores behandling. Vi forventer, at vores forskning yderligere vil guide udviklingen af biomarkører ved hjælp af neuroimaging som et værktøj.Dette bidrager til en bedre forståelse af det neurale grundlag for smerte, og vores håb er, at disse teknikker i sidste ende vil blive brugt til at vejlede klinisk diagnose og beslutningstagning for personer, der lider af smerte.

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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.