A review of burn symptoms and potential novel neural targets for non-invasive brain stimulation for treatment of burn sequelae.

Review

A

review

of

burn

symptoms

and

potential

novel

neural

targets

for

non-invasive

brain

stimulation

for

treatment

of

burn

sequelae

Aurore

Thibaut

,

Vivian

L.

Shie

,

Colleen

M.

Ryan

,

Ross

Zafonte

,

Emily

A.

Ohrtman

,

Jeffrey

C.

Schneider

*

_,

_Felipe

_Fregni

_*

a

SpauldingRehabilitationHospital,HarvardMedicalSchool,Boston,MA,UnitedStates

b_{GIGA-InstituteandNeurologyDepartment,UniversityofLiègeandUniversityHospitalofLiège,Liège,Belgium} c_{MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,MA,UnitedStates}

d_{ShrinersHospitalsforChildren-Boston,Boston,MA,UnitedStates}

e_{MassachusettsGeneralHospitalandBrighamandWomen'sHospital,Boston,UnitedStates}

a

b

s

t

r

a

c

t

Burnsurvivorsexperiencemyriadassociatedsymptomssuchaspain,pruritus,fatigue,impaired motorstrength,post-traumaticstress,depression,anxiety,andsleepdisturbance.Manyofthese symptomsarecommonandremainchronic,despitecurrentstandardofcare.Onepotentialnovel interventiontotargetthesepostburnsymptomsistranscranialdirectcurrentstimulation(tDCS). tDCSisanon-invasivebrainstimulation(NIBS)techniquethatmodulatesneuralexcitabilityofa specifictargetorneuralnetwork.Theaimofthisworkistoreviewtheneuralcircuitsofthe aforementionedclinicalsequelaeassociatedwithburninjuriesandtoprovideascientificrationale forspecificNIBStargetsthatcanpotentiallytreattheseconditions.Weranasystematicreview, followingthePRISMAstatement,oftDCSeffectsonburnsymptoms.Onlythreestudiesmatched ourcriteria.Onewasafeasibilitystudyassessingcorticalplasticityinchronicneuropathicpain followingburninjury,onelookedattheeffectsoftDCStoreducepainanxietyduringburnwound care,andoneassessedtheeffectsoftDCStomanagepainandpruritusinburnsurvivors.Current literatureonNIBSinburnremainslimited,onlyafewtrialshavebeenconducted.Basedonour reviewandresultsinotherpopulationssufferingfromsimilarsymptomsaspatientswithburn injuries,threemainareaswereselected:theprefrontalregion,theparietalareaandthemotor cortex. Based on the importance of the prefrontal cortex in the emotional component of pain and its implicationinvariouspsychosocialsymptoms,targetingthisregionmayrepresentthemost promisingtarget.Ourreviewoftheneuralcircuitryinvolvedinpostburnsymptomsandsuggested targetedareasforstimulationprovideaspringboardforfuturestudyinitiatives.

©2020PublishedbyElsevierLtd.

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Non-invasivebrainstimulation Transcranialdirectcurrent stimulation

Pain Pruritus

Psychosocialdisorders

Abbreviations:M1,primarymotorcortex;NIBS,non-invasivebrainstimulation;PTSD,post-traumaticstressdisorder;tDCS,transcranial directcurrentstimulation;tACS,transcranialalternatingcurrentstimulation.

* Correspondingauthorsat:Spaulding-LabuschagneNeuromodulationCenter,SpauldingRehabilitationHospital,79/96ThirteenthSt., Charlestown,MA02129,UnitedStates.

E-mailaddresses:jcschneider@partners.org(J.C. Schneider),Fregni.Felipe@mgh.harvard.edu(F.Fregni).

1

Co-seniorauthors.

https://doi.org/10.1016/j.burns.2020.06.005

0305-4179/©2020PublishedbyElsevierLtd.

Available

online

at

www.sciencedirect.com

ScienceDirect

Contents

1. Introduction ... 00

2. Searchmethodology ... 00

3. Results ... 00

3.1. Burnsymptom1:pain ... 00

3.2. Burnsymptom2:pruritus ... 00

3.3. Burnsymptom3:psychosocialdisorders ... 00

3.4. Burnsymptom4:sleepdisturbance ... 00

3.5. Burnsymptom5:fatigue ... 00

3.6. Burnsymptom6:impairedmotorstrength ... 00

4. Discussion ... 00 5. Conclusion ... 00 Funding ... 00 Conflictofinterest ... 00 Acknowledgments ... 00 References ... 00

1.

Introduction

Burn survivors experience myriad associated symptoms suchas pain, pruritus, fatigue,impaired motor strength, post-traumatic stress, depression, anxiety, and sleep

disturbance [1]. Many of these symptoms are common

andremainchronic,despitecurrentstandardofcare.Given these persistent symptoms, there is a need for novel targeted interventions. Burn injuries often have lasting ramifications on survivor physicaland mental health.In regards to mental health, symptoms of post-traumatic stress,depression,andanxietyhavebeenobserved persist-ingafterinjury,creatinglastingpsychosocialconsequences withimpactonsocialfunctioninganddisability[2].Abouta thirdofburnsurvivorsreportmoderatetosevere psycho-logicalorsocialdifficulties[3,4]whichdramaticallyimpact returntowork,socialintegration,andconsequentlyquality oflife[5].Similarly,symptomsofpainandprurituscause equally concerning sequelae for burn patients, affecting sleep [6], daily activities [7], and quality of life [8]. The prevalence and chronicity of these post burn symptoms thereforeunderscorestheneedtoidentifyeffective thera-pies to ameliorate these symptoms and ensuing effects. Treatmentofthesechronicsymptomswouldthushavean impactonmanypatients’qualityoflife.

Onepotentialnovelinterventiontotargetthesepostburn symptomsislowintensitytranscranialelectricalstimulation (tES) [9]. tES is a non-invasive brain stimulation (NIBS) technique that modulates neural excitability of a specific targetorneuralnetwork.Moststudiesusedtranscranialdirect current stimulation(tDCS),which modulatescortical excit-abilitythroughtheapplicationofaweakelectricalcurrentin the form ofdirect current brain polarization [10]. Another technique is transcranial alternating current stimulation (tACS),whichissimilartotDCSbutitoscillatesasinusoidal current ataspecific frequency tointeractwith thebrain's naturalcorticaloscillations[11].Inthecurrentliterature,tES has been shown to reduce pain, improve motor function, enhance cognitiveabilities and treatdepression invarious

populations.However,thereisapaucityofliteratureinregards totESuseonpost-burnsequelae.

Theaimofthisworkistoreviewtheneuralcircuitsofthe aforementionedclinicalsequelaeassociatedwithburn inju-ries and to provide a scientific rationale for specific non-invasivebrainstimulationtargetsthatpotentiallytreatthese conditions.Thisreviewfocusesontheadultpopulationonlyas the issuesassociatedwithgrowth anddevelopment ofthe braininthepediatricpopulationareextremelycomplex.We reviewthemechanismsinwhichtESmodulatestheseneural circuits and their related behaviors in various patient populations as wellas the current state ofthe science on tDCS to improve burn related symptoms. Given that the currentliteratureislimitedintheburnpopulation,thisreview aimstoprovideamodel-drivenapproachforpotentialneural targetstotreatburnassociatedsymptomsthatwillopenareas offutureinquiryinthefieldofburncare.

2.

Search

methodology

We searchedon PubMedusingthefollowingsearchterms: “burn”andtDCS“transcranialdirectcurrentstimulation”or “neuromodulation”or“non-invasivebrainstimulation”.

We includedstudiesinvestigatingtheeffectsoftDCSon burn related symptoms (i.e., pain, pruritus, psychosocial disorders, sleep disturbance, fatigue and impaired motor strength)inburnsurvivors.Weincludedcase-reports, open-label studies and randomized clinical trials. We excluded studiesnotwritteninEnglishorFrench,reviewsoropinion papers,conferenceabstracts,andthosenotusingtEStotreat burnrelatedsymptomsinburnsurvivors.

WefollowedthePRISMAstatementtoevaluatethearticles wefoundandreportedtheresults.

3.

Results

31 studies were found; only three matched our inclusion criteria(seeflowchart)[12 14].

Pleasecitethisarticleinpressas:A.Thibaut,etal.,Areviewofburnsymptomsandpotentialnovelneuraltargetsfornon-invasive brainstimulationfortreatmentofburnsequelae,Burns(2020),https://doi.org/10.1016/j.burns.2020.06.005

TwostudieshaveinvestigatedtheeffectsoftDCSonpain whenappliedoverthemotorcortex(M1).Afirstpilotstudy including 4patients withburninjury and chronic pruritus showedthatasinglesessionofactiveanodaltDCSoverthe primarymotorcortexinducedadecreaseincortical excitabil-ity(i.e.,decreasedalphaactivityintheoccipitalareaandlow beta activityin the frontalarea) [12]. Another studyusing similarparameters(anodaltDCSoverM1)evaluatedtheeffects of10 sessions oftDCS on pain and itchlevels in31 burn survivors[14]butactivetDCSdidnotinfluencepainoritch levels.Finally, onerandomizedcontroltrial on 60patients testedtheeffectsofasinglesessionofcathodal(orsham)tDCS overthesensorycortexaimingtoreduceself-reportedpain andanxiety[13].Painandanxietyscoresweresignificantly lowerintheactivetDCSgroupcomparedwiththeshamgroup.

3.1. Burnsymptom1:pain

Painmanagementafterburninjuryiscriticalsinceitmayhave an important impact on burn recovery and quality of life

[15,16].Almosthalfofburnsurvivorsstillpresentwithpain

yearsaftertheincident[17].Further,two-thirdsofsurvivors reportthatpaininterfereswiththeirrehabilitation,andabout halfreportthatpaininterfereswiththeirdailylives[17],thus underscoring the significant impact of pain on patients’ qualityoflife.Painisthereforeacriticalelementtoconsider at the acute, rehabilitative, and chronic phases of burn

recovery. In the acute stage, following burn injury, some nerveendingsareundamaged,resultingintheexperienceof significantpainatthesiteoftheinjury.Conversely,ifthenerve endingisentirelydestroyed,excisedorsignificantlydamaged, theinjuredareaisinsensate,anddoesnotexperiencepain. Burn survivors mayalsosuffer fromneuropathic-likepain, whichcanbecomechronic[18].Chronicpainconditionsare characterizedbyseveralmaladaptiveneuralchanges,suchas centralsensitization[19].

Acutepainperceptionbeginswithactivationofperipheral nociceptorsandviathespinothalamictractthatreachesthe thalamus and the somatosensory cortex. In acute pain, processes areinplaceto preventtissuedamage. However, this pain may become chronic when maladaptive neural changesoccur,includingcentralsensitization[20].Theneural mechanismsofcentralsensitizationinchronicneuropathic conditionsareonlypartiallyunderstood [21,22]. Bothacute andchronicpainprocessesaremultidimensional,comprising of nociceptive, cognitive, emotional, and affective compo-nents,eachoftheserelatingtospecificbrainstructures[23]. Corticalandsubcorticalbrainareashavebeeninvestigatedin previousstudies and associatedwitha commonformation called the pain matrix [23,24]. This large neural network consistsoftheprimaryandsecondarysomatosensorycortex, the prefrontal lobe, anterior cingulate cortex, amygdala, insula, andthethalamus.Besidesthesomatosensory areas activated during pain, neuroimaging studies have also

demonstratedthatthedorsolateralprefrontalcortex, thala-musandmedialprefrontalcortexplayacrucialroleinpain modulationaswell[25,26].Inaddition,theanteriorcingulate cortex and the insula, part ofthe limbic system, are also importantfortheemotionalaspectsofpain[27](Fig.1).

tDCSapplied overthe sensorimotor cortexmayhelp in normalizingpainprocessesandmanagingneuropathicpain symptoms. Manystudies have demonstratedthe analgesic effectsoftDCSappliedoverthesomatosensorycortex,aswell asovertheprefrontalcortextoreducepainlevelinvarious conditions, such as fibromyalgia, osteoarthritis or chronic visceralpain(forareviewsee[28]).Inhealthysubjects,tDCS hasbeenshowntomodulatethepainthresholdand condi-tionedpainmodulation[29],amarkeroftheendogenouspain inhibitorysystem, whichisaltered inpatientswith neuro-pathic pain [30]. Given that burn injury may result inthe developmentofchronicneuropathicpainduetocentralneural changes associatedwithsensory deafferentation,tDCS ap-pliedoverthesensorimotorcortexmayinduceadecreasein maladaptiveplasticityandthereforereducepaininpatients withburninjuries.Therationaleformotorcortexstimulation istoenhancethalamocorticalconnectivityandthus compen-sateforsomeofthelostsensoryafferencethatisobservedwith severeburninjury[31].Infact,thegoalistoenhanceactivityof primarymotorcortexwithanodaltDCS.

Inthecurrentliteratureofburninjuryonlytwostudieshave investigatedtheeffectsoftDCSonpainwhenappliedoverthe motorcortex(M1).Afirstpilotstudyincluding4patientswith burninjuryandchronicpruritusshowedthatasinglesession ofactiveanodaltDCSovertheprimarymotorcortexinduceda decreaseincorticalexcitability(i.e.,decreasedalphaactivityin theoccipitalareaandlowbetaactivityinthefrontalarea)[12]. Anotherstudyusingsimilarparameters(anodaltDCSoverM1) evaluatedtheeffectsof10sessionsoftDCSonpainanditch levelsin31patients[14].However,inthisstudy,activetDCS failedtoreducepainoritchintensitiesattheendofthe10 sessionsandatfollow-up.Themainreasonislikelybecause thesubjectsinsuchstudyhadmorepruritusthanpain[14].

AthirdstudytestedtheeffectoftDCSonpainandanxiety duringburnwoundcareinacutepatients[13].Theauthors foundthat asinglecathodaltDCSsessionappliedoverthe sensorycortexinducedasignificantreductionofabout10%of anxietyrelatedtopain,comparedtotheshamgroup.

Giventhelimitedliteratureonthistopic,furtherstudiesare meritedtoinvestigatethepotentialtherapeuticbenefitsofthis modalityonpost-burnpain.Wealsosuggestthatsuchstudies should includesubjectswithtruly neuropathicpain asthe maincomponentofpain.

3.2. Burnsymptom2:pruritus

Pruritus is a commonly reported symptom among burn

survivors affectingas manyas 87% ofsurvivors 3months post-injuryandstill67%at24monthspost-injury[32].Factors foundtobepredictorsofitchincludedeepdermalinjury, post-traumaticstresssymptoms,femalegender,totalburnsurface area >40%, and injuries requiring >3 weeks to heal [32]. Further,post-burnpruritushasbeendemonstratedto signifi-cantlyimpactsurvivorqualityoflife,affectingsleep,activities ofdailyliving,andpsychosocialhealth[6].Asmanyas94%of survivors with chronic pruritus in a cross-sectional study describeditasunbearableandasmanyas86%ofsurvivors withacuteitchdescribeditasunbearableaswell[6].

Theprimarymechanismofitchinvolvesmediationofthe A-deltaandC-nociceptors[33]inthetoplayersoftheskin[34]

withactivationoftheprimarysomatosensorycortex,located inthepost-centralsulcusandthesecondarysomatosensory cortex, located in the upper lateral sulcus [35]. Once a pruritogenicagentinstigatestheitchmechanism, unmyelin-atedCfibersactivateandrelaythesensationofitchtothebrain

[33,36].Inaddition,itishypothesizedthatperipheral

sensiti-zationdecreasestheactivationthresholdandthusincreases the activityof itch-relatedreceptors and nerve fibers [36]. Centralsensitization,however,occursinthespinalcordand brain,andcausesnon-pruriticstimulitobepresentedinstead asitch,thusincreasingandexacerbatingthesymptomologyof itch [36]. Neuropathic itch, however, may result from increasedperipheralfiringorimpairedcentralinhibitionof neuronsinvolvedintheitchneuralpathway[37]whichmaybe relatedtoacompensatorymechanism.Patientswithchronic

itch have been noted with developed changes in the

excitabilityandorganizationintheirbrains[34].

Despite thefrequencyofreportedpruritusamong survi-vors,themodulationofthissymptomwithtDCSisnotwell investigatedinliteraturethusfar.ItishypothesizedthattDCS Fig. 1 – Afferent pain pathways. Nociception information

from the spinal cord reach the thalamus, parabrachial nucleus (PB),and the peridaqueducal grey nucleus (PAG). Fromthethalamus,nociceptioninformationisprojectedto theinsula,anteriorcingulatecortex(ACC),primary somato-sensorycortex (S1), and secondarysomatosensory cortex (S2).FromtheACC,theprefrontalcortex(PFC)willalsobe activated.WhereasfromthePB,informationwillreachthe amygdala(AMY)andisthenprojectedtothebasalganglia (BG).Corticaltargetstomodulatepainperceptionvia non-invasive brain stimulation are enclosed within the blue circles.M1representthe primarymotorcortex,preferably selectedasatarget.*thestimulatedregionoverlapsM1and S1.Adaptedfrom[27].

canreducesymptomsofpruritusbymodulatingpathwaysof neuronalfiringandaffectingneuralexcitability[38,39].The neuralpathwayofitchhasbeennotedtobecloselyassociated withthatofpain,specificallywithoverlapinpain-processing networks[34].Correspondingly,tDCSmodulatespain proc-essingpathwaysincludingtheperiacqueductalgrayarea,with evidenceofitchrelief[34,35].However,differencesinthetwo pathwaysremain.Whilecloselyrelated,chronicpain seem-ingly involves more extensive changes in neuroplasticity compared to chronic itch, thus resulting in decreased receptivenesstotDCSstimulationcomparedtoitch[34]. In addition,brainareasinvolvedinpruritusinvolveactivationof thethalamus,somatosensorycortex,parietalcortex, motor areas(primary,supplementary,premotorcortex).However,in differentiationtopain,thesecondarysomatosensorycortexis notactivatedwithitchsymptoms[40].

Inastudyonhealthysubjectsandhistamineinduceditch sensation,bi-hemispherictDCShasbeenmoreeffectivethan uni-hemispherictDCSforsymptomalleviation[41].Inacase reportbyKnotkovaetal.(2013),apatientwithchronicpruritus wasadministered20minutesoftDCSfor5dayswithresultant reductioninpruritusfor3months[34].

Inthesettingofburninjuryrelateditch,astudynotedthat activetDCSoverM1wasineffectiveintreatingitchreportedby burninjurypatientswhiletheshamconditiontDCSeffectively decreasedsymptomstwoweeksafterstimulation[14].tDCS increasesthesensorythreshold,asshowninhealthysubjects

[29]andmaythusdecreasetheresponsetoperipheralsensory afference of itch, leading to such effects [14]. In fact, we hypothesizedinthatstudythattDCSforchronicpainwouldbe differentthantDCSforchronicpruritus.Inthelattercase,an inhibitorytDCSmaybeeffective.Currently,nootherstudies have investigated the use oftDCS inalleviating post burn pruritus,orinotherpopulationsofpatients.Therefore,given thelackofliteratureinregardstoburnrelateditchandtDCS, furtherinvestigationismeritedonthetopic.

3.3. Burnsymptom3:psychosocialdisorders

Psychosocial disorders encompass, amongothers, anxiety, depressionandpost-traumaticstressdisorder(PTSD).Anxiety referstofeelingsofexcessivefear,worry,anduneasecaused byexternalor internalpotentialthreats[42]lastinggreater than6months[43].Depressionischaracterizedbylowmood ofteninconcordancewithlowself-esteem,lossofinterestin normallyenjoyableactivities,andlowenergyforatleasttwo weeks[44].Finally,PTSDisdefinedasamentaldisordercaused ortriggered byexposureto eitherdeath, seriousinjury,or sexual violence [43]. Symptoms may include disturbing thoughts,feelings,or dreamsrelatedtotheevents, mental orphysicaldistresstotrauma-relatedcues,andattemptsto avoidtrauma-relatedcues[45].

Following a burn injury, rates of depression are high, reportedupto10 23%at1yearpost-injury[46].Somefactors, suchasseverityofpain,havebeenshowntobeapredictorof suicidalideation[47].Therefore,painmanagementmayhelp manage depression and reduction of suicidal ideation. Similarly,the prevalenceofPTSDin burnsurvivorscan be ashighas40%at6monthsandupto45%at12months post-injury[2].Mainsymptomsreportedbysurvivorsincludesleep

disturbances, recollections of the injury and avoidance of thoughts orfeelings associatedwiththe burn anddistress whenremindedoftheburn.

StudieshavereportedhighratesofPTSDinburnsurvivors rangingfrom20%to69%[48 50].Mainsymptomscompriseof sleepdisturbances,recollectionsoftheinjuryandavoidanceof thoughts orfeelings associatedwiththe burn anddistress when reminded of the burn [51]. The high incidence and severity ofPTSDhavebeenassociatedwithextensive post-burn scarring,female gender,largeburnsurface area, pre-traumaticdepressivebehaviors,lowpsychologicalresilience, andinadequatesocialsupport[49].

The prefrontal area, similar as for other psychosocial dysregulation pathologies, playsa critical role.Indeed, the neuralcorrelatesofthesepsychiatricdisorders,neuroimaging andlesionstudieshaveidentifiedthemedialprefrontalcortex (mPFC)asoneofthemainstructuresinvolved[52 54].More specifically,PTSD isthoughttobelinkedtoadysregulated neurocircuit that mainlyinvolves the amygdala,prefrontal regions,andhippocampus.Arecentmeta-analysisof trans-cranialmagneticstimulation(TMS)onthemPFCinpsychiatric disordersconfirmstheinvolvementofthiskeystructureinthe managementofsuchsymptoms[55].

tDCSuseinmanagementofdepressivesymptomshasbeen widely studied. Regarding the most efficient target, tDCS studiesfocusingontheprefrontalregionhaveshowntoreduce depressionsymptomsinmultiplestudies[56].Themost well-knowntrialistheELECTnon-inferioritytrialpublishedin2017

[57]inwhichtheanodeandcathodewereplacedontheleft andrightdorsolateralprefrontalcortexesofparticipantsfora total of 22 sessions. This study demonstrated the non-inferiorityoftDCSascomparedtoescitalopramandthatboth escitalopramandtDCSweresuperiortoplaceboinreducing depression[57].

From a therapeutic perspective, it is hypothesized that tDCStreatmentovertheprefrontalareasmayhelp manage-mentofexecutivecontroloffearresponsesandthus,reduce PTSD symptoms. In this context, tDCS applied over the prefrontalareahasbeeninvestigatedforvariouspsychiatric

disorders including reduction of PTSD symptoms with

promisingresultsinveteranswithPTSD[58,59].BesidesPTSD, tDCShasalsobeendemonstratedtoreducestresslevelswhen appliedovertheprefrontalregion(i.e.,rightmedial-prefrontal cortex[60]).Anincreaseincerebralbloodflowwasobservedin therightmedial-prefrontalcortexandintheamygdalaafter 20minutesofanodaltDCS.Theseresultsdemonstratedthat application oftDCS overthe prefrontal cortex mayreduce stressandPTSDsymptomsinpatientswithburninjuries.

FordepressionandPTSDnotrelatedtoaburninjury(e.g.,in veterans),theprefrontalareamaybethebestregiontotarget for treatment. No clinical trial, or open-label studies have testedthe effectsofprefrontaltDCSonthesesymptomsin patientswithburninjuries.Followingaprotocollookingatthe effect of M1-tDCS on pain and itch level, the injury's psychosocialimpactwasalsomeasured(seesupplementary material). Thedatademonstrates that tDCS, whenapplied overM1didnotinduceasignificantimprovementonimpactof event,depression,anxiety,orsleep.Itmaybehypothesized that, if pain and/or itch levels would have been reduced following M1-tDCS [14], an impact on the associated

psychiatricsymptomsmayhavebeenobservedviaanindirect pathway.However,asneitherimprovementofpainnoritch wasobservedinthisstudy,itmayexplainwhynoreductionof depression, PTSD or anxiety was found and targeting the prefrontal area may induce stronger effects as for other populations.

Indeed,tDCSappliedovertheprefrontalregionhasbeen showntoreducedepression[61]andPTSDsymptoms[62]in patientssufferingfromthesepathologies.

3.4. Burnsymptom4:sleepdisturbance

Sleep disturbances encompass disorders of initiating and maintainingsleep,excessivesomnolence,sleep wake sched-uleperturbation,andanydysfunctionsassociatedwithsleep, sleepstages,orpartialarousals[63].Sleepdisturbancecanbe duetotraumaticexperience,psychiatricdisordersor neuro-logicaldiseases.Thoughsleepaffectsasignificantproportion ofthepopulation,littleisknownabouttheexactmechanisms ofthese symptomsgiven the heterogeneousnature ofthe disorders[64].

Amongtheburnsurvivorpopulation,sleepdisturbancemay be relatedtopain, itch orbehavioral healthconditions.The proportionofpatientswithsleepdisturbancefollowingaburn injuryis ashighas 74%.Mostfrequently reportedproblems includenighttimeawakenings,daytimenapping,nighttimepain anddifficultywithsleeponset[65].Poorsleepqualityhasbeen showntobeassociatedwithhighlevelsofpainandanalgesic intakeduringthedayandamyriadofothersymptoms[66].

Somerecent studies have shown the positiveeffects of tDCS on sleep to promote vigilance and sleepiness [67]. Specifically, prefrontal tDCS applied during a wake period mayimprovethequalityofsubsequentsleep[68,69]intwo differentconditions,post-poliosyndrome[68]andeuthymic bipolarism[69].tDCS mayalso improvesleepefficiency in patients with fibromyalgia [70]. Another study tested the effectsofprefrontalstimulationappliedduringstage2sleep. Inthisstudy,tACS(transcranialalternatingcurrent stimula-tion)at0.75Hzininsomniacpatientswasused.PrefrontaltACS maythusamelioratesleepqualityanddecreasethenumberof waketimesaftersleeponset[71].Thesebehavioralfindings werecoupledwithelectrophysiologicalchangesasanincrease ofstage3durationandadecreaseofstage1durationwerealso observed.

Based on the current literature on non-invasive brain stimulationtomanagesleepdisturbance,theprefrontalarea hasbeenshowntobeaneffectivetargetbothwhenstimulated duringwakefulnessandduringsleep.Unfortunately,thereare nocurrentstudiesinburnoutcomesevaluatingtheeffectsof tDCS on sleepquality. As mentioned previously, M1-tDCS appliedinpatientswithburninjuriesdidnotleadtosleep qualityimprovement.Assleepdisturbanceislinkedtopain anditch,itmayalsoexplainwhyM1-tDCSdidnotpromote sleep.Therefore,targetingtheprefrontalregionmayinduce morepromisingeffects.

3.5. Burnsymptom5:fatigue

Fatigueisacommonsymptomreportedafterburninjury,with manypatientreportsofpersistenceevenat24months

post-injury[72].Symptomsoffatiguemaycontributenegativelytoa survivor's recovery from hindering their ability to fully participate in rehabilitation exercises to affecting injury healing[73].Largerburnsizewasfoundtobeassociatedwith symptomsoffatigue[72].Further,post-injuryfatiguehasbeen demonstratedtoimpactsurvivors’post-injuryqualityoflifeas well as work-related disability [74]. Given the persistent implications of fatigue on quality of life, it is therefore imperativethatfutureresearchtargetsstrategiestoalleviate thispost-burnsequela.

Fatigueisoftentimessubjectiveandisdefinedclinicallyby anincreasedsenseofeffortintheinitiationandmaintenance ofbothphysicalandcognitiveactivities[75].Fatiguemaybe further categorized as myopathic or subjective fatigue. Symptomsofmyopathicfatigueareduetomuscleweakness resultingfromdecreasedmuscleforceoutput[75].Thistypeof fatigueiscommonamongpatientswithmyopathicdisorders, neuromuscular junction disorders, and peripheral nerve disorders.Conversely,symptomsofsubjective,orcognitive, fatigueareduetolesionsinpathwaysimplicatedinarousal andattention,thebasalganglia,andthereticularandlimbic systems[75].Thistypeoffatigueismorecommonlynotedin peripheral,autonomic,andcentralnervoussystemdisorders

[75].

Cognitive fatigue, differing from myopathic fatigue, is observedinmostacuteandchronicinflammatory diseases

[76]. In chronic inflammatory disorders, fatigue has been foundtobecorrelatedwithhighobservedlevelsof inflamma-torycytokinessuchasIL-6,IL-1,andTNF[77].Itis hypothe-sized that theincreasedlevelsofthesemarkerssignal the centralnervoussystemtosubsequentlyrespondandgenerate thefeelingoffatigue.Similarly,inburninjury,inflammation markers of IL-6, TNF-

a

b

tDCS has been previously investigated fortreatment of fatigue, specifically,inmultiplesclerosis (MS).Inthe treat-ment ofmultiple sclerosis,tDCS modulates the postulated disrupted cortico-subcortical loop [79]. In addition, in the diseaseprocessofmultiplesclerosis,neuralcellaxonsbecome demyelinatedduetoacombinationofinflammation, demye-lination, and oxidative stress [80]. tDCSis also thoughtto improvetheactivationandmigrationofneuralstemcellsand thereforepromoteaxonalregeneration[79,81].Byimproving conductionthoughaxonalregenerationofthedemyelinated neuralcellaxons[80],tDCSmayfurtheralleviatesymptomsof fatigue[79,80].Giventhe implicationsofinflammationand fatigue, tDCSmayworktomodulate thispostburnfatigue throughsimilarmechanismsaswithfatigueobservedinMS. Further,whilenostudieshaveinvestigatedtheuseoftDCSon post-burnfatigue,previousstudieshavenotedtheuseoftDCS insubjectivecognitivefatigue.tDCShasbeendemonstratedto have a positive effect on patients with mild-moderate cognitivefatiguecomparedtopatientswithseverecognitive fatigue with parietal stimulation [82]. In addition, tDCS stimulation,appliedovertheparietalandfrontalarea,was abletoimprovefatigue-relatedreactiontimewhileperforming cognitivetasks[82,83].

Currently,therehasnotbeenliteraturedemonstratingthe useoftDCSintreatingsymptomsoffatigueafterburninjury.

However, giventhe efficacy oftDCSin improvingmultiple sclerosis related fatigue, tDCS applied in the parietal and frontalareamaybealikelytargetforfutureinvestigationwith promising results. Given the safety profile and ease of implementation,tDCSmaybeapotentialfavorabletreatment optiontoalleviatefatigue[38,84],especiallygiven pharmaco-logic limitationsin treatmentthat patientsmayencounter

[79].

3.6. Burnsymptom6:impairedmotorstrength

Muscularweaknessiscommonlyreportedafterburninjury whether due to muscle wasting or due to the increased catabolism of skeletal muscle, with resultant loss of body mass,experienced afterinjury [85,86]. Critical illness poly-neuropathy,adiffuseneuropathythatmayoccurwithsevere burninjuries,maybeanother sourceofweakness,causing extremityflaccidweaknessduetoaxonaldamageofthemotor neurons[87].Thedegenerationofsensoryandmotorneuron nervesleadstoresultantskeletalmuscledegeneration[88]and subsequentsymptomsofmotorweakness.Amongtheburn population,thistypeofweaknessoccursanywherebetween 2%and29%ofsurvivors[89,90].Predictorsofimpairedmotor strength, or muscular weakness, include initial myostatin serumconcentrationlevelsandgreatertotalburnsurfacearea

[91].Inordertogeneratefinedistalmovements,activationof theprimarymotorcortexisrequired[92].Whenonesideofthe motor cortex becomes impaired, increased transcallosal inhibitionfromtheunaffectedmotorcortextotheaffected cortex disrupts the primary motor cortex. The resultant decrease in cortical excitability thereby impairs muscle strength[92 94].

tDCShasbeenshowntobeefficaciousinimprovingmotor functionandstrengthinvariabledisordersthroughactivation of motor areas and enhancement of action potentials for movementexecutionwhenappliedoverM1[95].AnodaltDCS increasesmotorlearningbydecreasingGABAergicactivityin the motor cortex and subsequently increasing functional connectivityofthemotornetwork[96].Variousstudieshave demonstratedpositiveeffectsoftDCSstimulationon move-ment and strengthimprovement. In a studyby Kim et al, anodaltDCSappliedtotheaffectedhemisphereofpatients withsubacutestrokewasfoundtoimprovefunctionofthe affectedhand[97].Similarly,inastudyofchildrenwithspastic hemiparetic cerebral palsy, anodal M1 tDCS was noted to improveupperlimbmovementsofthesepatientsas quanti-fied through decreased total movement duration time, decreased returning movement time, and overall reduced movementexecutiontime[95]. Further, M1tDCSmayalso improvethe maximumforce ofkneeextensioninpatients withchronicsubcorticalstroke[98],aneffectsuggestedtobe resultantoftDCSinducedcorticospinalexcitabilityoverthe lowerlimbprimarymotorcortex[39,99,100].Finally,several studies have shown that motor cortex stimulation does enhance exercise performance, including muscle strength andalsophysicalendurance[101 104].

Thoughothertherapiessuchasstrengthtraining[86]have been demonstrated to be efficacious improving muscular strengthpost burninjury,theroleoftDCSinaffectingthis symptom has not been investigated. However, given the

positive outcomes of tDCS applied over the motor cortex observedinotherdisorders,futurestudiesmaybefocusedon thisareaofstimulation.

4.

Discussion

ThereisevidenceinotherfieldsthatsuggestthattESmaybea successfultreatmentforcommonpostburnsymptomology. AlthoughthereisalackofdataontheeffectsoftESintheburn population,giventhefrequencyofchronicsymptomsthereis a need for novel interventions. This paper reviews prior literaturetodevelopananatomicalmapofpotentialareasof

brain stimulation to treat burn symptoms. Many burn

symptoms share well described neurophysiology seen in otherpopulationsandliteratureexaminingtheutilityoftES treatments.

Based on these observations we can draw three main conclusions:(1)Theprefrontalcortexmaybeabettertarget than the motorarea toreducebothpain and psychosocial symptomsrelatedsymptoms.(2)tESappliedovertheparietal cortexmayhelpwithfatigueandimprovevigilance,though dataislimitedeveninotherconditions.(3)tESappliedoverM1

could be useful to help with muscle weakness in the

subpopulation of patients with burn sufferingfrom motor disorders.

1. tESappliedovertheprefrontalareahasbeenshownto improvecognitivesymptoms,suchasattentionand memory,invariouspathologies[e.g.,105,106],aswellasto helpwithpsychosocialsymptomsofPTSDoranxietyand sleepdisturbance[e.g.,107,108].Inaddition,theprefrontal regionmayalsoplayaroleintheemotionalreactionto pain.Inthepastdecade,manyneuroimagingand neuro-physiologicalstudieshavedemonstratedthecriticalroleof theDLPFCnotonlyinpainprocesses[109]butalsoin fatigue[79],depression[110],orattention[111],including theattentionalcircuitdedicatedtonoxiousstimuli[112]. Therefore,modulatingtheprefrontalcortexvia non-invasivebrainstimulationcouldalsohelpmanageacute andneuropathicpaininpatientswithburninjury.Similar tomanagementoffibromyalgiaorneuropathicpainin patientswithmultiplesclerosis[113],tESoverthe prefrontalareadidshowpromisinganalgesiceffects. Similarmontageshouldalsobetestedinpatientswithburn injury.Thisapproachappearsmorepromisingasthis populationofpatientsoftensuffersfromdepressionand fatigue,symptomsinvolvedbytheprefrontalarea. 2. tESappliedovertheparietalcortexmaybeefficaciousin

reducingfatigue,aspreviouslyinvestigated,suchasin multiplesclerosis.Inaddition,theparietalcortexisalso involvedinitchregulationasdemonstratedby neuroim-agingstudies.tESeffectsonfatiguemaybelinkedtoan improvementofvigilancelevel,asneuroanatomically, vigilancedependsonanetworkinvolvingthebrainstem, thethalamus,andthefrontalandparietalcortices[114]. 3. tESappliedoverthemotorcortexmaystillbeusefultohelp

rehabilitation,especiallywhenpatientsremainbedridden foranextendedperiodoftimeandsufferfromensuing muscleweakness.Patientswithextensiveburninjuries

oftenstayinintensivecareunitsbeforebeginning rehabilitationtherapy.Duringthistime,muscleatrophy canoccur,consequentlyslowingdownfunctional im-provement.Inthisscenario,applyingtESoverthemotor cortexduringrehabilitationmayspeedupthefunctional recovery.However,basedonourpreviousdata,M1tES, especiallyusingtDCS,doesnotseemtoinduceananalgesic effectortoreduceitchsensationinpatientswithburn injury[14].Itdoesnotseemtohaveaneffecton

psychosocialsymptoms,whilestimulatingtheprefrontal cortexseemstohaveamorestraightforwardapproachto improvesuchfactors(Fig.2).

TechniquessuchastDCS,tACSorotherNIBStoolshave severaladvantagesaswellassomelimitations.Inouropinion, especiallyintheburnpopulation,oneofthemainadvantagesis thenon-pharmacologicalnatureoftES.Whileopioidsremain thecornerstoneofpainmanagementintheburnpopulation

[115];giventheriskofaddiction,alternativesto

pharmacologi-caltreatmentarenecessitated.tESrepresentsasafe, inexpen-sive, and well tolerated modality as compared to other treatment strategies[116].Mechanistically, NIBStechniques havethepotentialtomodulatespecificbrainareasdepending ontheunderlyingsymptomstotreat,vialong-termpotential anddepression-likeplasticitymechanisms[117 119]. Howev-er,currentlythistechniquetypicallyinvolvesadministration by trainedstaffunderclinicalsupervision,requiringthe adminis-trationoftEStotakeplaceinresearchfacilitiesorhospitals.In addition,dosingisanimportantparameterasthedurationof the effects is thought to be linked to the duration of tES application.Repeatedsessionsmayhave cumulativeeffects leadingtolong-lastingclinicallyrelevanteffects,asshownin previousstudiesevaluatingtheeffectsoftDCSinpsychiatric

[120],motor[121],andpainconditions[122].Recently,some

studieshaveutilizedhome-basedtDCSdeviceswithpromising resultsand,mostimportantly,withnoside-effects[123 125]. Thus,home-basedsupervisedsessions,asrecommendedby Charvet andcolleagues[126],couldbe an alternative to facilitate tDCSandtACSimplementationandreduceattritionratesas

oftenobservedinclinicaltrialsoflongduration[127],aswellas topromotelong-lastingtES-relatedeffects.Besidesthenumber ofsessions,theintensityofstimulationisanotherparameterto takeintoaccount.Recentevidencehasshownthat4mAtESis safeand canpotentiallyinducestrongerneurophysiological effects, and thus stronger behavioral effects too [128,129]. However, a direct link between clinical effects and higher intensitiesofstimulationstillneedstobeproven.

5.

Conclusion

Non-invasivebrainstimulation(NIBS)techniquesrepresenta valuable alternative to pharmacologic interventions in the managementofchronicneuropathicpain,psychiatric morbid-ities and sleepdisturbance.However, current literatureon NIBSinburnfortreatingtheseandotherassociatedsymptoms remainslimitedandfuturetrialsaremeritedtoinvestigatethe efficacyofthisapproach.Specifically,home-basedsupervised devices maybe utilized inorder tolimit attrition rates as observed in previoustrials [127]. Our review ofthe neural circuitry involved in post burn symptoms and suggested targeted areas for stimulation provides a spring board for futurestudyinitiatives.Giventhesignificantimpactofthese symptomsonsurvivors’lives,definitionofthesetargetareas allowforfocusedstudiesoftreatmentofthesesymptomsand eventualimprovedqualityoflife.Basedontheimportanceof theprefrontalcortexintheemotionalcomponentofpainand itsimplicationinvariouspsychosocialsymptoms,thisregion mayrepresentthemostpromisingtreatmenttarget.

Funding

Thecontentsofthismanuscriptweredevelopedunderagrant fromtheNationalInstituteonDisability,IndependentLiving,

and Rehabilitation Research (NIDILRR grant number

90DP0035). NIDILRRis a Center within the Administration for Community Living (ACL), Department of Health and HumanServices (HHS).Thecontentsofthis manuscriptdo notnecessarilyrepresentthepolicyofNIDILRR,ACL,HHS,and

you should not assume endorsement by the Federal

Government.

Conflict

of

interest

Theauthorsreportnoconflictofinterest.

Acknowledgments

Dr.AuroreThibautisaFNRSisapost-doctoralresearchfellow. Thecontentsofthismanuscriptweredevelopedunderagrant fromtheNationalInstituteonDisability,IndependentLiving,

and Rehabilitation Research, NIDILRR grant numbers

90DP0035, 90DPBU0001,and 90DP0055.NIDILRR isaCenter within the Administration for Community Living (ACL),

Department of Health and Human Services (HHS). The

contentsofthismanuscriptdonotnecessarilyrepresentthe Fig.2–Mainsuggestedcorticalregions(redcircles)fortarget

treatment.(Forinterpretationofthereferencestocolourin thisfigurelegend,thereaderisreferredtothewebversionof thisarticle).

policy of NIDILRR, ACL, HHS, and youshould not assume endorsementbytheFederalGovernment.

Appendix

A.

Supplementary

data

Supplementarydataassociatedwiththisarticlecanbefound, intheonlineversion,athttps://doi.org/10.1016/j.burns.2020.

06.005.

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