Co-Founders
Thomas Burton
Ideja Bajra
Innovative Writers
Lydia Mao
Nimue Lilith Romeikat
Shiksha Guru
Hannah Betts
Rishi Ravishankar
Leo Elliott
Violet Melcher
Teddy Henderson
Head ofEditing
Laila Deen
Deputy Head of Editing
Sushmhitah
Sandanatavan
What began 2 years ago as an ambitious dream to enhance scientific communication and foster innovation across the University of St Andrews has blossomed into the creation of STATIC and the production of our second Scientific Innovation Review
This Review showcases the recent and significant advancements made in the fields of Natural Science and Medicine Our team of dedicated and passionate writers have meticulously researched their report topics, drawing upon a wide range of scientific journals, databases, and other reputable sources
STATIC is a rapidly growing initiative, and we are committed to hosting inspiring and influential collaborations with powerhouses within the fields of STEM Our aspiration is to continue establishing a robust networking system that connects like-minded, accomplished, and motivated individuals This Review is a testament to the synergy and collaboration within the STATIC amongst the committee members, innovative writers and editors Together, we have worked to outline the groundbreaking innovations that have contributed to the betterment of our society
We are immensely proud of the work presented in this year's Review and are grateful for the support and contributions of the University of St Andrews community We look forward to the continued growth and impact of STATIC in the years to come
Sincerely,
Thomas. B Ideja. B
We are so thrilled to have had the opportunity to be part ofthis year's editorialprocess, working alongside the innovative writers who contributed to this journal. It has been a rewarding experience to help refine articles, focusing on sentence structure, content flow, and meticulous referencing. The dedication and creativity we've witnessed have truly inspired us, and we are grateful to have played a role in bringing these ideas to life.
Our journey with STATIC has been nothing short of extraordinary. We have thoroughly enjoyed attending the various events throughout the year, which have not only enriched our understanding but also strengthened our sense of community within the university. Being part of this team has been a highlight of our university experience, and we look forward to continuing this journey alongside such a talented and passionate group of individuals.
Thank you forallowing us to contribute to this journal, and we hope that the efforts of both the writers and the editorial team resonate with you as much as they have with us.
Warm Regards,
Editors
Laila Deen
Sushmhitah Sandanatavan
Thomas Burton
01 Review of Current Surgical Management of Diabetic Foot Burns Using SplitThickness Skin Grafts
02 A new hope forAlzheimer's – is Deep Brain Stimulation advancing beyond Parkinson's?
03 Brief Exploration of the Molecular Basis of the Different Types of Multiple Sclerosis (specifically Relapsing Remitting and Primary Progressive)
04 Earning Their Stripes:The Zebrafish (Danio rerio)’s Promising Future as a Developmental Alternative In Vivo Model of Neurodegenerative Diseases
05 Neuroplasticity-Based Interventions in Stroke Rehabilitation
06 Bioengineering Breakthroughs: Transforming Clinical Psychology for the Future
07 Exploring the Complexities and Innovations within Electric Vehicle Battery Technology
08 Improving Crop Resilience to Climate Change
Lydia Mao
Nimue Lilith Romeikat
Shiksha Guru
Hannah Betts
Rishi Ravishankar
Leo Elliott
Violet Melcher
Teddy Henderson
LydiaMao Bsc(Hons)Medicine
SushmhitahSandanatavan Bsc(Hons)Medicine
Abstract—Thisreviewaimstoevaluatethequalityofcurrentsurgicalmanagementoflowerextremity burnsusingsplit-thicknessskingraftsamongstdiabeticpatients.Theescalatingfiguresofdiabetics andtheassociatedcomorbiditiesthatactasriskfactorsfordiabeticburnsarenotadequately addressedinthecurrentliteratureandinpublishedclinicalguidelines.Thisworkprovidesan extensiveoverviewofthefactorsaffectingboththeclinical,andcosmeticoutcomesoftherelevant graftingprocedureintheshortandlongterm.Thereviewconcludesthatspecialisedunitsandpatient educationarerecommendedtopreventrecurrenceinhigh-riskdemographicsfordiabeticburns.
conditionsglobally,affecting1in10people(Saeedi, 2019).Itisacomplexdisease,oftenaccompaniedby arangeofseriouscomplications.Amongthemost significantoftheseareperipheralneuropathyand vascularcompromise,particularlychronicendothelial injury(Galliero,2023).Thisneurovascularcompromiseslowstherateofwoundhealingandfurthers complicationssuchasinfectionsandcosmeticscarring. Oneoftheprevalentmanifestationsoftheseissuesis diabeticfootburns,whichareoftenprolongeddueto neuropathyandabsentreflexesresultingfromautonomicdysfunction(Barsun,Palmieri,andGreenhalgh, 2013).
Whenburnsaretoolargeandareunabletobe managedthroughprimarywoundclosurebystitching ittogether,skingraftsareusedinstead.Approximately 60%ofdiabeticpatientswithafootburninjury undergowoundexcisionsuchasdebridement,and skingraft(Momenietal,2018).Amongstthevarious formsoftissuereconstruction(Figure1,Reaveyand
Gottlieb,2019),thisreviewwillprimarilyfocuson skingraftingusingeitherautografts,whichareskin graftstakenfromthepatientthemselves,orallografts, whicharesourcedfromahumancadaver.Thesegrafts arethenmeshed,stretched,andappliedtothesiteof theburninjury.Specifically,thestudiesreferencedin thisreviewanalyseatypeofhumanskingraftcalled thesplit-thicknessskingrafts(STSG),whichcontains theepidermisandpartofthedermisisusedcommonlyforlargewoundsforextremityburns.Wound healinginskingraftposessignificantchallengesin diabeticpatientsduetodamagedbloodvesselsin lowerextremities.Sincethegraftdoesnotcontainits ownbloodsupply,awell-vascularisedwoundbedon therecipientisessentialforgraftuptakeandoptimal woundclosure.However,thisisoftencompromised indiabeticfeetbecauseofavascular,necrotictissue commonlyassociatedwithfootulcers(Galliero,2023). Long-termcomplicationssuchasimmobilityandscar contracturescanoccurinthefoot,leadingtoprolonged recoveryimpactingbothgaitandcosmeticoutcomes (Yammineetal,2019).Additionally,thedemographic factorsofdiabeticpatientssufferingfromfootburns
Figure1. ReconstructiveLadder(RieveyandGottlieb,2019) alsoinfluencethehealingprocess.
Thisreviewaimstodisseminatethefactorsabove toevaluatethequalityofcurrentsurgicalmanagement ofdiabeticfootburnswithskingraftsandproposerelevantclinicalrecommendations.Additionally,itaims tohighlightcurrentlimitationsindiabeticwoundmanagementandtherelevantgapsintreatmentprotocols. Thereviewhypothesisesthatpoorgraftuptake,along withinsufficientmonitoringandspecialisedcarefor long-termwoundmanagement,aretheprimarychallengesassociatedwithSTSGindiabeticfootburns.
Informationsources,Selectionstrategy
Studiesweremanuallyidentifiedbytheauthor throughsearchesinPubMed,GoogleScholar,Science Direct,JSTORandEuropePMC.Clinicalguidelines andrecommendationsweresourcedfromCochrane Library,WileyOnlineLibrary,NICEandtheNHS publicdatabase.Mostofthestudiesselectedare systematicreviews,followedbymeta-analyses,cohortstudiesandcross-sectionalstudies.Thefollowing searchtermswereused:“diabetesmelllitus”,“diabetic burns”,“peripheralburns”,“peripheralneuropathy”. Furtherstudieswereidentifiedthroughthereferences
oftheselectedarticlestoprovidebroadercontextand understanding.
Studieswereindependentlyidentifiedandmanuallycomparedbytheauthoragainstspecificinclusion criteria.Literaturethatexaminedthechallengesand complicationsofgeneralburnmanagementamongst diabeticpatients,andspecifically,operativemanagementwereselected.Theselectedliteratureincluded bothpatientswithTypeIandTypeIIdiabetes,irrespectiveofageandgender.
Casestudieswereexcludedtoensurearepresentativescopeofpatients.Onlypaperspublishedinpeerreviewedjournals,inEnglish,andinbetween20022023wereincluded.
Theauthoridentifiedindividualstudiesdenoting thechallengesandcomplicationsofburnmanagement amongstdiabeticpatients,aswellasretrospective cohortstudiesontheclinicaloutcomesofsurgical managementofdiabeticburns.Forcontextandrelevantdiscussion,epidemiologicalanalysesofdiabetic burnswerealsoidentifiedandreferenced.
Theeffectivenessofskingraftslargelydepends onthespecificconditionofthepatientandthequality ofpost-graftcare.Thisreviewwillexplorethemain aspectsofwoundhealingassociatedwithskingrafts (amongstotherlesscommonlyperformedsurgical proceduresforthirddegreeburns),aswellasflap reconstruction,althoughitisnottheprimaryfocusof thisreview.
Theunderlyingbiochemicalandcellularprocesses ofwoundhealingisvitaltounderstandingtheprolongedandoften,lessoptimalgraftoutcomesforburns amongstdiabeticpatients.Severalpublicationshave confirmedthatskingraftsusedwithstandardcare increasethehealingrateoffootulcersandwounds (Santemaetal,2016).Thehealingrateistypicallyassessedbasedonthereductioninwoundarea.However, theinabilitytopreciselymeasurewoundsize,along withtheexclusionofwounddepth-acriticalfactor inevaluatingtheseverityoftheburnsite-makesit difficulttoaccuratelycomparehealingrateswithand withoutaskingraft.Thelong-termoutcomeofskin
graftonthewoundwouldneedtobefurtherinvestigatedconsideringthatmostoftherelevantstudies beingretrospectivecohortstudieswithuncontrolled patientvariables,makingitchallengingtoestablish aclearassociationbetweenskingraftsandimproved outcomes(Landsman,2015).
Completewoundclosureisnotalwaysachieved indiabeticpatientsduetopreexistingdiabeticulcers (e.g.pressurewoundsonsole)aswellascomorbidities suchaschronichyperglycaemiaandperipheralarterial disease(Ramanujametal,2013).Thevarieddefinitionsof“completewoundclosure”limitsrigorous analysisofitsfrequencyindiabeticwounds.Some definitionsdescribeitas“fullepithelialisationwith absenceofdrainage”whileothersinclude“...absence ofdressing”orthepresenceofsmoothscars(Santema etal,2016).Therearemorenovelformsoftissue replacementssuchasbioengineeredorartificialskin thatcontaingrowthfactorsandculturesoffibroblasts whichcanpromotecompleteclosure,thoughthelimitedresearchdoneonthesetechniquesexcludesthem forthepurposeofthisreview.Instandardcareof burnwoundswheresaline-soakeddressingsareapplied,only65%ofdiabeticpatientswithfootwounds healedafterayear,with15%requiringamputations (Oyiboetal,2001).Amongstdiabeticpatientsadmittedwithfootburns,75%requiredgrafting,and20% ofthoserequiredre-grafting(Momenietal,2018). Thisprolongshospitalisation,oftenexposingthemto increasedriskofnosocomialHAIs.Re-operationwas necessaryin33%ofcasesduetograftrejection,poor woundadherence,orevenamputation(Momenietal, 2018).Atfirstglance,thehigherratesofamputation withskingraftscomparedtostandardcareappear contradictorytotheverypurposeoftheintervention. However,skingraftrequiresspecificconditionsfor successfuluptakewhichdiabeticpatientsoftendonot fulfil.Neuropathy,whichaffectsanestimated30%of diabeticpatients(Barsunetal.,2013),canresultin hypoesthesia,leadingtoburns.Additionally,theloss ofneurologicaltransmissioncancauseflattenedfoot archesandunequalweightdistributiononthesole, resultinginpressurewoundswheretheskingraftis unabletoadheretotheburnsite,leadingtofailed graftuptakeandanincreasedneedforregrafting. AccordingtoDukeetal,2016,unstableclinicaloutcomesfordiabeticburnsaredenotedbyanincrease
inpostburnadmissions.Diabetic,pre-diabeticand non-diabeticpatientsutilisedmorelong-termhospital servicefordiabetesaftertheirdischargefortheir burninjurywithinthepast5years,thanthosewho didnotexperienceaburninthatperiod.Sustained disruptiontoglucosemetabolismwasreportedwithin 5yearspost-injury,associatedwithinsulinresistance andendoplasmicreticulumstressresponse(Jeschke etal,2012),allcontributingtoahypermetabolicand hyperinflammatorystateinthepatient.Thestudy, however,didnotaccountforeachparticipant’sindividualmedicalhistoryinitsstudymodel,makingit unclearwhethertheburncauseddiabetesmellitusor exacerbatedpre-existingmetabolicconditions,causing diabetic-relatedhospitaladmissions.Inthiscontext, skingraftsshouldbeviewedasatemporary,shorttermsolutionthatcanbiologicallycovertheburnsite forhealing.However,theirlong-termoutcomesarenot guaranteed,asthepatient’sabilitytohealwoundsand fightinfectionsremainscompromised.
Burnwoundsresultinwoundcontracture,anormal physiologicalresponseoffibroblastsinwoundhealing. However,scarcontracturescanalsooccurduetoexcessfibrotictissuemadebymyofibroblasts,presenting ashypertrophicscars.Thiscausesareducedareaof theskinorskingraft,inadditiontoincreasedtension inthatarea.Contracturesaroundajointcanresult inlong-termlimitedmobilityofthejointandeven deformity.Severalstudieshaveattemptedtoassess theprevalenceofskingraftscarringandresulting deformities.Contractureswerefoundtoforminthe earlystagesofburnrehabilitation(within2weeks post-graft),withtheiraetiologymorecloselylinkedto “therapeuticpositioning”and“intensivecaretherapy” ratherthantheskingraftprocedureitself(Goverman etal,2017).Thissuggeststhatpost-operativecare, ratherthanthegraftingprocess,playsasignificantrole inthedevelopmentofcontractures.Differentstudies havedevisedvariousmethodstoassesstheseverity ofcontractures(Oosterwijketal,2016).Somerely onvisual,subjectivedeterminationoftheamountof scarring;whileothersmeasureobjectivelythedegree ofmovementofanisolatedjoint,whichcanoftenbe underestimatedduetosurroundingsofttissuepadding andpatient’spain.Clinically,thereisnostandardised methodofassessingtheseverityofburncontractures throughanaccuratemeasurementoftheirfunctional outcomes.Incasesinvolvingdeeperjointswithex-
tensivegrafting,itmaybenecessarytorenewthe skingraftcovertorelievesuperficialskintensionand restoreafunctionalrangeofmovementoftendon, ligamentsandjoints.Initially,itwasthoughtthat theexistingsuperficialskingraftcanberemoved andreplacedinasingleoperation.However,repeated operationsareneededasdeeperstructuressuchas bonesandjointshadtobemanipulatedandrepositionedfromthecontracture(Shakirov,2006).Hence, thisreflectstheinadequatepre-operativeplanningin managementofpost-burncontracturesandthelongtermrehabilitationofpatients,asthisarearemainsambiguousandunder-researched.Preventivestrategies, suchasactiveandpassivejointmovementscanhelp managelessseverecontractures(Goverman,2017). Thesestrategiesareapplicabletoallpatientswhohave undergonearecentskingraftprocedure.However, theireffectivenessdependsonfactorssuchasthe patient’snaturalmobility.Olderage,diabetesmellitus, painorweaknessfromage-relatedneuromotordeficits canallimpacttherangeofmovementavailableinthe joint.Therefore,theeffectivenessofthesepreventativestrategiesishugelydependentonthepatient’s complianceandphysicalcondition.Diabeticpatients withsevereand/orchronicdiabeticulcersoftenrequire moreextensivewounddebridement.Ulceratedskin maywarrantremovinghealthytissueinexcessofthe avascularisednecrotictissuetoexposeasufficiently vascularisedwoundbedforskingrafting.Thisresults inalargerareaofskingraftandconsequently,greater surfaceareawherewoundandscarcontractureswould takeplace.Plantarfootburns,themostcommonsiteof footburnindiabetes,anddiabeticfootulcerscanlead tohyperflexionoftoes,adecreasedlongitudinalarch ofthefootandincreasedflattening(pesplanus),allof whichcanexacerbatethegaitdisturbancesanddelay thewoundclosureprocess(Yammineetal,2019).
Withthemeanageofdiabeticburnpatientsbeing 62.7yearsold,managingburninjuriesinelderly patientspresentsuniquechallenges,especiallyinadditiontodiabetes.Thereisadisproportionatelyhigh incidenceofdiabeticburnpatientsadmittedaged65 andolder,exceedingtheproportionseeninthegeneral population(Abu-Sittahetal,2016).Moreover,there isahigherriskofcomorbiditiesalongsidediabetes, suchasdiabeticretinopathy,amputations,strokeand end-stagerenaldisease(McCampbelletal,2002). Elderlypatientshavethinnerdermallayerswhichcan
complicatethehealingofSTSG.Inthesecases,the patient’shealthyskinmaystruggletointegratewith thegraft,leadingtograftfailure(graftdoesnotstick tothepatientaspartofthewound).Additionally, aSTSGisstrictlycontraindicatedinwoundsthat arepoorlyvascularised,hence,thisposesaconcern toelderlypatients,manyofwhomhaveperipheral vasculardiseaseanddiabetes.Theslowerrateoftissue regenerationwithagefurtherdecreasesthelikelihood ofsuccessfulgraftuptake(Abu-Sittahetal,2016). Thesefactorsunderscorethenecessityforcarefuland intensiveburnmanagementinelderlydiabeticpatients. Earlyexcisionandgraftinghavebeenkeymilestones inburncare,firstintroducedin1970.Excision,the removalofburned,necrotictissue,hasbeenshownto reducemortalityandshortenhospitalstaysinselected studyparticipants(Kecketal,2009).However,this approachiscontradictedbystudiessuchasHousinger etal(Housingeretal,1984),whichconcludedthatpatientsaged60oraboveexperiencedlesscomplications andbetteroutcomesinlongtermrehabilitationcomparedtopatientstreatedwithexcisionandgrafting. Althoughthemeasurementofthequalityoflong-term rehabilitationofthepatientsinthisstudywasambiguouslydefinedasfunctionaloutcomesandthestudy isratheroutdatedsomaynotapplytocurrentburn care,itsuggeststhatconservativemanagementmay offerbettershort-termoutcomesthanskingraftingfor elderlypatients.Thisraisesfurtherquestionsabout themosteffectivelong-termmanagementofelderly diabeticburnpatients.Regardlessofthepresenceof peripheralneuropathyinapatient,elderlyindividuals aremorelikelytohaveslowerreactiontimes,delayed withdrawalreflexes,andpotentiallydeterioratingcognitivecapacity(Mandelletal,2013).Thesefactors couldexplainGoeietal’s(2020)findingthatburn coolingstronglydeclineswithage.Elderlypatientsin thestudycohortdidnotcooltheirburnsordelayed doingsoformorethan10minutes,whichresultedin exacerbatedburnseverityandmorepressingly,ledto furtherappraisaldelayswhenpresentingthemselves tomedicalassistance(Woodetal,2016).Thissuggeststhatpre-hospitalburncareandpreventativefire educationmaybemoreeffectiveformanagingburn injuriesintheelderlythanexcisionandgrafting.It wasalsoobservedthatelderlyburnpatientshadshorter waittimesbetweenhospitaladmissionandtheirfirst surgicalprocedure,aswellasmoreprimarywound closure(Goeietal,2020).However,excisionandgraftingtypicallyoccurredaweekafteradmission,possibly
Figure2. Comparisonoffull-thicknessandsplitthicknessskingrafts(BritishSocietyforDermatologicalSurgery)
duetodelaysinadmissionandagenerallyconservative approachtoelderlyburninjuries.Overall,predicting survivalratesandthelengthofhospitalstaysfor elderlyburnpatientsremainsunder-researched.From themyriadofstudiesreferencedabove,itissuggested thatburnmanagementoftheelderlyvariesbyhospitalandcountries,potentiallyduetotheconflicting evidenceofwhetherearlyexcisionandgraftingor conservativewoundcareispreferredintheelderly. However,manyauthorscommonlyexpressaneed forpreventativeeducation,specialisedguidelinesfor elderlyburncareandlong-termcommunitycarefor comprehensiverehabilitation.
Asofnow,theNationalInstituteofClinicalExcellence(NICE)hasnotpublishedanyspecificguidanceonthemanagementofdiabeticburnsusingskin grafts.Thiscomplicatesclinicaldecision-makingdue toalackofstandardprotocol.Inadditiontothe choicebetweenaskingraftandconservativedressing,surgeonsarerequiredtoaccountforuncontrolled variablesinthepatient’slong-termoutcomes,such astheirnutritionalstatus,non-complianceandwound carepractices.Additionally,thechoiceofusinga split-thicknessskingraft(STSG)orafull-thickness skingraftisnotdeterminedbyanysetcriteriaand solelyreliesonthesurgeon’sestimation.Full-thickness skingraftsoffergreaterdurabilityandbettercosmetic outcomesduetolessshrinkagecomparedtoSTSG andareoftenpreferredforgraftingthesoleofthe foot,whilstthelatterhasalowerriskoffailureas seeninTable1(BritishSocietyforDermatological Surgery).Thisrequirescosmeticoutcomes,functional outcomesandoptimalwoundhealingtobebalanced ontheindividualpatient’ssite,potentiallyleadingto treatmentdelay.
Thisreviewprovidesamulti-facetedevaluation ofthesurgicalmanagementofskinburnsindiabetic patients,focusingontheuseofskingrafting.
Summaryofthemainfindingsofthisreview
Theskingraftitselfprovidesarapidandimmediatereliefforburninjuriesindiabeticpatients, significantlyreducingtherateofprimaryinfections causedbywoundexposure.
However,thesuccessofskingraftuptakepostprocedureremainsthegreatestchallengeduetopredisposingfactorssuchasimmunopathy,poortissue perfusion,andvascularisationissues,aswellasthe hypermetabolicresponsetoburninjuriescharacteristicindiabeticpatients.Allofwhichprolongsgraft uptakeandwoundclosurewhichexposespatientsto ahigherriskofcontractures,infectionsandfurther interventionssuchasre-graftingandamputation.
Thelong-termcomplicationsofskingraftingin diabeticpatientsareexploredintermsofclinicaloutcomes,specificallywoundhealingtime;andfunctional outcomes,suchastheseverityofcontractures.The referencedpublicationsontheseareashighlightedpoor outcomesfordiabeticpatients.Additionally,studies measuringfunctionaloutcomesofskingraftsapplied todiabeticburnslackclarityduetotheabsenceof astandardisedmeasurement.Theseverityofcontracturesweremainlyevaluatedintheformofcase studies(excludedfromthisreview’scriteria),varied greatlybasedonage,pre-existingfootulcerationsand wounds.
Keyproblem-Howcanweimproveskingraft uptake?
Barrierstoskingraftuptakeindiabeticpatients aredifficulttoeradicate.Doneganetal’s(Doneganet al,2014)studyprovidesanoverviewoffactorsthat canbeimprovedtooptimisegraftuptake.Woundbed preparationisidentifiedasacriticalfactortoensurea well-vascularisedwoundbed.Thestudysuggeststhat surgicalbypasstoarteriesinthelowerextremities(e.g. posteriortibialartery,dorsalispedisarteryandtarsal arteries)iseffectiveinincreasingtissueperfusionin theory,althoughinpractice,manydiabeticpatientsare ineligibleforsurgicalrevascularisationduetocoronaryheartdiseaseanduncontrolledhyperglycaemia forsome;inaddition,vascularby-passisperformed electivelyoftenasitnecessitatespriorimagingstudies andoptimalrenalfunction(Siahetal,2019).Such
prerequisitesexcludeitsapplicationtoacuteburninjuriesindiabeticpatients.Alternatively,percutaneous transluminalangioplasty(PTA)wasproposedtoreperfusediabeticpatientswithperipheralarterydisease. (Siracuseetal,2014)’sretrospectivereviewconcluded PTAtogetherwithstentingandatherectomyasthe gold-standardtreatmentfordiabeticpatients.65%of patientsdidnotexperiencere-stenosisinoneyear,as wellasagenerallylowershort-termrestenosisrate indiabeticthaninnon-diabeticpatients.Itsextensive applicationinemergenciesdeemsitsuitableforacute burninjurieswiththecaveatofthisprocedurebeing long-termstatinusepostoperatively.Overall,itsusage beforeaskingraftprocedureprovidesamuchmore promisingclinicaloutlookinfuturepreventionoflimb ischaemia.
Thepresentfindingsofthisreviewalignwith thoseof(Sharmaetal,2023),whichobservedthe relationshipbetweenaetiologyofburninjuriesandthe resultingskingraftoutcomesindiabeticpatients.Both Sharmaetal’spublicationandthisreviewidentified prolongedorfailedwoundclosureasaconsequence ofco-morbidities,operativecomplications,andthe uniquepathologyofwoundhealingsuchasperipheralneuropathyandvasculopathy,indiabeticpatients comparedtotheirnon-diabeticcounterparts.Although thisreviewdidnotincludecasereportsandcaseseries, incontrasttoSharmaetal’s,conveyingthetherapeutic complicationsofskingraftingindeep,aggravated footburns,theconclusionremainsconsistent:skin graftoutcomeshadnosignificantdifferencebetween diabeticandnon-diabeticpatientsintheshortterm, buttheformerhadexacerbatedcomplicationsinthe longterm.Thesystematicreviewalsoaddressedthe rootcausesofburnsamongstdiabeticpatientswhich fallsoutsidethescopeofthisreview,althoughfuture studiesmayevaluatethevaryingoutcomesofskin graftindifferentmechanismsofburninjuriestobetter consolidatethisresearchquestion.
Thefindingsofthisreviewmustbeinterpreted inlightofsomelimitations,mainlybeingthelack ofavailablestudieswithintheoutlinedinclusioncriteriaandnon-standardisedmethodsofmeasurement anddefinitionspertainingtotheresearchquestion.A majordownsideidentifiedwiththecurrentsurgical managementisthelackofcleartreatmentalgorithm
forspecificvulnerablepopulations,includingdiabetic patientsandtheelderly,particularlythosewithdiabetes.Althoughmoststudiesreferencedinthisreview accountedforvariablessuchasco-morbidities,age, andlocationofburns,itcannotbeaccuratelydeterminedastowhethertheseinterindividualvariations affectedtheefficacyofskingraftsorwhetherskingraft isitselfaflawedsurgicaltechnique.Thismaylimitthe applicationoftheconclusionsofthisreviewtodiabetic patientsspecifically.Thisreviewspecificallyfocuses ontheapplicationofskingraftsforlowerextremity burnsindiabeticpatients,which,whilstbeingthemost commonsiteofburninjuriesinthisdemographic, isanareawithlimitedtargetedandvalidstudies. Tobroadenthescope,theauthoralsoconsidered generalstudiesonburnsindiabeticpatientsandlower extremityburnsinpatientsofanytype.Thevariability incomplicationsoffootburnsindiabeticpatientsare bestexploredthroughcasestudies.However,thesefall shortinreliabilityandevidencequalitycomparedto themeta-analysesandsystematicreviewsreferenced inthisreview.Casestudiesunderscoretheneedfor specialisededucationinhandlingdiabeticburnswith bothclinicalandcosmeticintentionstooptimiselongtermwoundhealingandfunctionalmobility.They alsonarrowdownonwoundsize,depthandlocation whichprovidesgreaterprecisionasthelattertwoare oftennegatedinlarge-scalestudies.However,larger cohortsandmorerigorousstudydesignsareessential tocreateacomprehensiveunderstandingofdiabetic burns,incorporatingfactorssuchasage,weightand vascularhealthinanepidemiologicalcontext.
Therehasbeenalongstandingdebateonthetiming ofwoundexcisionpriortografting–whetherearlyor delayedexcisionismoreeffective.Earlyexcisionis associatedwithdecreasedbacterialcolonisationand initialinfections,althoughgraftuptakeratestendto besimilar.Limitedstudieshavebeenconductedon theoutcomesofearlyanddelayedexcisionindiabetic patientsspecifically,althoughdouble-blindrandomised controlledtrialshavereportedagreaterrestorationof footfunction,lessjointdeformitiesandcontractures (Shakirov,2011)(Ayazetal,2019).Variousartificial skinsubstitutes,suchasAlloDerm®andBiobrane®, havebeenusedastemporarydressingstomanage woundsbeforehumanskingraftsareavailable.These substitutescanreduceoccurrencesofpainandwound desiccation(Nit¸escuetal,2012).However,theyare
notwithoutlimitations;theyaremorecostlythan humanskingraftsandcarryariskofimmunological rejectionandinfection.Despitetheirbenefitsinthe shortterm,thesesubstitutespaleincomparisonto humanautograftsorallografts,whichremainthegold standardforpermanentwoundcoverage.
Novelresearchshouldequallybeconsidered,such astheroleofhoneyinadheringthegrafttothewound bed,whichhasheavyimplicationsinoptimisinggraft uptake(MaghsoudiandMoradi,2015).However,the researchonthismethodislimitedbysmallsample sizesandhasnotbeentestedondiabeticpatients orthosewithpre-existingskinconditions,makingit difficulttogeneralisethefindings.Therefore,while innovative,thesealternativesrequirefurtherinvestigationbeforetheycanbeconsideredviableoptions forbroaderclinicaluse.STSGisaversatiletechnique whichoffersahigherchanceofgraftuptakeand completewoundclosure,butmaynotbethemost resistantwithdirectpressureinweight-bearinginfoot burns.Hence,thisnecessitatesevaluationofwound locationandco-morbiditiesofthepatientinpreoperativeplanning.Tighterglycaemiccontrolisan effectivepreventativestrategyinpromotingskingraft uptakeandasolutiontotherootoftheproblemburns.Moreover,hyperglycaemiaremainsinthebody afteraburninjuryandacuteinsulinresistancemay developasaresult.InRaeletal,2019,regularexercise resultsinprolongedgraftsurvival,althoughfurther humanstudiesareneededtoestablishaclearcellular mechanismforwiderclinicalapplication.Nonetheless, thestudysupportsexerciseasaclinicalrecommendationfollowingskingraftprocedures.
Forburnpatients,withorwithoutdiabetes,regularcheck-upsafterdischargecanreducetherates ofreadmissionbymonitoringbloodglucoselevels, whichmayhelppreventprogressiontoadiabeticstate. Specialisedcutaneousburnunitandarecoveryplan shouldbedevisedforhigh-riskgroupssuchasthe elderlyanddiabeticpatients.Astandardisedprotocol shouldbeconstructedtoincludequantitativemetrics ofwounddepthandpercentageoftissueoxygenationthatcancategorisethewoundandtranslateinto specifictreatmentdecisions,usingfunctionalnearinfraredspectroscopywhichisshowntobepromising (Kimetal,2023).Thisissothedecisionofskin graftanddressingisnotsubjectedtogrossvisual inspection.Fireeducationandfirst-aidmanagementof
burnsshouldbepromotedamongdiabeticpatientsto helppreventburninjuriesandensurepromptcooling anddressingbeforemedicalassistancearrives.For elderlydiabeticburnpatients,socialprescriptionsmay helpmaintainjointmobilityandreducecontractures. Communitycareshouldalsobeconsideredforwound dressingchanges.
Futurestudiesmayexplorethevariabilityofskin graftoutcomesacrossdifferentskincoloursandethnicitiestobetterunderstandtherangeofsuitability indiversedemographics.Thesurgeon’sexpertiseand experiencemayalsohaveanimpactonthequality ofspecialisedburncareforhigh-riskdiabeticpatients withuncontrolledhyperglycaemia.Therearegapsin theliteratureregardingstandardisedpreventativeand recoveryregimensforburninjuriesindiabeticpatients thatmustbeaddressed.Morestudiesareneededto investigatewhetherearlyordelayedexcisionoptimises theclinicalcourseofskingrafting,aimingtoreacha wellbalancedconclusionwhichwouldcomefromhigh levelsofevidence.
Asdiabetesanditscomplicationsremainanincreasinglycentralprobleminpatient’slives,burnpreventionandmanagementmustbeaddressed.Thisreviewestablishedanoverviewoffactorssuchasrateof woundhealing,skingraftcriteria,elderlymanagement, andfunctionalandcosmeticoutcomes;allofwhich significantlyinfluencethelong-termclinicalcourseof diabeticfootburns.Toprovidepersonalisedcarefor diabeticpatientsandtheirco-morbiditiessuchasneuropathyandvasculopathy,appropriatepre-operative planningandspecialisedpost-operativemanagement shouldbeimplementedinastandardisedmanner.
*Disclaimer:Thisauthordeclaresnoconflict ofinterestsandnoaffiliationsorinvolvementin anyorganisationwithanyfinancialornon-financial interests.
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LydiaMao isa1styearMedicineStudentatthe UniversityofStAndrews,Contactat:lem29@standrews.ac.uk
NimueLilithRomeikat Bsc(Hons)Medicine
SushmhitahSandanatavan
Bsc(Hons)Medicine
Abstract—ThesignificanceandrisingpopularityofDeepBrainStimulation(DBS)intreating Parkinson’sdisease(PD)isunmistakablyevident,demonstratedbyits’featureinourpreviousSTATIC edition.Anincreasingnumberofresearchersengagewithitsrevolutionarybenefits.Thefocus currentlyliesuponestablishingDBS’possibleroleinthetreatmentofnon-motorconditions.This reviewwillfocusonthepublishedevidenceonDBS’applicationtoAlzheimer’sDisease.
DBS ISANEUROMODULATIONTECHNIQUE that beginswithacomprehensivebrainmapping.The procedureinvolvesusingastereotacticheadframe toguidetheplacementofathinwireattachedto electrodesintothespecificbrainregiontobestimulated.Theseelectrodesareconnectedtoapulse generatorsittingundertheskinclosetothecollarbone -similartoaconventionalpacemaker(Senevirathneet al.,2023).Followingsurgery,aseriesofconsultations areconducted,inwhichavarietyofparameterswill beadjusted.Theparametersthatcanbealteredincludepulsefrequency,voltage,andimpulseduration. This“fine-tuning”processreliesonpatientfeedback, typicallyfocusingonminimisingmotorsymptoms, suchastremors.Theeffectsofthestimulationare saidtoincludesynapticplasticity,neuroprotection,and neurogenesis(Herringtonetal.,2016),whicharekey improvementswaitingtobeutilisedforseveralmore conditions.
Currently,DBSisprimarilyusedtotreatlatestagePD,focusingontheminimisationofmotor deficiencies.Thetargetstimulationareasincludethe subthalamicnucleusandtheglobuspallidusinternus (HarizandBlomstedt,2022).DBShasbeenroutinely
appliedtoothercloselyrelatedmotordisorderssuch asdystonia,epilepsy,andessentialtremor.
Presently,effortsareunderwaytoreplicatethis successintreatingnon-motorconditions,i.e.cognitive andneuropsychiatricdisorderssuchasmajordepressivedisorder(MDD).However,itisessentialtonote thelimitationsofDBSapplicationtoneuropsychiatric conditions,duetothescarcityofpredictiveanimal modelsandprominentethicalchallengeswithconductingclinicaltrialsinpsychiatricpatientpopulations whenreferringbacktocapacityofconsent(Rabins etal.,2009).Anotherpointsparkinghesitationin thisfieldwouldbethepotentialforsuddenrelapse ifthestimulationisabruptlyterminated,suchasdue tobatteryfailure,whichcanbedetrimentaltoan individualexperiencingpsychiatricsymptoms.
Parkinson’sDisease&Alzheimer’sDisease
Hence,thisreviewisfocusingonevidenceexploringDBStomitigatecognitivedeclineindementia, specificallyAlzheimer’sdisease(AD).Areasonfor thisfocusisthatwhilePDandADpresentvery differentlyclinically,theysharesignificantsimilarities intheirunderlyingpathogenesis.Bothareproteinmisfoldingdisordersresultinginaggregationofmisfolded amyloidproteinsinneurons–inPDthisisalphasynucleinprotein,incontrasttotauandalpha-beta proteinsinAD(Senevirathneetal.,2023).
AnadditionalreasonforexploringADisthe limitedefficacyofitscurrentfirstlinetreatment. Pharmacologicaltreatmentoptionsarecentredaround symptomminimisationratherthancurativetreatment. Availableagentsactbyincreasingcholinergicorantagonisingglutaminergictransmission(F.Massoud,2011) andareonlymildlyandtemporarilybeneficial,reflectinganeedformoreeffectivetherapies.Incontrast, DBSoffersreversible,adaptableandindividualised treatment,inadditiontoalowerriskofbrain-wideor systemiceffectswhichcanoftenlimittheeffectiveness ofconventionaldrugtherapy(Sankaretal.,2014).
Methods
Theevidenceforthisreviewreportwascollated byinputtingthekeywords“DeepBrainStimulation”, “DBS”,“Alzheimer’sDisease”,and“AD”intothe searchenginesCochrane,Embase,GoogleScholar, MedlineandPubMed.Clinicaltrialsofallstagesas wellascase-controlstudieswereincluded.Despitethe statisticallimitationsduetosmallsamplesizesofthe case-controlstudies,theywerechosentobeincluded inthisreviewduetothesparsityofresourcesavailable inthisnewfield.Theinvasivenatureoftheprocedure andfollowinghesitationofpatientsarebigfactors contributingtothislackofcompletedclinicaltrials (Targumetal.,2021).
Toensureclarity,thestudieswhicharebeing investigatedhavebeengroupedaccordingtoareaof stimulation.Theareasthatweretargetedinthestudies consistofthefornix,hippocampus,frontallobeand nucleusbasalisofMeynert.Eachstudyhasdiffering groundsfortheirtargetanditsrelationtothepathogenesisofAlzheimer’sDisease.
Thestudywiththemostextensiveprogressis theADvancetrial(Ponceetal.,2016)–aphaseII trial(Lozanoetal.,2016)thatincludedafollow-up (Leoutsakosetal.,2018)whichwasmulticentred, double-blindandrandomised.Itconcentratedonthe stimulationofthebilateralfornix(“DBS-f”)which isaworkingmemorybundlewhichconstitutesa coreelementofthelimbiccircuits,aswellasone ofthemostimportantanatomicalstructuresrelated tomemory(OishiandLyketsos,2014).Thisareais unequivocallysignificanttotheprogressionofAD.
TheinitialaimofthisstudywasfocusedonprovingsafetyofDBSratherthanefficacy–animportant steptofacilitatefurtherstudiesusingthismethod.
InphaseII,theprimaryobjectivestillremainedto evaluatethesafetyofDBS-finpatientswithmildAD, butwiththesecondaryaimofassessingchangeinclinicalandfunctionalimagingoutcomes.Theparticipants wereindividualsaged45to85withmild,probable AD,enrolledbetween2012-2014.TheyhadtheDBSfimplantedwithoutreceivinganystimulationfor12 monthsandthenprogressedintoactivestimulationthat wascontinuousanddeliveredat130Hz,between3.0 and3.5Volts,andapulsewidthof90microseconds. Therewerenoadjustmentsmadetothisduringthe 12months.Throughassessmentbycognitivefunction testsandPETimagingat6and12months,DBS-f wasshowntoinitiallyincreaseglucosemetabolism, althoughthiswasnotsustainedat12months.The olderpatientpopulationexhibitedclearclinicalbenefit, butthiswasoffsetbytheyoungerpatientpopulation, whichresultedinDBS-fnotshowingasignificant clinicalbenefitoverall.Thefollow-upinvestigatedthe effectofearly-onanddelayedtreatment–onegroup received2yearsofactivestimulationandtheother receivedoneyearofactivestimulationafteroneyear delay.Althoughnosignificantdifferenceswerefound inthisaspect,theresultsdidsupportthefindingof previoustrials,thatpatientsover65yearsoldexperiencedgreaterbenefits.
Aroundthesametime,a2015studyinvestigated theeffectsofDBSontheHippocampus(Sankaret al.,2015),whichisasignificantareainvolvedwith theprocessoflearning,memoryprocessing,andthe generationofepisodicmemory.Intheearlystages ofAD,thehippocampusshowssignificantatrophy andisbeingusedasastructuralmarkerinmagnetic resonanceimaging(MRI).Thestudyconsistedof6 patientswithearlyADwhowerefollowedforthree yearswithactiveDBS.Theassessmentconsistedof MRIscanningtoassessstructuralvolumechanges ofthebrainwhichwereassociatedwithlevelsof glucosemetabolism.Itwasfoundthatthemeanrate ofhippocampalatrophywassignificantlylowerin theDBSgroupwhencomparedtotheirmatched ADgroup.In2out6patientsa5-8%increasein hippocampalvolumewasevenfoundwhichappears tobeofamagnitudesufficienttobringhippocampal volumebacktopre-diseasestate.Inadditiontothe MRIassessment,theADAS-Cogscalewasusedto concludethathippocampalvolumemaybelinkedto cognitivefunction.
Anareawhichwasinvestigatedbuthasnotproven tofindclinicalbenefitisthenucleusbasalisofMeyn-
ert(NBM).Itisacholinergicnucleusinthebasal forebrainwhichprovidesextensiveprojectionstoall corticalareas–thiscorticalcholinergicinputfromthe NBMisimportantforcognitiveprocessing(Nazmuddinetal.,2021).Thusfar,onlyafewphaseItrials havebeencompletedwithnosignificantoutcometo benoted(Kuhnetal.,2015,Turnbull,1985).Although thesestudiesdidnotdemonstrateclinicalbenefits,they didreaffirmthesafetyoftheprocedure.
Amorerecentstudyfrom2018wasinvestigating theeffectofDBSonthefrontallobe(Scharre,2018). Thefrontallobeplaysacrucialroleincognition andbehaviour–includingenergisation(theprocessof initiatingandsustainingaresponse),monitoring,task setting,andbehaviouralandemotionalself-regulation. Theadjacentseptalnuclearcomplexisanimportant sourceofacetylcholine.Thisstudywasthefirststudy notfocusingonthedementiaelementofAD.While theimpactofdementiaonpatientswithADissevere, thisstudymentionedthehardshipthatcomeswith otherfactorssuchasapathy,decreasedinitiativeand curiosity,aswellaspoordecision-making.
Thisstudywasaverysmall,non-randomisedphase Itrialconsistingof3subjectswithmildAD,whowere matchedtocomparisongroups.Continuousstimulation wasappliedforatleast18monthsandtheprimary outcomemeasurewasCDR-SBwhichisawidelyused globalmeasuresummatingsixdomainsofcognitive andfunctionalperformance.Anoteworthyaspectof thisstudywastheadjustmentofparametersbased onthebest-observedneurocognitivetaskresponseand feedbackfromthepatientandcaregiver–thisissimilar totheprocessusedinPDwheretheparametersareadjustedinresponsetomotorcontrolfeedback.Whilethe samplesizeistoosmalltodrawdefiniteconclusions, oneneedstohighlightthesignificantimprovements thatthepatientshavemadewithinthistrialaspatients andtheircaregiversreportedfeelingsofincreased energy,focus,alertness,andattentionwithDBS.One patienthighlightsthiseffectverywell;priortoDBS shewasunabletodoanymealpreparationbutafter2 yearsofDBSshewasabletoorganisetransportation andremembertobringmoneytoindependentlybuy groceriesandprepareasimplemealforherself,even regainingindependencetoselectherownattire.
Onemustnotethesafetyoftheprocedurebeing reconfirmed,whichisacrucialstepforfurtherin-
vestigationstobelaunchedexploringtheefficacyof thetreatment.Mosttrialsinvestigatedtheefficacyas asecondaryobjectivebyusingcognitivescalessuch asADAS-CogandPETimagingtomonitorcognitive improvementandglucosemetabolismlevels–the studyfrom2015alsoincludedhippocampalvolumeas ameasurement.Whilemoststudies,withtheexception oftheADvancetrial,wereattheearlyphaseItrials, somepromisingresultshavebeenfound-especially inelderlypatientswithmildAD,asnotedbythe ADvancetrial.
Theimprovedresponsebyelderlypatientsisunexpectedandtypicallycontrastswithoutcomesseen inothertreatments.Oneexplanationforthisfindingis thattheyoungerpatientshadmoreseverebrainpathologythanolderpatientsdespitebeingsymptomatically comparable,suchthatDBS-fcouldnolongerbeof benefit.Thisaspecthighlightstheheterogeneityof ADandtheneedforfurtherunderstandingofthe underlyingmechanismsandmoreconciseinclusion criteriawhichcanreflectthisheterogeneitywithinthe trials.Furtherresearchonnewbiomarkerscouldbe instrumentalinachievingthisgoal.
Anotherissuethatpreventscoherentcomparison oftheseearlystudiesistheirvaryinglevelofprogress aswellasthedifferingmethodsofassessingDBS’ effectonpreventingADprogression.Thus,inorderto fullybeabletosupporttheuseofDBSanddetermine inwhichareaitisthemosteffective,werequire notonlyahighernumberofparticipantsinlatertrial stages,butalsoabetterunderstandingofthemolecular backgroundofADtofacilitatemoreconciseinclusion criteria.
Areallyimportantfactorthathasnotbeenexploredinallofthesestudies,exceptforthemost recentone,istheaspectofadjustingparameterspostoperation.WhentreatingPDthisisoneofthemost crucialstepsthathavebeenseeninaidinginDBS’ successinPDtreatment.Theadjustmentofparameters(e.g.,voltage,pulsewidthandfrequency)is donewithexternaldevicesthatcancommunicatewith theneuromodulatorofthepatient.Thisadjustment isperformedusuallyinresponsetomotorsymptoms whichprovidesinstantfeedbackduringtheadjustment session(Lozanoetal.,2016).However,ADlacksthis kindofinstantfeedback–thereisnotremorthat canvisiblyreduce.Thus,thereisaneedtoestablish thebestcognitiveteststouseinthisinstance.The omissionofadjustingparametersinthecurrentstudies couldaccountforthelackofstatisticallysignificant
resultsandcognitiveeffect,itsbeneficenceisshown bytheoutcomesofthemostrecentstudywhichdid utilisetheparameters.
Whilethesafetyoftheprocedurehasbeenproven throughanumberofthesestudies,itisimportantto acknowledgetheoccurrenceofsomeadverseeffects.
IntheearlyphaseoftheADvancetrial,otherbrain areasthatareusuallysparedinADprogressionbut werenotspecificallytargeted,werealsostimulatedand producedresults,presumablyrelatedtosubcorticalcorticalorcortical-corticaltrans-synapticeffectsof stimulation.
Asidefromusualsurgicalcomplicationssuchas infection,notablesideeffectsinresponsetotheDBS procedure,includedfallsandheadachestoaltered mentalstatusandseizures.
Anumberofemergingpapershavediscussed DBS’roleinpersonalitychangeinpatientsafteror duringtreatment(Phametal.,2015).Opinionson thistopicvary(Gilbertetal.,2018)andmostof theresearchthathasbeenconductedinDBS’PD treatmentcontinuestolackempiricalevidence,while thenewareasofstimulationproposedbyADtreatment areyettobeinvestigated.Nonetheless,itopensup criticalethicalconcerns.
Moreneuroethicalresearchisessentialtoincorporatefindingsregardingpersonalitychangesintoclinicalpractice,especiallywhenestablishinginformed consent.Apatient’sperceptionoftheiridentitymight playacrucialroleintheirdecisiontoundergothe procedure.
Thesenewfindingswillhavetobeevaluated withinalegalcontext(KlamingandHaselager,2013). Takethehypotheticalscenarioofapersonaccusedof violatingthelawandthatindividualhasjustrecently startedDBS.Couldtheindividualblametheiractions onthenewlyfoundimpulsivenessandaggressiondue totheprocedureandthus,beregardedasnotbe liablefortheiractions?Furtherworkneedstogointo assessingthementalcompetenceandresponsibilityof DBSpatientsinordertoformulatefittingguidelines.
Overall,currentstudiesprovidelimitedcertaintyof theefficacyofDBSinADpatients,theydohowever providecertaintyofitssafetyandpromisingresults
thatneedtobeinvestigatedfurtherinmoreextensive trials.FutureworkneedstotargetanincreasedunderstandingoftheunderlyingmechanismofADand diagnosticmethodswhichcanaccountfortheheterogeneityofthediseaseforthistobereflectedinthe trialsthemselves.Oncestudiescanaccustomcoherent waysofassessingefficacyandadjustingparameters foreachareaofstimulation,comparisonofthebest mechanismandapplicationofDBSwillbeevident. TheintroductionofDBSnotonlyunlocksremarkabletreatmentbreakthroughssurpassingpharmacologicalalternativesbutalsointroducesarealmofethical complexity.Thisrapidlyevolvingsphereofinnovation intechnologydemandsattentionandexploration,presentingunparalleledopportunitiesthatshouldnotbe missed.
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TARGUM,S.D.,FOSDICK,L.,DRAKE,K.E., ROSENBERG,P.B.,BURKE,A.D.,WOLK,D. A.,FOOTE,K.D.,ASAAD,W.F.,SABBAGH,M., SMITH,G.S.,LOZANO,A.M.&LYKETSOS,C. G.(2021).EffectofAgeonClinicalTrialOutcome inParticipantswithProbableAlzheimer’sDisease.J AlzheimersDis,82,1243-1257.
TURNBULL,I.M.(1985).Stimulationofthe basalnucleusofMeynertinseniledementiaof Alzheimer’stype.Apreliminaryreport.AppliedNeurophysiology,48,216-21.
NimueLilithRomeikat isa2ndyearMedicine StudentattheUniversityofStAndrews,Contactat: nlr6@st-andrews.ac.uk
ShikshaGuru Bsc(Hons)Medicine
SushmhitahSandanatavan
Bsc(Hons)Medicine
Abstract—MultiplesclerosisisatypeIVhypersensitivityreactionthatresultsintheformationof fibrousovergrowthswhichcoverthedamagedsectionsoftheaxons.Theseovergrowthsgradually harden,formingplaquesknownasscleroses.ItisadisablingconditioncausedbyTcellsthatdestroy myelinsheathsaroundneuronsandattackoligodendrocytes(myelin-producingglialcellsofthe centralnervoussystem(CNS)),thereforeslowingconduction,resultinginmotor,sensoryand cognitivedeficits.Thereactionsmanifestindifferentneurologicalpatterns(types),withthemost commonbeingRelapsing-RemittingMS(RRMS),wherepatientshaveintermittentboutsofsymptoms flaringupwithperiodsofimprovementinthemiddle;andthemostseverebeingPrimaryProgressive MS(PPMS)wherethepatientgetsoneattackthatisaconstantprogressionofdisabilities(Osmosis). ThispaperaimstounderstandthedifferencebetweenRRMSandPPMSatamolecularlevelby discussingthegrossdifferencesinMRIfindingsofthetwotypes,foundationalpathophysiologyofthe disease,andlastlyexploringthepotentialmechanismsthatcausethepatterns.
SCLEROSIS isMRI,whichisalsousedtodeterminethespecificpatternthepatientisinflictedwith. Gadolinium,atransparentagent,makeslesionsmore apparentinMRIs,hencemakingthemrepresentatives ofactiveinflammationwithintheCNS(Siger,2022). Assuch,gadolinium-enhancinglesionsareacharacteristicfeatureofRRMS.Eveninlaterphasesofthe disease,PPMSpatientshavefewerlesionsthanRRMS patients.ThisisreinforcedbyinformationfromT2weightedMRIresults.Thefrequencyofactivelesions (plaques)isfoundtobefarhigherinRRMSthan inPPMS.Instead,PPMShasbeenshowntohave increasedplaquesinthespinalcord.Ontheother hand,atrophyinthecerebralcortex(Ritccitelli,2010), deepgreymatterstructures(likethalamus,putamen, hippocampusandcingulategyrus)(Fisher,2008),and cerebellumwasmuchfurtheralonginPPMS.This cerebralatrophyexplainstherapidrateatwhichPPMS
patientsdevelopeddisabilities,andcerebellaratrophy correspondedtothephysicalandcognitiveimpairment patterns.ThiswasalsocitedasevidencethatRRMS andPPMShavedifferentunderlyingmolecularmechanisms,giventhattheirgreymatterlesionpatternswere sodissimilar.
Theinitiation(Loma,2011)ofthisreactionis drivenbytheinteractionbetweenantigenpresenting cells(APCslikeBcells,microglia)andT-cells.This activatestheTcells—inthisscenario,theCD4+and CD8+types—whichtraveltothebloodbrainbarrier (BBB)fromthethymustoinfiltrateit.ThreetypesofT cellsareinvolvedinthediseaseprogressiononcetheT cellshavecrossedtheBBB:Th1,Th2andTh17.They producethemultipletypesofcytokinesresponsiblefor axonallossanddemyelination(asshowninFigure1).
Theseseriesofreactionscontributetothethree maincomponentsofMSpathologythatare:CNS plaques,inflammationandaxonalloss.AlthoughT
Figure1. SummarisingtheimmunereactionsresponsibleforcausingmultiplesclerosisinCNS cellsarenotaloneinthisautoimmunereaction,the demyelinationcanalsobeassociatedwiththeinvolvementofCNS-specificglialcellslikeastrocytesthat actasthoughtheyarerespondingtoanactiveinjury, thereforeproducingscarsinthebrain.
Moleculardifferencesinthepathophysiologyof RRMSvs.PPMS
ApaperfromCellPressReview(Baecher-Allan, 2018)explainsthedifferencebetweenRRMSand PPMS:RRMSisanimmune-dependentreaction(i.e. drivenbyimmunecellsmigratingtoCNS)whereas PPMSisbothimmune-dependentandimmuneindependent.Thatis,alongwithcytokine-mediated inflammationandplaqueformation,thereisalsoinjuryasaresultofoxidativestressandmitochondrial injury.RRMSisprimarilyimmune-dependent.ItprogressesbecauseofautoreactiveTcellsthatattack theCNS.Dendriticcellsthatareantigen-presenting activatenaıveTcells,whichmaturetobecomeeither CD4+TcellsorCD8+Tcells,aspreviouslydiscussed.CD4+TcellsarealsoclassedasThelper cells(Th),whileCD8+TcellsareclassedascytotoxicTcells(CT).Thisisparticularlyrelevantto theprogressionofRRMSbecauseofitsroleinthe maturationofimmunecellsandtheproductionof memoryBcells.RRMSis,however,knowntoprogress intosecondary-progressiveMS(SPMS)inlaterstages becauseimmune-independentreactionsoftenbecome responsibleforinflammatorymediatorsafterCNShas beendamaged.
Dysfunctionofmitochondria(Correale,2017)can leadtoaxonallossbycausinganenergydeficiency inthecell,leadingtoionicimbalancethateventually resultsinoxidativedistresswhichinturncausestoxic
hypoxiainthecellandeventuallykillsit.Exploring thisfurtherinconjunctionwithdatafromareview thatusedPETscansonSPMS(whichhasthesame symptomsasPPMS)(Rissanen,2014);showedPET scanspickedupsignsofdiffusemicroglialinflammationinSPMSpatientsincontrasttocontrol.Hence, thisexpandsonthepropositionthatprogressiveMS iscausedbytheCNS’sglialcellsincludingastrocytes andmicroglia.Anotherpaper(Liddelow,2017)identifiedaparticularlyneurotoxicvarietyofastrocytes calledA1whoseprimarydriverismicroglia.From thispoint,especiallypost-CNSdamage,inflammatory moleculesarereleasedincascadereactionsprimarily bynon-Tcells(i.e.Bcells).Bcellsthemselvescan eitheractivateCD4+Tcells(again)orcrossthe BBB,become“follicle-likegerminalcentres”within theCNS,ordifferentiateandbecomeantigen-secreting plasmacellsthemselves.Theycanalsosimplysecrete pro-inflammatorymarkersasseeninFigure1and causeCNSinflammation.Thiswouldexplainwhy immunomodulatorytherapyworkswithPPMSonly untilitdoesnotevolveintoSPMS,anddoesnotwork atallforPPMS.
BothRRMSandPPMSaredemyelinatingautoimmunediseasesthatcausephysicalandcognitive disabilityastheyprogress.Fromthecollectionof reviewsabove,itcanbeconcludedthatRemittingRelapsingMSisdrivenbyTcellsfromtheperipheral adaptiveimmunesystem,whereasPrimary-Progressive MSisdrivenbymicroglia,astrocytesandBcells whicharepartoftheinnateimmunesystemoftheCNS itself.Understandingthisdifferenceintheunderlying mechanismbetweenthevarioustypesofMScan helpmakemoreaccurateinterventionstocombatthe afflictionstheypresent.
OsmosisNotesCNSDemyelinatingDisorders.Availableat: https://www.osmosis.org/notes/CNS Demyelinating Disorderspage-1(Accessed:19thSeptember2023) Siger,M.(2022)‘MagneticResonanceImaginginPrimaryProgressiveMultipleSclerosisPatients’,ClinicalNeuroradiology,32(3),625-641.doi: 10.1007/s00062-022-01144-3
Riticcelli,G.,Rocca,M.,Pagani,E.Rodegher,M., Rossi,P.,Falini,A.,Comi,G.,Filippi,M.,(2010) ‘Cognitiveimpairmentinmultiplesclerosisisasso-
ciatedtodifferentpatternsofgreymatteratrophyaccordingtoclinicalphenotype’,HumanBrainMapping, 32(10),1535-1543.doi:10.1002/hbm.21125
Fisher,E.,Lee,J.,Nakamura,K.,Rudick,R., (2008)‘Graymatteratrophyinmultiplesclerosis:a longitudinalstudy’,AnnalsofNeurology,64(3),255265.doi:10.1002/ana.21436
Loma,I.,Heyman,R.,(2011)‘Multiple Sclerosis:PathogenesisandTreatment’,Current Neuropharmacology,9(3).409-416.doi: 10.2174/157015911796557911
Baecher-Allan,C.,Kaskow,B.,Weiner,H.,(2018) ‘MultipleSclerosis:MechanismsandImmunotherapy’, Neuron,97(4),742-768.
Correale,J.,Gait´an,I.,Ysrraelit,C.,Fiol, P.,(2017)‘Progressivemultiplesclerosis:from pathogenicmechanismstotreatment’,Brain,140(3), 527-546.doi:10.1093/brain/aww258
Rissanen,E.,Tuisku,J.,Rokka,J.,Paavilainen, T.,Parkkola,R.,Rinne,J.,Airas,L.,(2014)‘InVivo DetectionofDiffuseInflammationinSecondaryProgressiveMultipleSclerosisUsingPETImagingandthe Radioligand11C-PK11195’,TheJournalofNuclear Medicine,55(6),939-944.
Liddelow,S.,Guttenplan,K.,Clarke,L.,Bennett, F.,Bohlen,C.,Schirmer,L.,Bennett,M.,Munch, A.,Chung,W.,Peterson,T.,Wilton,D.,Frouin,A., Napier,B.,Panicker,N.,Kumar,M.,Buckwalter,M., Rowitch,D.,Dawson,V.,Dawson,T.,Stevens,B., Barres,B.,(2017),‘Neurotoxicreactiveastrocytesare inducedbyactivatedmicroglia’,Nature,541,481-487. doi:10.1038/nature21029
ShikshaGuru isa3rdMedicineStudentatthe UniversityofStAndrews,Contactat:sg341@standrews.ac.uk
HannahBetts Bsc(Hons)Neuroscience
ThomasBurton Bsc(Hons)Mathematics
LailaDeen Bsc(Hons)Physics
Abstract—Neurodegenerativediseasesaredebilitatingwithadetrimentaleffectonthelivesofthe millionsofpatientssufferingfromthem.Thesediseasesarenotablycomplexinaetiologyandonset. Consequently,themodernpharmaceuticalindustrystrugglestodevelopdrugswhichsuccessfully treatorsignificantlyimprovepatients’symptoms.Thedevelopmentofinnovativediseasemodels aimstofurtherinvestigateneurodegenerativediseasestoachievemoresuccessful pathogenesis-targetingtherapies.Thezebrafish(Daniorerio)modelofneurodegenerativediseasesis providingnovelfindingsregardingneurodegeneration,andpromisingdiscoveriesinthefutureof neurodegenerativediseaseresearch.
NEURODEGENERATIVEDISEASESAREASIGNIFICANTPUBLICHEALTHCONCERN. In2019,57 millionpeoplesufferedfromAlzheimer’sdisease (IHME,2022).By2050,thisnumberisestimated toriseto139million(Alzheimer’sSociety,2024). Neurodegenerativediseasesaccountformorethan500 billionUSDinhealthcarecostsannuallyintheUnited States(US)(Cornblathetal.,2020).Predictionsfrom theWorldHealthOrganization(WHO)forecastneurodegenerativediseasesasthesecondleadingcauseof deathby2040(Wangetal.,2021).Withthissignificant healthcrisisloomingonthehorizon,thedevelopment
ofnoveldrugstotreatneurodegenerationisessential. Developingnoveldiseasemodelstotestthesetreatmentsiscrucialtothefutureofdrugdevelopment. Withaimstofacilitatethesafesttransitionfromthe laboratorytopatients.Thisessaywillexplorethe revolutionaryutilisationofzebrafish(Daniorerio)asa developmentalalternativetocommoninvivomodels ofneurodegenerativediseasesandreportsomeofthe remarkablefindings.
Adrugcanshowenormouspromiseinpreclinical modelsbutstillfailinhumanpatients.Thisgap inresearchispartiallyduetothelargelydistinct physiologiesofhumansandanimals.Thisbarrieris
relevantinneurodegenerativedisease(NDD)research andhasimpededsuccessfuldrugdevelopment.Thus, thereisaconstantsearchforalternativepreclinical modelswhichbettersimulateandpredicttheresultsof neurodegenerationcombattingdrugsandtherapeutics (Fontanaetal.,2021)
Neurodegenerativediseasesaffectmillionsofpeopleworldwideandareinfamousfortheirparticularly debilitatinghallmarksymptoms(Lampteyetal.,2022). TheNDDsthatIwillfocusoninthispaperare themostcommon:Alzheimer’sDisease(AD)and Parkinson’sDisease(PD).IwillbrieflycoverAmyotrophicLateralSclerosis(ALS)andHuntington’s Disease(HD)(Lampteyetal.,2022).Ageisthe primarycontributortoNDDonset,butgeneticand environmentalfactorshavealsobeenattributedtocausation(Lampteyetal.,2022).NDDisprimarilycharacterisedbyneurodegeneration,theprogressivelossof neurons,neuronalstructure,andfunctions(Lamptey etal.,2022).Proteinaggregationormisfoldingis theprimaryculpritofthediseaseprocess(Cornblath etal.,2020).NDDsarechallengingtostudyand treatpredominantlyduetotheirdiverseandcomplex aetiology(Wangetal.,2021).Today,thereisasevere lackofpathogenesis-targetingtherapiestotreatNDD (Lampteyetal.,2022).
Alzheimer’sDiseaseisthemostcommontype ofdementia(Alzheimer’sSociety,2024).Thedisease ischaracterisedbytheaccumulationofamyloid-beta (A)andtauproteins.AccumulationofAleadsto theformationofA-containingplaques.Theseplaques linktoneurofibrillarytangles(NFTs)composedof hyperphosphorylatedtau.Plaqueformationcorrelates withdisruptionofthehippocampalcircuitry,interruptingthebrain’sabilitytoconsolidatememories fromshorttolongterm.ThisleadstoAD’shallmark characteristics:memorylossandmemoryimpairment (Cornblathetal.,2020).
Parkinson’sdiseaseisdefinedbyitscharacteristic symptoms;tremors,musclestiffness,unsteadywalking,anddifficultieswithbalanceandcoordination. Thisdiseaseischaracterisedbyfrontalcortexatrophy, ventricularenlargement,thepresenceofLewybodies withinneuronalcellbodies,misfoldingoftauprotein,
Figure1. ExamplesofInVitro,InVivo,andInSilico ResearchModels(Fontanaetal.,2021).
NFTformationfromhyperphosphorylatedtau,and thedeathofdopaminergicneurons(Cornblathetal., 2020).TheonsetofPDisusuallyaroundage50, afterwhichlifeexpectancysignificantlydeclinesas PDprogresses(Chiaetal.,2022).PDisincurableand moderntreatmentsareonlyeffectiveinprovidinga slightlyincreasedqualityoflifeandlifeexpectancy (Chiaetal.,2022).
IntroductiontoDiseaseModels
Modelsareessentialtoensurethesafety,efficacy, andbodilyresponsetonewdrugsandtherapeutics priortoclinicaltrialtestinginhumanpatients.These modelscanbeinvivo,invitro,orinsilico(Fig.1) (Fontanaetal.,2021).
Insilicomodelsincludebioinformatictoolsand computermodels.Thesearebeneficialduetotheir abilitytoscreencompoundscost-efficiently,availabilityoflargedatasets,andusefulnesswhenrepurposing olderdrugsfornovelapplications.Thedownsideof thismodelisthatitisheavilydependentuponhighprecisiondatawhenbuildingthemodelsandclarity inthealgorithmsused.Thestrongestbenefitsofin silicomodelsarefoundintheirintegrationwithother models(Fontanaetal.,2021).Invitromodelsinclude cellcultures,tissuecultures,andorganmodels.These modelsarefast,simple,andcheap(Fontanaetal., 2021).Withhighreproducibilityandoutputdatathat iseasytoanalyseandintegratewithothermodels,in-
vitromodelsarecommonandfavouredinresearch. Nonetheless,thismodelhasitssetbacks:changesin physiologycanmakethismodelinapplicableinclinicaltrialtargets.Furtheritissusceptibletounnatural growthkineticsanddatacollectionmaynotcorrelate withresultslaterseenininvivomodels(Fontanaetal., 2021).Finally,thereareinvivomodels.Thesemodelscanincludelargevertebrates:mice,rats,rabbits, andnon-humanprimates(primarilymacaque).These modelshaveshorterlifecyclesthanhumans,allowingresearcherstoobservedrugeffectsthroughouta lifespan.Manyofthesemodelsadditionallypresent geneticsimilaritytohumans,lesseningtheriskofunforeseencomplicationsinclinicaltrials.Furthermore, animalmodelscanbegeneticallymodified,allowing forthestudyofspecificphysiologyandpathophysiologyofdiseases(Fontanaetal.,2021).Althoughhighly beneficialinresearch,theissuessurroundinginvivo modelsaresignificant.Firstly,ethicalissuesareraised inanimalsbeingpurposelybredforexperiments.The processofconductingresearchonliveanimalsfails toaccountfortheemotionalandmentalimpacton researchersandanimalcaretakers.Additionally,these modelsareexpensive,requiringdailycare,licensesto workwiththem,housing,painkillers,anesthetics,and associatedinstruments.Alternativelivingorganisms likemicroorganisms(e.g.,Saccharomycescerevisiae (yeast),lowervertebrates(e.g.,fish),andinvertebrates (e.g.,roundworms,fruitfly)arealsousedasin-vivo researchmodels.Thesemodelsarebeneficialasthey arenotrecognisedtopresentethicalbarriersandare morecost-effectivemodelsthatcanstillbewidely appliedtostudymechanismsofdrugeffects(Fontana etal.,2021).However,itisworthnotingthattheir lackofmammalianphysiologyreducestranslatability tohigherorganismsandhumans(Fontanaetal.,2021).
Thezebrafish(Daniorerio)modelisanalternative invivomodelutilisedinresearch.Ithasbecome increasinglypopularasareplacementforlargervertebrateanimals(Fontanaetal.,2021).Overthepast twodecades,zebrafishhavegainedsignificanttraction asamodelorganisminformingourunderstandingof thepathologyofdiseasesanddrugtoxicity(Steven etal.,2020).Initially,thezebrafishmodelwasused tomonitorwatercontaminationandtestfortoxic substances(Wangetal.,2021).Itsapplicationsin medicalresearchoriginatedfromtheUniversityof Oregon,wherescientistsfirstusedthemodeltoexplore thegeneticbasisofvertebrateneuraldevelopment (Eisen,2020).Thezebrafishisatropicalfreshwater fishthatisabout5cmlongwhenmature.Ithasbeen usedinlaboratorysettingsinexperimentsonsocial behaviour,somaticmutationsandrecombinanttests, developmentalbiology,andseizureassays(Freireset al.,2017).Thesefishareusedextensivelytoresearch thebiologicalandtoxicologicaleffectsofchemicals, includingenvironmentalcontaminantsandpharmaceuticaltoxicology(Stevenetal.,2020).Further,theyare usefulinlocomotionstudiesandareusedtostudy convulsantandantiepilepticdrugs(Stevenetal.,2020). Geneticmanipulationinzebrafishhasevenallowedfor theanalysisofneurodevelopmentaldisorders(autism), neuropsychiatricdisorders(anxietyanddepression), andneurodegenerativediseases(ADandPD)(Steven etal.,2020).
EthicsofAnimalModelsinResearch
Animalmodelsremainindispensableinresearch. Despiteeffortstofindalternativemodelsandexpand theusageofinvitroorinsilicomodels,theywill likelystaythiswayfortheforeseeablefuture.Thereis asignificantdemandformoreresearchtobeinvested indevelopingandoptimizingalternativestoinvivo modelstoovercometheestablishedandsignificant ethicalconcernsinmodernresearchstrategies(Fontana etal.,2021).
Thezebrafishwasestablishedasanexcellentresearchmodelbasedonseveraldevelopmentalcharacteristics.Unlikemanyfishspeciesandotherprospectivemodels,thezebrafishisnotaseasonalbreeder, meaningembryoscanbeobtainedthroughouttheyear. Additionally,asinglefemalezebrafishcanproduce hundredsofeggsinasinglespawning,allowingforthe potentialofhighnumbersofcloselyrelatedembryosto beusedwithinasingleexperiment.Zebrafishembryos developrapidly,hatchinginthreedays,atwhich pointthedevelopmentofindividualcells/structures canalreadybeobserved.Additionally,unlikemiceor humans,zebrafishcanregeneratetheirlimbs,hearts, retinas,spinalcords,andevenbrains(Eisen,2020). Zebrafishmodelsareeasytohandleinthelab,andas alow-costmodel,presentfewerobstaclesthanlarger vertebratesintheircareandstudy.
Further,theirbodiesarenearlytransparentduringearlydevelopment(Fontanaetal.,2021).This
transparencyallowsfordetailedvisualisationofthe zebrafishanatomyandnon-invasiveobservationin research(Freiresetal.,2017;Stevenetal.,2020). Additionally,thezebrafish’srapiddevelopmentcycle meansitsblood-brainbarrierisdevelopedjust72hours postfertilisation(Wangetal.,2021).
Humansandzebrafishhaveahighhomologyof 71%,whichiscrucialtotheirtranslationtotreating diseasesinhumans(Freiresetal.,2017).Withthe zebrafish’swholegenomesequencealreadyavailable, thesemodelsareanunderstandablyappealingalternativeformolecularandgeneticstudiesincancers, heartdiseases,andneurodegenerativediseases.Itis alsoemergingasapromisingpreclinicalmodelfor screeningnanomedicines(Fontanaetal.,2021).
Chemicalsanddrugscanbeefficientlydelivered tothezebrafishsimplybyaddingthemtotheirwater enclosure(Freiresetal.,2017).Additionally,zebrafish aresmallenoughtofitintoindividualwellsonamultiwellplate,allowingforhundredsofwholeorganisms tobestudiedallatoncewithinaplatformthatcan fitinaperson’shand.Experimentslikethisapplytest substancesnecessaryforthedosageofonlyoneortwo micetohundredsofzebrafishatonce(Stevenetal., 2020).
Withadvancesinnovelimagingstrategies,traceablebehaviouraltests,andinnovativehigh-throughput drugscreeningmethods,zebrafisharebeingwidelyacceptedasmodelsformanynewdrugtargets,including apromisingfutureinNDDtreatment(Wangetal., 2021).
ZebrafishasModelsofNDD
Zebrafishareshowinggreatpromiseinstudying theunderlyingmechanismsandpathologyofneurologicaldiseasesvianeurotoxicityandbehavioural analyses(Stevenetal.,2020).Thezebrafish’scentral nervoussystem(CNS)iscomparativelysimilarto othervertebratesandiswell-establishedinmultiple stagesofitslifespan.Further,behaviouralstudieshave shownastrongassociationbetweenzebrafishneural functionsandhumanbrainregions(Stevenetal., 2020).Itpresentsneurotransmittersystemsrelevantto neuropharmacology,includingdopamine,GABA,glutamate,acetylcholine,andmore(Stevenetal.,2020). Zebrafishmodelsadditionallyhavehuman-resembling neurochemicalpathwaysanddisplayhallmarksofhumanbraindisorderpathologysuchasproteinaggregation,neurodegeneration,andactivationofglialcells (Chiaetal.,2022).
Figure2. TheNDDZebrafishModelsandHigh ThroughputDrugScreeningPlatform(Wangetal., 2021).
Figure3. ZebrafishModelComparedtoHumanDiseaseConditionofAD:HumanLeft,ZebrafishRight (Chiaetal.,2022).
Zebrafishhavesuccessfullybeenappliedtomodel AD,PD,HD,andALS(Chiaetal.,2022).Further, theyhavebeenfoundtosharemanyriskgeneswith humansthathavebeenidentifiedinvariousneurodegenerativediseases(Chiaetal.,2022).Through imaging,researcherscanobservethemigrationofneuronalprecursors,movementsofmicroglia,andeven neuronalcelldeathwithinthezebrafishmodel(Fig. 2),(Chiaetal.,2022).
TheZebrafishmodelofADissuccessfulinrecapitulatingA-sheetaggregation,increasedneuronal toxicityandneuronaldeath(Fig.3)(Chiaetal.,2022).
ThezebrafishADmodelactsasatautransgenic model,expressingtauhyperphosphorylation,tauaccumulation,andneuronalcelldeath,closelyresembling
theneurofibrillarytangles(NFTs)seeninhumanAD. Inarecentstudy,azebrafishlinegeneratedexpression ofamutanthumantau:A152T.Thisincreasedcellular apoptosis,neurodegeneration,andimpairedlocomotorbehaviourinresponsetostimuli.Itrecapitulated classichallmarksofADpathology,includingtauhyperphosphorylationandNFTformation.However,the tauzebrafishmodelhaslimitations.Tauhyperphosphorylationonlyaccumulatedinthespinalcordand notinthebrainofthelarvalzebrafish.Additionally, hyperphosphorylationofanothermutanthumantaudid notresultinneurodegenerationorNFTsformationin thezebrafishbrain(Chiaetal.,2022).
AnotherzebrafishADmodelistheAmodel.In thezebrafish,Aplaysasignificantroleinmaintaining healthycerebrovascularfunctioning,butincreasedA canleadtounordinarycerebrovascularbranchingin thehindbrain.InthezebrafishmodelofA,thezebrafishreceivesmicroinjectionsofsyntheticApeptides;thisisthemostdirectapproachtomodellingA aggregation,tauproteinphosphorylation,andinduced toxicityofADpathologyinzebrafish.
OkadaicAcid(OKA),mostwidelyusedinpharmacologicallyinducingAD-likephenotypes,hasalso beenappliedtoproducezebrafishADmodels.OKA successfullyinducedtauhyperphosphorylation,depositionofA,andformationofsenileplaques,mimicking thehallmarksofADpathology.Italsoresultedin learningandmemorydeficitsinthezebrafish(Chia etal.,2022).
ZebrafishADmodelscanalsobeusedtomodel PSENgenes,whichareimplicatedinthehereditary formsofADandplayaroleinplaque-buildingA peptides.WhilecompletePSEN1wasfoundtobe lethalinmicemodels,zebrafishwereviableasPSEN models(Chiaetal.,2022).
Overall,theADmodelinzebrafishislimitedbut hasremarkablepotentialasadevelopingmodelfor modernresearchintopotentialADtreatments.
PotentialTreatmentsforADintheZebrafishAD Model
Theendgoalofutilisingzebrafishasamodel ofADandotherneurodegenerativediseasesisto developrelateddrugsthatminimisesideeffectsand avoidtriggeringunwantedpathways,agoalthathas yettobeachieved(Wangetal.,2021).CurrentAD therapiesareonlytemporarilyeffectiveinimproving learningandmemory.Thesetreatmentsworkthrough themaintenanceofAChlevelsandcholinergictrans-
Figure4. DrugsIdentifiedforADTreatmentinZebrafishModels(Wangetal.2021)
missionbyAChEinhibitorsandregulatingglutamatergictransmissionbyblockingNMDAreceptors(Wang etal.,2021).Basedonfindingsfromresearchon thezebrafishADmodel’saetiologyandbehaviour, severalhypotheseshavebeenproposedregardingwhat mayinduceADdevelopment.Theseincludetheamyloidcascadehypothesis,tauhyperphosphorylation,the cholinergichypothesis,neuroinflammation,andmetal ions(Tbl.1),(Wangetal.,2021).
Theproteininhibitor,GSK3,isknowntophosphorylatetauatmultiplesites.Itsisoform,GSK-3, iscrucialinthehyperphosphorylationofabnormal tau,anADpathologysimilartothatseeninhuman ADpatientsandzebrafishmodelsofAD.InembryoniczebrafishADmodels,whereA42,acommon biomarkerofADpathology,wasinjectedintothe hindbrainventricle,Lithiumchloridewasfoundto actasaninhibitorofGSK-3,reversingcognitive deficitsandtauhyperphosphorylation.Thiswasfurther establishedwhenLithiumchloridewasappliedin additionalzebrafishmodels,whereitwasfoundto controlandprotectzebrafishlocomotorfunctionand dephosphorylatetau.Furthermore,itdemonstratedthe preventionofmemoryimpairmentandregulationof AChEactivityinotherzebrafishmodelsofAD.The commerciallyavailableinhibitorofGSK-3,TDZD-8, effectivelyreducedthezebrafishmortalityrateand improvedcognitiveimpairmentinducedbyokadaic acid.AnotherGSK-3inhibitor,AR-534,wasfound tominimisetauhyperphosphorylationinzebrafish embryos.Overall,GSK-3inhibitorsshowpromisein
thedevelopmentofADtreatment.However,thereare stilllimitationstobeovercomeinthesemodels,and furtherresearchisneededtodeterminewhichinhibitor isthemosteffectiveandleastlikelytocausesecondary effects(Wangetal.,2021).
Numerousdrugtargetshavealsobeenidentified andareactivelybeingresearchedintheregulation ofthecholinergicsystem,whichhasguidedAD treatment.Additionally,manynaturalcompoundshave raisedinterestingleadsforADdrugdesign.Further, novelanti-tauopathydrugsforADtreatmenthavebeen discoveredinthepreventionoftauhyperphosphorylation.Onesuchexampleisthecyclin-dependent kinase5(CDK5)inhibitors,whichhavebeeneffectiveagainstneurodegeneration,neuroinflammation, andsynapsedensityinzebrafishADmodelsbymodulatingthephosphorylationofmicrotubule-associated proteins.Nanoparticleresearchhasalsoaccelerated ADdrugdiscovery,withstudiesbeingconductedto developnanomedicinesagainstADorhumanamyloid diseasesusingthezebrafishmodel(Wangetal.,2021). NanoparticletreatmentresearchhasprovidedneuroprotectionfromA-inducedtoxicityinADzebrafish models(Chiaetal.,2022).
ThePDmodelisoneofthemostestablished inzebrafishresearch.Thezebrafishmodelpresents systemswithahighresemblancetothoseofhumans, includingthesynucleinfamily.Synucleinsareafamily ofneuronproteins,including-,-,and-synuclein.Zebrafishandhumansynucleinssharehighsequencesimilarity.ThemostrecognisablePD-associatedgenein humans,SCNA,whichencodes-synuclein,ispresent inthezebrafishmodel.Mutationsin-synucleinare associatedwithearly-onsetfamilialandsporadiccases ofPD.Studiesfoundthattheaggregationofhuman -synucleinproteininzebrafishlarvaemodelsledto areductioninmitochondrialactivityandanoverall increaseinthepresenceofreactiveoxygenspecies (ROS).Thisconsequentlyledtoneuronalapoptosis andcelldeath,reflectingPDpathology(Chiaetal., 2022).Thismodelalsosuccessfullyreplicatesclassic PDsymptoms,includingneuroinflammation,locomotion,andbehaviouraldysfunction(Fig.4).
Further,thesemodelsallowforbehaviouraltests, enablingresearcherstomeasuredepression,anxiety, socialinteractionaversion,andaggression.Theseare allmoodchangesnotedinpatientswithPD(Chiaet al.,2022).Thismodelisalsogoodforinvestigating
Figure5. ZebrafishModelComparedtoHumanDiseaseConditionofPD:HumanLeft,ZebrafishRight (Chiaetal.,2022).
themechanismsofaggregateformationandtheconsequencesofgenemutationorpesticideexposurein theCNS(Chiaetal.,2022).
WhileprovidingnovelinsightsintoPD,thismodel hasitslimitations.Firstly,thezebrafishmidbrain lacksdopaminergicneurons,andthedegenerationof dopaminergicneuronsisahallmarkofPDpathology. Additionally,resultsfromstudiesusingthismodel havebeenfoundtovary,andthereisanotedneedto enhancebehaviouralscreensforpsychiatricsymptoms ofPDinthezebrafishmodel(Chiaetal.,2022).
PotentialTreatmentsforPDfromtheZebrafish PDModel
CurrentPDtreatmentshaveshowntemporaryreliefofmotorandnon-motorPDsymptomsandasimultaneousslowingofPDprogression.However,there isstillnoidealtreatmentthatcaneffectivelydelaythe progressionofthisdebilitatingdisease.Thisisdone throughL-DOPAdopamineagonists,MAOinhibitors, catechol-O-methyltransferase(COMT)inhibitors,and anticholinergics(Wangetal.,2021).
ThereplacementofL-DOPAdopamineprecursor isthemosteffectivetreatmentforimprovingmotor function,butinlong-termapplication,thistherapy hasbeenfoundtoworsendyskinesia.Researchinto drugdiscoveryusingthezebrafishPDmodelhasadvantageouslyemployedhigh-throughputscreeningto evaluatenumerouspotentialdrugtargetsandproposed therapies.
MAO-Binhibitorswithhighpotencyhavebeen designedtoimprovetherapeuticbenefitsanddecrease thesecondaryeffectsofthesetherapies.Further,PD therapiestargetingthemitochondrialdysfunctionimplicatedinPDpathologyhaveshownpromisein research(Wangetal.,2021).Onestudytested1600 FDA-approvedbioactivedrugsinzebrafishmodels andhighlightednovelmoleculeswithantiparkinsonian potential.Thesediscoveriescouldbetransformedinto
drugtargetsandsignificantlyimpactthefutureofPD treatment(Wangetal.,2021).
Theincreaseinmodernnanoparticleresearchhas alsoreachedPDdrugdiscovery,asnanoparticlesare beingdevelopedforzebrafishPDmodelstoprotect DAneuronsagainstcytotoxicitywithnospecifictoxic secondaryeffects(Wangetal.,2021).Additionally,a growingbodyofevidencehassupportedtheuseof immune-targetedtherapiesaspotentialtreatmentsfor PD.Epidemiologicalstudieshaveconfirmedthatnonsteroidalanti-inflammatorydrugsmayplayabeneficial roleindrugsbeingdevelopedtotreatPD.Zebrafish modelsofPDwereusedtoverifythesefindings, andanti-inflammatorydrugswerealsofoundtobe effectiveinimprovingPD’smotorsymptoms.
Otherneurodegenerativediseases,suchasALS andHD,haveemployedthezebrafishasanin-vivo diseasemodelintreatmentdevelopmentandthefurtheringofknowledgeofdiseasepathology(Wanget al.,2021).
InALS,geneticzebrafishmodelshavesignificantlyacceleratedthedevelopmentandproposalof newdrugcandidatesfortreatment.Fromstudyingthe pathologyanddiseaseonsetofALSinzebrafish,it hasbeenfoundthatcalciumchannelagonisttreatment ofzebrafishcanrestorebehaviouralandcellulardeficienciesconsequenttoALSonset(Wangetal.,2021). However,currentALStherapiesthathaveachieved FDAapprovalonlyprovideamoderateimprovement insurvival(Wangetal.,2021).
Further,inHD,geneticzebrafishmodelsarealso beingusedtostudydiseasecharacteristicstodevelop futuretreatments.Researchershavefoundthatamyloidprecursorproteins(APP)maycontrolneuronal excitabilityviatheirinteractionwithprionproteins, makingthemapotentialpharmaceuticaltargetfor futuretherapiesforpriondiseasesandassociatedneurodegenerativedisorders(Wangetal.,2021).
LimitationsoftheZebrafishModel
Thismodelcomeswithitslimitations.Forexample,zebrafishlacksomeofthemammalianorganshumanshave,includinglungs,prostate,skin,andmammaryglands(Freiresetal.,2017).Additionally,they lackaneocortex,meaningthismodelcannotbeused tostudycognitiveprocessesthatrelyonthatregion (Stevenetal.,2020).Althoughdisplayingincredible
innovativepotentialasamodelinneurodegenerative diseases,thezebrafishmodelfacessomelimitations. TheuseofMOknockdownsinzebrafishmodelshas produceddiscrepanciesbetweenmorphantphenotypes andmutations,leadingtogenedeletion,prematurestop codons,andoff-targeteffectssuchasmorphological deformities(Chiaetal.,2022).
Further,duetothegapbetweenzebrafishand humansintermsofneurodegenerativedisordermorbidityanddrugtreatment,challengeshavearisenin translatingdrugsfrommodeltoclinicaltrial.Many drugscreeningsperformedinzebrafishmodelshavea shorttherapeuticwindow,anditisdifficultforthese drugstocrosstheblood-brainbarrierbeforedegrading withoutemployingsuitabledrugdeliveryapproaches. Additionally,thegeneticandenvironmentalfactorsinvolvedinthepathogenesisofsomeneurodegenerative disorders,andthegeneralnecessityforadeepened understandingofneurodegenerativediseases,present obstaclesinattemptingtotreatuniformlyandincrease thepotentialneedtopersonalisetreatmentapproaches (Wangetal.,2021).
Thereisanecessityforfurtherdevelopmentof thezebrafishmodelandtheexperimentalmethods associatedwithit.Better-designedbehaviouralassays couldbettermirrortherepertoireofprogressivemotor disordersinneurodegenerativediseases.Additionally, moreresearchneedstobedoneintohowzebrafish metaboliseandexcretedrugsintheiraqueousenvironmentscomparedtomammalianmodels(Chiaetal., 2022).
UndeniableInnovationandtheFutureof ZebrafishinNeurodegenerativeDisease Research
Thezebrafishmodelhasnumerousadvantages, providingessentialfoundationsforNDDpathology, drugdiscovery,andinnovationinthefutureoftreatmentforNDD.Moreresearchisbeingperformed tounderstandthemechanismsbehindmoderndrug discoveriesinthezebrafishmodeltofurthertheunderstandingofsecondaryeffects,predicttheviabilityof drugsinclinicaltrials,andidentifymorepotentialdrug targets,furtherinstigatingthepromiseandpermanence ofthismodelinNDDresearch.
Themostsignificantinnovationutilisedinzebrafishresearchisthedevelopmentofrapid,highthroughputreadoutsonlargesamplesizes.Thisis particularlybeneficialinclinicaldrugdiscoveryand isuniquetozebrafish,ashundredsofsamplescan
Figure6. VertebrateAutomatedScreeningTechnology(VAST)BioimagerforHighThroughputScreeningofZebrafishandDrugCandidates(Chiaetal., 2022).
Neurodegenerativediseasesareaprevalentand increasingpublichealthissue.Theseparticularlydebilitatingdiseases,characterisedbytheirextremely complexaetiology,affectmillionsofpeopleworldwide andcostbillionsinhealthcare.
Anumberofpharmacologicaldrugshavebeen designedforuseinNDDtreatment,butoverthepast severaldecades,therehasbeenastruggletotranslate frommodeltoclinicaltrial(Wangetal.,2021).The developmentofinnovativediseasemodelsthatcan serveasalternativestomodernin-vivoandin-vitro modelsisimperativeintestingthesenewtreatments andcarryingthemfromthelabtopatients.
beplacedintoawellplateandsimultaneouslychemicallyscreened.Oneexampleofinnovativetechnologyfurtherdevelopingthislabtechniqueforfuture studiesusingzebrafishisthevertebrateautomated screeningtechnology(VAST)Bioimager(Fig.5).This technologyisshowingsignificantpromiseinassessing blood-brainbarrierpermeability,whichisessentialto developingnovelneuro-specifictherapies.Itisalso anexcellenttechnologytotestnovelnanoparticle researchandevaluatebiocompatibilityandtoxicity. Furthermore,innovativepigmentationmutantsarebeingdevelopedinthehopestheycanbeappliedinthe imagingofadultzebrafish(Chiaetal.,2022).
ModerninnovationsinCRISPR/Casgeneeditinghaveshownsignificantpotentialinovercoming alimitationofthezebrafishmodel:MOknockdown discrepancies.MOknockdowndiscrepanciesareresponsibleforsecondarymorphologicaldeformitiesand off-targeteffects.GeneeditingusingCRISPR/Casis beingemployedtopreventsucheffectsandimprove zebrafishmodels,especiallyforADresearch(Chiaet al.,2022).
Finally,argumentshavebeenmadethatthezebrafishmodel’suseislimitedtoitslarvalstage,where itpresentsastransparent.However,innovativeresearch isprovingthatthisisn’tentirelytrue,asthezebrafish provesusefulasamodelthroughoutitslifespan.An increasingamountofresearchisexaminingzebrafish adulthoodandworkingtodefinedevelopmentalages andmodelmaturity(SinglemanHoltzman,2014).
Thezebrafishmodeliscontributingto groundbreakingprogressindrugdiscovery.Diseasemodifyingtreatmentshavegainedtractionduetotheir effectivenessinalteringtheearlystagesofdisease onset(Wangetal.,2021).Thezebrafishmodelhas proposednumerousbreakthroughsinunravellingthe mysteriesbehindNDDaetiologyandaidingindrug developmentandnewtreatmenttherapies.
FromitsbeginningsinexaminingwatercontaminantsandtoxicologyatalabinOregon,thislittlefish hascomealongway,provingitselftobeamodelwith significantbenefitsinresearch.Itstransparencyduringdevelopmentalstages,cost-effectiveness,andefficiencyasalaboratorymodelarekeyadvantages.Furthermore,theintegrationofthezebrafishmodelwith newtechnologiesandadaptationsofhigh-throughput drugscreeningplatformshasfurtherestablishedits roleinNDDresearch.
Ithasledtotheidentificationoftheprotein inhibitorGSK3intauphosphorylationinADonset andfurtherinvestigatedtheapplicationsoflithium chloride,naturalcomponenttherapies,regulationof thecholinergicsystem,andnanoparticletreatments intreatingAD.Additionally,ithasunderlinedthe importanceofL-DOPAdopamineagonistsandMAO inhibitorsinPDpathologyandallowedforthetesting ofover1600FDA-approvedbioactivedrugs,highlightingnoveldrugtargetsforprotectingDAneuronsin PDonset.Thezebrafishmodelhasalsounveilednovel findingsinfurtherNDDresearchasamodelforALS andHD.Needlesstosay,thislittlefishhasearnedits stripesandhasundeniablycementeditsplaceinthe futureofNDDresearchanddrugdevelopment.
Alzheimer’sSociety(2024)Factsfor themediaaboutdementia.Availableat: https://www.alzheimers.org.uk/about-us/news-andmedia/facts-media::text=How
Cassar,S.,Adatto,I.,Freeman,J.,Gamse,J., Iturria,I.,Lawrence,C.,Muriana,A.,Peterson, R.,Cruchten,S.,andZon,L.(2019)‘UseofZebrafishinDrugDiscoveryToxicology’,Chemical ResearchinToxicology,33(1),pp.95-118.doi: 10.1021/acs.chemrestox.9b00335.
Chia,K.,Klingseisen,A.,Sieger,D.,andPriller,J. (2022)‘Zebrafishasamdoelorganismforneurodegenerativedisease’,FrontiersinMolecularNeuroscience, 15,pp.1-27.doi:10.3389/fnmol.2022.940484.
Cornblath,E.,Robinson,J.,Irwin,D.,Lee,E.,Lee, V.,Trojanowski,J.,andBassett,D.(2020)‘Defining andpredictingtransdiagnosticcategoriesofneurodegenerativedisease’,Naturebiomedicalengineering, 4(8),pp.787–800.doi:10.1038/s41551-020-0593-y.
Eisen,J.(2020)‘HistoryofZebrafishResearch’, APAcademicPress,pp.3-14.doi:10.1016/B978-012-812431-4.00001-4.
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Freires,I.,Sardi,J.,deCastro,R.,Rosalen,P. (2017)‘AlternativeAnimalandNon-AnimalModelsforDrugDiscoveryandDevelopment:Bonus orBurden?’.SpringerLink,34,pp.681–686.doi: 10.1007/s11095-016-2069-z.
Lamptey,R.N.L.,Chaulagain,B.,Trivedi,R., Gothwal,A.,Layek,B.,Singh,J.(2022)‘AReview oftheCommonNeurodegenerativeDisorders:Current TherapeuticApproachesandthePotentialRoleof Nanotherapeutics’,Internationaljournalofmolecular sciences,23(3),pp.1851.doi:10.3390/ijms23031851.
Singleman,C.andHoltzman,N.(2014)‘Growth andMaturationintheZebrafish,DanioRerio:AStagingToolforTeachingandResearch’,Zebrafish,11(4), pp.396-406.doi:10.1089/zeb.2014.0976.
Wang,X.,Zhang,J.B.,He,K.J.,Wang,F.,and Liu,C.F.(2021)‘AdvancesofZebrafishinNeurodegenerativeDisease:FromModelstoDrugDiscovery’, FrontiersinPharmacology,12(713963),pp.1-19.doi: 10.3389/fphar.2021.713963.
HannahBetts isa2ndyearNeuroscienceStudent
attheUniversityofStAndrews,Contactat:hkb2@standrews.ac.uk
RishiRavishankar
Bsc(Hons)Medicine
SushmhitahSandanatavan
Bsc(Hons)Medicine
LailaDeen Bsc(Hons)Physics
Abstract—Strokeisadiseasewithhighmortalityandmorbidity,carryingwithitmanydebilitatingand permanentimpacts,suchasmotor,sensory,andcognitiveimpairmentsduetobraininjury. Neuroplasticity,thebrain’sabilitytoformnewconnections,playsacrucialroleinneuralrecoveryas it’sdrivenbylearning,behavior,andinjury.Whileneuroplasticityisanongoingprocess,thelevelof neuroplasticitythattypicallyoccursthroughoutlifeisnotveryeffectiveforneurologicalrecovery post-stroke.Thishasledtotheemergenceofnewtechnologiesinthefieldofstrokemedicine,aiming totacklethisissue.Theideaistopromoteneuroplasticitywithinthebraintoenhancestrokerecovery. Amongtheseinnovationsarebrain-computerinterfaces(BCIs),whichtranslatebrainactivityinto computercommandsenablingtheoperationofdiversetechnologicaldevicesandvirtualreality therapy(VRTherapy),thesimulationofavirtualandinteractableenvironmenttorestorefunction. Thereisanever-growingbaseofevidencetosuggestthattheseapproachesareeffectiveinstroke rehabilitationandhavethepotentialtobeusedinclinicalpractice.However,moreresearchisneeded tounderstandthespecificmechanismsofeachtreatmentandtheiradaptability.
NEUROPLASTICITYISDEFINEDASTHENERVOUSSYSTEM’SCAPACITY toadaptandrestructure itsorganization,function,andconnectionsinresponse tointernalorexternalstimuli.Insimplerterms,it referstothenervoussystem’sabilitytobringabout structuralandfunctionalchanges(Crameretal.,2011). Learning(Galv´an,2010)andmeaningfulbehaviour (KolbWhishaw,1998)arekeydriversthatinduce thesechanges.Muchlikelearninganddevelopment, injuryplaysasignificantroleindrivingneuroplasticity, actingasahugedrivingforceforneuralchangesona cellularlevel,suchassynapticchanges,axonalsprouting,dendriticremodellingetc(Zoteyetal.,2023).
Neuroplasticityisdefinedasthenervoussystem’s capacitytoadaptandrestructureitsorganization,function,andconnectionsinresponsetointernalorexternal
stimuli.Insimplerterms,itreferstothenervous system’sabilitytobringaboutstructuralandfunctionalchanges(Crameretal.,2011).Learning(Galv´an, 2010)andmeaningfulbehaviour(KolbWhishaw, 1998)arekeydriversthatinducethesechanges.Much likelearninganddevelopment,injuryplaysasignificantroleindrivingneuroplasticity,actingasahuge drivingforceforneuralchangesonacellularlevel, suchassynapticchanges,axonalsprouting,dendritic remodellingetc(Zoteyetal.,2023).
Strokeisdefinedasalocalizedandacuteneurologicaldeficit/injuryinthebrain,whichusually occursduetoinjuryofthebrain’svasculatureand happenstobethesecondleadingcauseofdeathand disabilityglobally.Theresultingbraindamagecan leadtodifferentaftereffectsthatcanvarythroughouta largespectrumofissues,includingproblemsrelatingto
motormovements,sensation,andcognition(Murphy Werring,2020)—whichcanhaveamajoreffect onapatient’squalityoflife.Overtime,however, neuroplasticitywithinthebrainoccursinresponseto thestroke-relatedinjurytoinducehealing(Careyet al.,2019).Thatbeingsaid,thelevelofneuroplasticity thatthebrainundergoesthroughoutadultlifeisnot sufficienttoallowanyformofmajorrecoveryfollowingbraindamage(Mar´ın-Medinaetal.,2023).Thisis substantiatedbythefactthatdespitebestpost-stroke rehabilitationefforts,one-thirdofpatientsshowpoor recoveryoneyearaftertheevent(Laietal.,2002).To tacklethisissue,therehavebeenmanynewemerging technologiesinthefieldofstrokemedicinetoenhance theseneuroplasticchangestoaidrehabilitation.
Figure1. Graphicshowingtherelationshipbetween experience,neuroplasticityandstrokerecoveryas showninCareyetal.(2019)
Brain-computerinterfaces(BCIs)areoneofthe newtechnologiesthathavecometotheforefrontof neuroplasticity-basedinterventionstoimprovefunctionaloutcomesforstrokepatientsexperiencingvariousdegreesofneurologicalimpairment.ABCIsystem offersareal-timeviewofbrainactivity,allowing interactionwiththeenvironmentthroughcontrolsignalsgeneratedbybrainactivityalone(Maneetal., 2020).Insimpleterms,theyworkbyconvertingbrain signalsintocomputercommands,allowingthecontrol ofvarioustechnologicaldevices.Thishasbeenfound tostimulateneuroplasticchanges,indicatingitsuseful widerimplicationsinthefieldofstrokemedicine (Mar´ın-Medinaetal.,2023).Whenitcomestorehabilitatingthemotorsystemspecifically,BCIsystems caninterprettheintentiontomovethelimbthat’sbeen affectedanduseittoprovidesensory-motorfeedback indifferentforms,includingactualmovement,visual feedback,andtouchfeedback.Thereisincreasing
evidencethatBCIscanpromotefunctionalrecovery bybridgingthegapbetweenthedesireformotor movementandthecontingentsensoryfeedbackthat hasbeencreatedbystroke(Maneetal.,2020).
BCIsfunctionviathreemainstages:signalreception,signalprocessing,andmachineresponsegeneration.Thefirststep(signalreception)canbeclassified asbeinginvasiveornon-invasive.Althoughcarrying surgicalrisk,theformerproducesamuchclearersignal (e.g.,ECOG,corticalpenetratingelectrodes,etc.).The latterismorecommonlyusedandismorescientifically supportedintermsofitsefficacy(e.g.,EEG).Thesecondstep(signalprocessing)involvessiftingthrough andfilteringbrainsignalstoallowinterpretationvia variousmethods(sensorimotorrhythms,visualevoked potentials,event-relatedpotentials,etc.).Thesesignals arethenfurtherprocessedandanalyzedtoproduce aspecificcommandtobeexecutedbythecomputer interface.Thefinalstep(responsegeneration)involves translatingthesignaltoallowthedevicetoperformthe codedfunction,suchasproducingamotoroutputto contributetowardsstrokerecovery.Thisentireprocess canleadtothereorganizationofthemotorcortex (neuroplasticity)oneitherthesameoroppositeside oftheinjury(Mar´ın-Medinaetal.,2023).
VRtherapyisanotheremergingtherapythathas beenusefulinrestoringmotorfunction,contributing toanincreasedqualityoflifepost-stroke.Muchlike BCIs,itinvolvesaninterfacebetweenacomputer andthepatient;however,itisusedasasimulation torecreateaninteractablevirtualenvironment.The rationaleisthatthroughimmersivesensoryandmotor simulation,newconnectionswithinthebrainarecreatedthatcloselymimicreality.Thisallowsthepatient topracticeactivities/exerciseswithintheenvironment, afterwhichthesystemprovidessensoryfeedback. Thishelpspatientsunderstandtheirmovementand makenecessaryadjustments,improvingtherehabilitationprocess(Mar´ın-Medinaetal.,2023).There aredifferentlevels/versionsofimmersionthatpatients canexperiencebasedontheirrequirements.Total immersionisthemostengagingtype,whichallows thepatienttofullyinteractwiththevirtualworld, improvingtheircognitiveandphysicalfunction.There isalsostrategicimmersion,whichaimstoimprove thepatient’scognitionthroughproblem-solving,and narrativeimmersion,whichmakesuseofastoryline togivecontextforactivitiestoincreasepatienten-
gagementandupliftthepatientpsychologicallyand emotionally.VRtherapyhasparticularlybeenproven tobeveryeffectivewhenitcomestorestoringmotor function(skilfulimmersion).Completingvisualmotor tasksvirtually,suchasgrabbingacuporball,has beenshowntostimulatemirrorneuronsandpromoteneuroplasticity,thereforeleadingtofunctional improvements(Mar´ın-Medinaetal.,2023).
Figure2. VRsetup,viewandneuroplasticchanges asshowninMarın-Medinaetal.(2023)
Infigure1,image(a)showstheVRsetup.This includestheheadsetalongwithtwoinfraredcameras totrackthepatient’spositioninthevirtualsetting. Thepurplebandsonthepatient’supperlimbsact ascontrollerstotrackmotormovements.Image(b) showsthepatient’sview,whichcanbetrackedbythe healthcareprofessionaltoevaluatethepatient’smovementsandprogress.Image(c)showstheactivation ofmirrorneurons,contributingtothegenesisofnew synapticconnectionsthatstrengthenwithcontinuous virtualrepetition(Mar´ın-Medinaetal.,2023).
Intermsofefficacy,BCIshavebeenshowntobe highlyeffectiveforstroke-relatedinjuries.Forexample,ameta-analysisofrandomizedcontroltrialswas conductedtoevaluatetheeffectivenessofBCIsforthe rehabilitationofstroke-inducedupperlimbdysfunction,anditfoundthatBCIswereindeedbeneficial torecovery.Thismeansthatthereisstrongevidence thattheirinductionintoclinicalpracticeonawider scalecouldprovebeneficial.Furthermore,furthersubgroupanalysisofinterventiontimerevealedsignificant improvementsinupperlimbfunctioninchronicand subacutegroups,withgreaterimprovementwithinthe subacutecohort.Withinthesamemeta-analysis,it
wasfoundthatconnectionsacrossdifferentareasof thebrainwerealtered,substantiatingtheneuroplastic componentofBCIinterventions.Changeswerealso observedwithinthecorticospinaltractinvariousregions,suchasthecorpuscallosum,rightcingulate,and leftfronto-occipitaltract,viadiffusiontensorimaging, coincidingwithanimprovementinmotorfunctionas well(Yangetal.,2022).Therehavebeenmanystudies investigatingtheefficacyofVirtualRealityinstroke therapy,andtheevidencesuggestsitiseffective.A systematicreviewpublishedin2023foundthatfullimmersionvirtualreality(FIVR)hasbeenshownto positivelyaffectgaitandbalanceregardinglowerlimb dysfunctionpost-stroke,accordingtovariouscompiled studies.Anotherstudywithinthisreview,however, foundnostatisticallysignificantdifferencebetween FIVRandthecontrolgroup.However,thistreatment methodisstillconsideredbeneficialduetoitsnatural clinicalapplicabilityanditspositiveratingamong patientswithlittleriskinvolved,nottomentionits customizability.Thereisalsoaplethoraofevidenceto vouchforitsefficacyasanadjunctivetherapyalong withotherformsofrehabilitation.Onespecificstudy combinedvirtualrealitymirrortherapywithoccupationaltherapyinrehabilitatingtheupperextremities andfoundthatitsoutcomessurpassedthoseachieved usingoccupationaltherapyalone.Thepositiveeffects ofVRtherapyarenotonlymotorinnaturebut havealsobeenfoundtoimproveapatient’smental health.Forexample,anotherstudywithinthereview foundthatFIVRplaysaroleinimprovingdepressive symptomsafterstroke,whichincreasesmotivationand thereforeadherence,yieldingbetteroutcomesoverall. Furthermore,theintegrationofsensoryfeedbackcan improvecorticalneuroplasticityandcontributetoimprovedmotorfunction(Demecoetal.,2023).
AlthoughBCIsareeffectiveininstigatingand enhancingneuroplasticchanges,therearesomeissues whenitcomestotheirclinicalapplicationinstroke medicine.Oneofthemainchallengesisrelatedto healthinfrastructure.BCIimplementationcanbeseen asimpracticalduetothemultitudeofstepsinvolved initsexecution(setup,operation,andcleanup).This couldimpingeonthetimemeantformoretraditional methodsofrehabilitation.Thissuggeststheymaybe bettersuitedasadjuncttherapies,whichrequireadditionaltimeandresourcesandareoftennotcoveredby
insuranceinaprivatizedsystem(Rupp,2014).There arealsoseverallimitationsthatcomewithVRtherapy aswell.Thismethodofrehabilitationisveryresourceheavy,requiringreal-timemotionsensing,head-mount displays,andsensors,whichcouldpresentchallenges inhealthcaresystemsthatarefinanciallystruggling. Furthermore,thistechnologyisspecialized,meaning specifictrainingisrequiredtouseittoitsfullpotential. Itscomplextechnologicallearningcurvecanpresent difficultiesforpatientswhoaren’tverytech-savvy. Therearealsopatientprivacyissuesthatcanarisewith thistechnology(Aderintoetal.,2023).
Overall,neuroplasticity-basedinterventionsoffera comprehensiveandadaptableapproachtowardsstroke, possiblymoresothantraditionalmethods,andcanalso significantlyimproveoutcomesrelatingtopatients’ qualityoflife.Theircustomizablenature,alongwith theirpotentialtobeintegratedwithmoreadvanced technologiesmakeitanexcitingscientificfieldthat willnodoubtcontinuetoproduceevenmorebreakthroughswithdedicatedresourcesandresearch.We knowthatBCIsarebeneficialinstrokerehabilitation andthatneuroplasticityplaysalargeroleinstroke recoveryrelatingtoBCIs.However,theexactneurophysiologicalmechanismsthatleadtorecoveryhave notyetbeenfullyidentified.Despiteplentyofneurologicalchangesbeingobserveduponvariousinvestigations(fMRI,EEGetc),furtherresearchisneededto understandthemechanicsofthesechangesandhow theycancontributetowardscreatingabetteroutcome tofurtherpavethewaytowardsclinicalintegration (Mar´ın-Medinaetal.,2023).Thereisampleevidence thatshowsthepotentialthatVRtherapyhasandthe positiveimplicationsitcouldhaveinthefieldofstroke medicine-includingfurtheringpatientengagement andcustomizability.However,thistechnologyisstillin itsinfancy.Moreresearchisneededtofurthervalidate itsefficacy,includinglargerpatient-cohortstudiesto furtherunderstanditsadaptabilitytowardspatients’ specificneeds.Furtherresearchdownthelinecan unmaskthistechnology’spotentialtoreduceclinical burdenthroughthepossibilityofremoteassessment (Nathetal.,2022).
Inconclusion,thecentralrolethattheideaof neuroplasticityplaysinstrokerecoveryisundeniable -asisthepotentialofinterventionsthatleverage
neuroplasticity.BCIsandVRtherapy(amongothers) areonlysomeofthemanytherapiesatthisfield’s forefront.Moreover,itsresearchbaseshowingits clinicalpotentialisonlyever-expanding.Allthough therearesomechallengestobeovercomeregarding theirapplicability-withfurtherinvestigation–these methodscanbeproperlyadaptedforuseinhopesof decreasingthemortalityandmorbidityofthiscrippling disease.
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MurphySJX,WerringDJ.(2020) Stroke:Causesandclinicalfeatures. Medicine[Internet].561–6.Availablefrom: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7409792/
CareyL,WalshA,AdikariA,Goodin P,AlahakoonD,DeSilvaD,etal.(2019) FindingtheIntersectionofNeuroplasticity, StrokeRecovery,andLearning:Scopeand ContributionstoStrokeRehabilitation.Neural Plasticity[Internet].1–15.Availablefrom:: https://www.hindawi.com/journals/np/2019/5232374/ DanielStivenMar´ın-Medina,Arenas-VargasPA, Arias-BoteroJC,G´omez-V´asquezM,Jaramillo-L´opez MF,JorgeMarioGaspar-Toro.(2023)Newapproaches torecoveryafterstroke.NeurologicalSciences.45. LaiSM,StudenskiS,DuncanPW,PereraS.(2002) PersistingConsequencesofStrokeMeasuredbythe StrokeImpactScale.Stroke.33(7):1840–4.
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RishiRavishankar isa3rdyearMedicineStudent attheUniversityofStAndrews,Contactat:rr219@standrews.ac.uk
LeoElliott Bsc(Hons)Neuroscience
ThomasBurton Bsc(Hons)Mathematics
Abstract—Astechnologycontinuestotransformeveryaspectofthehumancondition,themedical worldprovestobenoexception.Throughouttherecentpast,technologyhasintegrateditselfwithin theA-Zofthemedicalworld,revolutionisingdailypracticeinallaspectsofthehealthcaresystem, includingpracticesdealingwithcognitiveprocessingandpsychologicalphenomena.Oneofthe fastestevolvingsynergiesseenbetweenbothworlds,technologyandmedicine,istheuseof bioengineeringinaidingclinicalapproachesinpsychology-basedfields,especiallyclinical psychology.Clinicalpsychologyhasbeenattheforefrontofpsychologyresearchfordecadessince itsintroductionin1907,followingLightnerWitmer’spublication“Thepsychologicalclinic”[1].Today, clinicalpsychologystandsasoneofthemostprevalentformsofhealthcarewithanaverageof22%of theUKpopulationhavingbeenthroughmentalhealth-orientatedtherapyorcare[2].Asinother scientificfields,psychologistsarecontinuouslypushingthemselvestoinnovatenewtreatment techniques,hopingtoadvancethefieldintorevolutionaryareasofresearchanddevelopment.As technologyhasadvancedexponentiallyoverthepastdecades,thedrivefordevelopmentinmany areasofresearchnowreliesontechadvancements.Withintherealmofhealthcarethisis predominantlyintheformofbiomedicalengineering,utilisingengineeringprinciplestodevelopnew therapies,instruments,medicines,anddeliverymethods[3].Throughoutthisreview,developmentsin clinicalpsychologyusingbioengineeringtechniquestoovercomecurrentlimitationsareinvestigated, withreferencetohistoricalelementsandpossiblefutureoutcomes.Conditionssuchasmajor depressivedisorder,attentiondeficithyperactivitydisorderandpost-traumaticstressdisorder,will proveexemplaryinhowsuchillnessesmaybetreatedmoreefficientlyinfuturepractices,supporting thenotionthatbiotechnologyaimstorevolutionisedailypracticeinclinicalapproaches.
Therapidevolutionbiotechnologycontinuously faces,duetoexponentialadvancementsinbothfields–biologyandtechnology,rendersitmerelyimpossible tobeencapsulatedwithinasinglereview.Bioengineering,arelevantsubsectionofbiotechnology,utilises theprogressiveandmodernnatureofengineering toaddressandaidbiologicalconcernsandresearch avenues.DescribedbyPhilipKosky[4]bioengineeringis“theapplicationofengineering,lifesciences,
andmathematicstodefineandsolveproblemsin biology,medicine,healthcare,andotherfieldsthat dealwithlivingsystems”,capitalisingonknowledge derivedfromengineeringfieldssuchaschemical,mechanical,andelectrical.Bioengineeringcontinuously demonstratesitsrelevancewithinbiologicalresearch. Withinamatterofyears,thewayinwhichbiologists interactandstudycertainprocesseshavetransformed completely,followingdiscoveriesunveiledutilising bioengineeredtechnologies.TheextremityofbiotechnologiesinfluencecanbeexemplifiedthroughFireet al[5]whereinthespaceofadecadethewayinwhich
geneticistsstudiedandcontrolledgeneticbehaviour wascompletelyalteredonceappliedbiotechnology revealeddoublestrandedRNA’sinherentcapabilityto blocktheexpressionofanygeneiftheypossessed matchingsequences[6].
Morerecentcutting-edgeadvancementswithinthe realmofbiologyderivedfrombioengineeringtechniquesincludeCRISPR-CAS9genomemodification (Figure1)andnanotechnology(Figure2),whichhave bothrevolutionisedbiologists’capabilitytounderstand andcontrollivingsystems.Intherealmofcancer treatmentCRISPR-CAS9hasproventobeessential, duetoitsabilitytodeactivatecancercausinggenesand activatevitaltumoursuppressors,bydirectlyaltering theindividual’sgenomethroughtargetingandcutting specificDNAsequences[9].Secondly,nanotechnologyhasrevolutionisedtheefficacyofdrugdelivery throughtheuseoflipidbasednanoparticleswhich encapsulatedrugsandbiomarkers.Thisnewlyformed unitismadetobespecifictowardscertaincelltypes, increasingthespecificityofdrugs,inturnreducing sideeffects[10].TheseBioengineeringtechniques, alongwithamagnitudeofothers,haveallowedforthe generationofnewfocalpointsinresearch,inevitably changingthetrajectoryofmultiplebiologicalfields. Theadvantageousnatureoftechnologicalimplementationinhopestoovercomebiologicalconcernsis activelyredirectingthewayinwhichresearchisapproachedandconducted,creatingrevolutionarybreakthroughsinsurroundingsciencebasedfields,including psychology.
Throughoutthe18thand19thcenturyapivotal shiftinthephysicaltreatmentofthementallyill withintreatmentinstitutionsmaterialised,amidthe pioneeringguidanceofpsychologistssuchasWilliam Luke,PhilippePinel,EliToddandDorotheaDix. Facilitiesbegantostrayfromtorturousdesignstowards morehumanemethods[11].Thistransformativeshift triggeredarippleeffect,allowingfortheevolutionof treatmentmethodswithrehabilitationattheforefront ofdesign,thusleadingtothecreationofclinical psychology.
TheimportanceofthisnewwavefieldwaswholefullyacknowledgedandintroducedinLightnerWitmer’spublication,wherehediscusseshowtreatment usingpsychologicalprinciplesasabasisinmethodologicalframeworkprovesbeneficialinhelpingboth morallyandintellectuallychallengedschoolchildren
[8]
[1].Thoughttobethefatherofclinicalpsychology Witmerthenangledhiscareertowardsteachingothers thebeneficialnaturehismethodshad,towardsboth thementallyillandwell.Thisone-of-a-kindclinic, foundedin1896,triggeredthegenerationofhundreds alike.Alongsidethisemergentfield,followedmany psychologistswhobegantospecialiseinthisnewwave clinicalmethod,helpingindividualswhootherwise wouldhavebeenlefthelplessprior.Nowoneof themostprevalentformsofhealthcare,clinicalpsychologycontinuestosupportamagnitudeofdiverse individualsglobally.
Clinicalpsychologyisnowabroadfield,under whichmultipleevidence-basedtreatmentmethodslay
[12].Arguablythemostprominentpracticewithin clinicalpsychologyispsychotherapy,wherepersonal growthanddevelopmentisachievedthroughtalking basedtechniquesandinteractiveactivities.Treated byrenownedpsychologistsBreuerandFreud,patientAnnaOcoinedthephrase“atalkingcure” afterexperiencingalleviationofdisturbingsymptoms throughverbalcommunicationofcirculatingthoughts andemotions.Thisprocess,nowtermedabreaction, ledtotheinnovationofpsychoanalysis.FurtherestablishedbyFreud,psychoanalysisisthoughttobe thefirstformofpsychotherapy,wheretalkingbased methodsareusedinattemptstotargetandchange bothconsciousandunconsciousprocessing.Stemming fromPsychoanalyticprinciplesnumeroustreatment techniquesmaterialised,includingthecommonlyused CognitiveBehaviouralTherapy(CBT),whichfocuses ontargetingconsciousprocessinginhopestogenerate morepositiveschemasrevolvingaroundoneselfand theproblemstheymayfrequentlyface,thusdevelopingeffectivecopingmechanismsfortheirreoccurring issues[14,15].
Asthisfieldgrewinrelevance,creativitygrew also,withmoreabstracttreatmenttechniquesbeing introducedandtested.Forexample,eyemovementdesensitisationtherapy(EMDT).DevelopedusingframeworksbasedinPTSD,EMDTfocusesonintegrating twomemorysystems,thesimultaneouslyaccessible (SAM)andverballyaccessible(VAM)systems,of whichPTSDaffectedindividualscannotlinktogether toinhibittraumarelatedtriggers.Thistreatmentstyle isthoughttoachievesuccessfulintegrationoftwo memorytypes[16]throughtheintroductionofa bilateralstimulus,typicallyamovingobject,whichthe patientfocusesonwhilstdiscussingcertainmemories associatedwiththeirtrauma[17].Theefficacyofthis treatmentbeingabletohelpthepatientreprocesstheir traumaticmemoriescanbeexemplifiedthroughSilver, RogersandRussells[18]casestudywhereanexveteranwasabletorecalladditionalfactorswithin thememorythattriggeredhisPTSDresponse.This memoryofhimkillingashoulderwasreprocessed usingEMDTallowingfortherecollectionofadditional factorslikehisfriendcallingfor“help”,allowingthe patienttofurtherunderstandthescenariograntinghim closureandunderstanding,thusremovingthenegative schemasabouthimselfthatleadtomaladaptiveprocessing.Thisuniqueformoftherapyprovesinnovation inclinicalpsychologyisofutmostimportancein developingnewtreatments,whicharesuccessfulin
targetingalternativeprocessingcircuitsandmemory systems.
Talkingbasedtherapyprovesbeneficialinaiding psychologicalillnesswithinmanyindividuals,However,insomecasestalkingtherapyalonelacksefficiencyduetoitsinherentdrawbacksandstrategy. Sincecommunication-basedtreatmentsrelysolelyon verbalcommunicationpatientswithseverepsychologicalillnessmaystruggletoeffectivelyarticulate andprocesstheirthoughtsandfeelings.Theymay alsoomitoraltercertainaspectsoftheirreportsin hopestoavoidcertainfeelingsand/ortalkingpoints. Bothhindrancesshallowthedepthofdetailasessionwouldbeabletoreach,renderingthismethod insufficientinachievingsubstantialchangewithinthe patient[15].Alternativetreatmentroutes,including theuseofmedication,canbeusefulintreatingpatientswhoareunabletoachieveresultsfromtalking basedtherapiesalone.Oftenusedinsynergywith talkingbasedmethods,medicationhelpstorelieve symptomsonabiologicallevel,allowingformore directtargetingoftheproblemedareas-inmanycases acceleratingtherateofsuccess.Thismethodisespeciallybeneficialtowardsmentalillnesseswhichhave specificbiologicalcomponents,suchasschizophrenia anddepression,wherespecialisedbrainareasdisplay abnormalactivity[19,20,21].Thebiopsychosocial modelinclinicalpsychologyincludesthesynchronous useofbiomedicineandpsychology-basedtreatments inprovidingpersonalisedtreatmentroutesforspecific individuals[22].Itisthisconceptofdrawinginformationfrombiologyinhopestocreatealternativesin psychologicaltreatmentwhichwillbediscussedinthe latterpartofthispaper.
Thefieldofclinicalpsychologycontinuesto evolveexponentially,withanexpansiverangeof medicinalandtalkingbasedtherapeuticsbeingdevelopedinhopestoeffectivelytreatnumerousillnesses. Whilsttheefficacyoftheseapproachesisundoubtedly apparent,optionsorientatedtowardsmoreextreme treatmentmethodsremainlacklustreintreatingindividualswhodonotrespondadequatelytoconventional methods.Asmentionedprior,talkingbasedtherapiesholdunavoidablelimitations,asdomedications whichcanbeineffectiveincertainindividualsdespitetheireffectivenessinthemajority.Fromthese
inherentdrawback’spsychologyhasdirectedrecent focustowardsbiotechnologyasapossiblesolution inovercomingsuchproblems.Aclinicalbasedscope willnowbedrawnoverthispaperwithfocusorientatedtowardsbiotechnologyanditscross-disciplinary applicationinovercomingtreatmentlimitationsseen withinmentaldisorderssuchasmajordepressivedisorder(MDD),attentiondeficithyperactivitydisorder (ADHD),andpost-traumaticstressdisorder(PTSD). UsingtechniquesincludingDeepbrainstimulation (DBS),Transcranialmagneticstimulation(TMS),and Vagusnervestimulation(VNS),respectively.Theseinnovativetreatmentrouteswillbeintroducedalongside relevantevidencesupportingtheiruseandpotentialfor futuredevelopment.
MajorDepressiveDisorder(MDD)currentlyranks asthemostprevalentpsychologicalcondition,being thesecondtopcauseofdisabilityworldwide-predictedtobecomefirstbytheyear2030.Withreoccurringsymptomsincludingsadness,hopelessness,and lackoffulfilmentwithindailyactivityMDDcontinues toaffectmillionsandissignificantlycorrelatedwith anincreaseinmortalityrates[23].Althoughitsdominancewithintoday’ssocietycannotbeundermined, littleisknownaboutthisdisease.Withinmostindividuals’symptomscanbeeffectivelyimprovedthrough talkingbasedpsychotherapiesand/ormedications,for exampletheuseofserotoninreuptakeinhibitors,which reducespresynapticreuptakeofmoodboostingneurotransmitterserotonin[24],andcommunicativetherapiessuchasCognitivebehaviouraltherapywhich targetssymptomsbydiscussingthenegativethought patternsandbehaviourswhichoccurthroughoutthe courseofthisillness,inturnfosteringpositiveprocessingandcopingstrategies[25].Althoughthese ‘lesssevere’treatmentroutesproveeffectiveamongst manycases,around20%donotrespondtocommontreatment,somoreextremealternativesareused -includingelectroconvulsivetherapy(ECT),where strongelectronicimpulsesareexternallydelivered, triggeringcontrolledseizureswhicharebelievedto alterthebrain’schemicalenvironmentincreasingthe efficacyofneuronalcommunication[26].WhenalternativemethodssuchasECTaredeemedineffective, shortcomingsinalternativeoptionsbecomeapparent. Depression’shighbiologicalcomplexityisviewedas systemslevel,meaningonebrainregionisn’tfully
responsibleincausingthisdisease,alternativelymultipleregionscontributetowardssymptomatology,where pathwayslinkingareassuchasthelimbic,cortical, andsubcorticalregionsbecomeineffectiveinnormal processing.Withcontributionsfromtheindividual’s genome,environmentalstressorsanddevelopment, manyaspectsofone’slifecontributetowardsthe likelihoodofdevelopingMDD.
Bioengineeredimagingtechnologies,suchasfunctionalmagneticresonanceimaging(fMRI),hasallowedresearcherstodevelopanunderstandingon whichbrainregionsareassociatedwithMDD,leading tothedevelopmentofhighlyspecialisedtreatments. WithinfMRIimagingofindividualswhoresponded positivelytoMDDtreatment,areductioninarea25of thesubgenualcingulatecortex(Cg25)wasmeasured, implyinghyperactivityinthisregiontobecausalof depressivesymptomatology.TheCg25isthemood regulatoryunitlocatedwithintheAnteriorCingulate Cortex(ACC),controllingfunctionsincludingerror processing,automaticemotionalresponsetophysical experienceandthecontrollingofbehaviourinreferencetopunishmentandreward.Whentheseprocesses becomedysregulatedacognitiveshiftinfailureexperienceiscaused.Thisshiftcausestheindividualto becomeoversensitivetofailure,inducingpersistent feelingsofguiltandnegativity.Abnormalactivation oftheCg25isalsothoughttocontributetowards otherMDDsymptoms,includingmooddysregulation, fatigue,andinsomnia.Theseadditionalsymptomsare thoughttobesourcedviaconnectionsfromtheCg25 tothemedialprefrontalcortex,thalamus,brainstem, orbitofrontalcortex,andbothanteriorandposterior cingulatecortices[27].
InreferencetothecorrelationallinkbetweenCg25 activityandMDDaclinicalstudyconductedbyMaybergetal[28]wasledinhopestomanuallytarget theCg25usingbioengineeredtechnology,DeepBrain Stimulation(DBS),withaimstocreateanalternative treatmentrouteintreatmentresistantdepressives.Deep brainstimulationisaresultofadvancedbioengineering,wherebrainactivityisdirectlymodulatedby electricalstimulationthroughneurostimulatorynodes, ofwhichareimplantedintospecificbrainregionswith theabilitytobemanuallyswitchedon/offaffectingthe specificneuronsaccordingly[29](Figure4).Within thistrialinhibitoryelectrodeswereimplantedwithin 6MDDaffectedindividuals,targetingtheCg25and itssurroundingwhitematter.Uponinitialactivationall patientsrecordedimmediaterelief,includingfeelings
ofcalmnessandconnectednesstotheirsurrounding environment,alsoreportinganabsenceofthe‘void’, whichinpsychotherapyisusedtodescribefeelings ofpersistentemptinessconsequenttothefeelingof destructioninaspectsthatoncewerewithinone’s mentalpsyche[31].Toquantifythesefindingsa depression-basedquestionnaire“positiveandnegative affectschedule(PANAS)”wasconductedbeforeand aftertreatment,withallhavinganincreaseinpositive scoresanddecreaseinnegativefollowinginitialstimulation.Astreatmentcontinued,increasesinenergy levels,psychomotorspeed,empathyandinterestdeveloped,alongsidereductionsinanhedoniaandapathy. Ofthe6participants4achievedlongtermsymptom relief,with3achievingalmostcompleteremissionof theillness.
Inparticipantswhoreportedlonglastingbenefits fromDBS,PETscansobtainedafter3monthsoftreatmentshowedsuccessfulreductioninCg25activity. Patientswhoexperiencedprolongedbenefitsatthe6th monthintervalalsoexhibitedareductioninactivation withintheirhypothalamus,anteriorinsula,andmedial frontalcortex.Alongsideincreasedactivationwithin thedorsolateralprefrontalcortex,posteriorcingulate, anteriorcingulate,parietalandpremotorregions-exemplifyingthedownstreameffectsofCg25stimulation inrelationtoMDDsymptomalleviation.
AlthoughthismethodshowsevidencedbasedDBS benefitsinMDDtreatment,viabilityinitsapplication withinotherdepressionsubdivisionssuchasbipolarandunipolardepressivesremainunexplored.This exposestheinherentdrawbacksofthistechnique’s replicability,aseachpatientneedsindividuallytailoredelectrodeplacementandvoltagestrength[28]. AlthoughDBSisn’twithoutdrawbacks,wideningits therapeuticcapabilityistherecentadaptationofdeliverynodesknownasdirectionalleads.NowfrequentlyusedwithinrecentDBStrials,thesestimulatorynodesgranthigherprecisionanddirectionalitywiththeirelectricalimpulses,achievinggreater specificitytowardsbrainregions,negatingprecision drawbackscritiquedthroughoutpasttrials.Duetoits unidirectionalcapabilities(meaningstimulationcanbe deliveredinspecificorientations)thissuperiormethod grantsresearcherstheabilitytoshapetheelectricalfieldaroundthenode-amanipulationdeemed impossibleusingpreviousomnidirectionalmethods [32].Theneurologicalcomplexityofdepressionmakes thisdiseaseanidealcandidatefordirectionallead stimulation,potentiallyleadingthistreatmentstyle
Figure3. UsingVagusNerveStimulationinhopesto treatpost-traumaticstressdisorder.[39]
towardsanincreasinglyadvancedspace,wherefinite precision,specifictotheindividual,couldbedelivered moreeffectively,reducingMDDsymptomologyonan unprecedentedlevel.
UsingTranscranialMagneticStimulationin hopestotreatAttentionDeficitHyperactivity Disorder
Describedasthemostcommonneurobehavioraldisorder,attentiondeficithyperactivitydisorder (ADHD)ischaracterisedbypersistenthyperactivity, impulsivityandinattentiveness,andismostprevalentwithinchildren,withasmallpercentageofindividualscarryingitthroughintoadulthood.Dueto diverseculturalandsocio-economicfactors,aswell assurroundingelementsincludingcomorbiddisorders whichinducesymptomssimilartothoseseenwithin ADHD,diagnosisvarieswidelyandislessdefinedin comparisontootherpsychiatricdisorders–occurring in2-18%ofschoolagedchildren[33].Ahallmark indicatorofADHDisthedysregulationofdopamine throughouttheindividual’sdopaminergicsystem.With asubstantialgeneticcomponent,thisdysregulation contributestowardsincreasingtheriskofADHD, alongsideexternalcontributionsfromfactorsincluding upbringing,sociallifeandhomelife.Comorbiddisordersarealsoseenwithin50-80%ofADHDcases, includingdepressionofwhichdopaminedysregulation andinattentivenessisassessedalso–accentuatingthe complexnatureofADHDdiagnosisandaetiology
[34].
Multipletherapeuticapproachesbasedinclinicalpsychologyhavebeendevelopedinhopesto providetheindividualwitheffectivecopingmechanismsandthinkingstrategies.Anexpansivelistof diversetherapeuticapproacheshasmaterialisedinthe pastdecade,resultantofthisdisordergainingrecent tractionamongstfellowpsychologists.However,a selectfewhaveprovenmoreeffectivethanothers, includingCognitivebehaviouraltherapy(CBT)which focusesonthegenerationofcompensatoryprocessingwhichnegatestheneurologicaldeficitscaused bythedisorder,andhelpstheindividualtodevelop alternativethinkingroutesinresponsetosymptoms occurrence.Cognitivetraining(CT)whichisused tostrengthencognitiveabilitiesincludingexecutive function,ofwhichADHDindividualspossessdeficits in.andDialectbehaviouraltherapy(DBT)whichaims tovalidateandacknowledgeADHDinducedsymptomsandsubsequentlyprovidethemwithefficient self-managementskills.AlthoughthesecommunicativetherapeuticsprovebeneficialamongstalargeproportionofADHDaffectedindividuals,progressisnot achievedineverycase.Thelackofreliable,positive, long-termbenefitsfromtalkingbasedtherapiesin treatingADHDalsohighlightstheimplicitlimitations thisapproachpossesses,withbeneficialeffectsofCBT onaverageonlylastingupto12monthsposttreatment[35].Suggestedtobearesultofthismethod’s inabilitytodirectlytargetneurobiologicalirregularities seenwithinADHD[36]limitationsincommunicative treatmentmethodspersists.Asystematiclimitationin Lambezetal[37]meta-analysisalsoexposeshow potentialtreatmentavenuesremainunexploreddue tomethodsbeingdevelopedsolelybaseduponpsychologicalconstructs,hintingtowardsanewwaveof promisingtreatmentswhichplaceotherscientificfields centrewithintheirframeworkofdesign.
ProposedbyAcostaandLeon-Sarmiento[38]a promisingalternativetocommunicativeandmedicinal basedtherapeuticswasintroducedintheformof transcranialmagneticstimulation(TMS).Transcranial magneticstimulationisanon-invasivebioengineered technologyusedtoinducechangewithincorticalbrain regions,viatriggeringorinhibitingneuronalactivation throughlocalisedmagneticfieldprojection,delivered usingasmallhandhelddevice(Figure5).Transcranial magneticstimulationpossessestheabilitytodirectly modifyneurotransmitteractivity,includingdopamine anditsmetabolites[40,41].WithinADHDthedysreg-
ulationofdopamine,particularlywithintherighthemispherefronto-striatum,triggersADHDsymptomatologybyaffectingbehaviouralprocessingcircuits,includingtherewardsystem.ItwashypothesisedthattargetingthisregionusingTMSmayprovebeneficialin negatingdopamineinducedsymptoms,bytreatingthe dopaminergicdysregulationwithinthepatient’sright hemisphere.FollowingAcostaandLeon-Sarmiento’s [38]proposalapilotstudybyBlochetal[40]was conductedtotesttheviabilityofthistechnologyin ADHDtreatment.Agroupof13adultindividuals, alldiagnosedwithADHDunderwentrepeatedTMS withintheirdorsolateralprefrontalcortex,thearea ofwhichthedopaminedysregulationisthoughtto occur.Followinginitialstimulation,incomparison topre-stimulationattentionscores,allparticipants scoredsignificantlyhigherjustminutesposttreatment, providingresearcherswithanevidence-basedreport showingthepositiveeffectswhichfollowTMSin ADHDtreatment.Thisadvantageousresultimplies modificationofdopaminergicactivityhastakenplace withineachsubject,echoingpreviousstudieswhich showsuchchangesindopaminesignallinginresponse todorsolateralTMS[41].Thispositiveresulthighlightsthecutting-edgepotentialityofTMSinrelation tobehaviouralillnesses,potentiallydevelopingselftreatmentroutes,givingtheindividualthechoiceto manuallyoverrideneurologicalabnormalitieswhich leadtoADHDsymptomatologyattheclickofa button.Thisoptionprovidesamorepreferabletreatmentmethod,alternativetolengthycommunicative basedmethodswhichprovelacklustreinlongterm efficacyaswellaspotentiallyharmfulpsychostimulant medications.
Asmentionedprior,ADHDismostcommon withinchildren,howevercriticisminusingneurostimulatorytechnologyintreatingchildreniswidelydebatedwithscepticismrevolvingaroundlongterm safety.Theunderdevelopedinfantbrainisconsidered tobemoreplastic,makingneuromodulationmoreeffectiveandcapableinalteringbrainactivity.Although seenasapositiveinmanyregardsthisincreasedsusceptibilitymayleadtoanincreasedriskofabnormal development,potentiallymaterialisingintolongterm deficitsand/ordisabilityinadulthood[42].Although risksareapparent,itisimportantwecontinuetolean intothesetechnology-basedtrialsinsearchforADHD treatments,ascurrentADHDtreatmentmethodsappearelementaryincomparisontocurrenttreatments aimedtowardsdifferentpsychiatricillnesses.Finding
effectivewaystotreatthisdisordershouldbeat upmostimportance,aswithinchildADHDcases3060%ofthemwilldevelopavarietyofpsychiatricand behaviouralproblemsintoadulthood[34],alongside significantincreasesinsuicideratesandharmfulbehaviours[35].
UsingVagusNerveStimulationinhopesto treatpost-traumaticstressdisorder.
Categorisedbytherecurrenceoffoursymptom clusters;re-experiencing,cognitivealterations,hyperarousalandavoidance,post-traumaticstressdisorder (PTSD)affects7-12%ofindividualsfollowingthe exposureofatraumaticevent.Symptomsderived fromtheseclustersconsistofflashbacks,nightmares, hypervigilance,socialavoidance,intrusivememories andsocialdeficits.Thesesymptomsarethoughttobe partiallycausedthroughabnormalautonomicnervous systemactivity,increasinglevelsofstressandsensitivity,inducingprolongedstatesofflightorflight[43, 44].Sinceallindividualswhoexperiencetraumatic eventsdonotcontractPTSD,ageneticcomponent isbelievedtoinfluencesusceptibilitytothisillness. Knownasthegenexenvironmentinteraction[45], thiscomplexsynergyofenvironmentalandgenetic contributionsleadingtoPTSDsymptomatologyhas synthesisedamorebiologicalapproachwithinPTSD research.Geneticinfluenceswhichimpacttheindividual’sCognitiveabilityandautonomicphysiological response,aswellasenvironmentalfactorsincluding traumaseverity,durationandtype,allpartakeindeterminingwhetherPTSDfollowsatraumaticexperience.Ahallmarkneurologicalirregularityassessed inPTSDisthedysregulationofthehypothalamus pituitaryadrenal(HPA)axis,apartofthestressinducingsympatheticnervoussystem.TheHPAaxis iscentralinregulatingthebody’sstressresponse, triggeringacascadeofbiologicalprocessesbeginning intheamygdala.Dangerdetectionprocessedinthe amygdalawillsendcautionarysignalstothehypothalamus,leadingtoincreasedsecretionofstress-inducing hormonecortisol,proportionaltotheseverityofthe evaluatedstressor.WithinPTSDtheHPAaxisbecomes insufficientinstressregulationfollowingtraumatic exposure.Regulatedbytworeceptorgroups,mineralocorticoid(MR)andglucocorticoid(GR),cortisollevels inhealthyindividualsremainbalanced.MineralocorticoidReceptorshavehighaffinitytocortisolhormones, increasingstresslevelsinresponsetotheonsetof increasedcortisolrelease.Ascortisollevelsincrease,
lowaffinityGRreceptorsbegintobindtothese molecules,triggeringanegativefeedbackloop,which returnscortisollevelsbacktobaseline.However,in PTSDthisregulatorysystembecomesineffectivein balancingcortisollevels,duetoadecreaseincortisol releaseratesandhypersensitivitywithinGRreceptors [44],Theresultsoftheseirregularitiesareconsistent withPTSDsymptomology,includinghypersensitivity tostressfulstimuli,increasedhypervigilance,startle, andirregulatedphysiological(autonomicnervoussystem)arousal[46]renderingtheindividuallessadapt intheprocessingofstressfulscenarios.Memorybased deficits,ofwhicharesuggestedtoberesponsiblefor symptomsincludingflashbacksandfalsememories, arelargelycorrelatedwithdecreasedhippocampal, amygdalaandprefrontalcortexactivity[47].TheCA3 regionofthehippocampusisresponsiblefortheinitial encodingofmemoriesandappropriateretrievalof specificmemoriesinresponsetocorrelationalques [48].InmammalsdamagetotheCA3regioniscaused inresponsetotraumaandstressinducingexperiences,loweringhippocampalfunctionality,volume, andinhibitingthesynthesisofnewneurons.Itisthis neurodegenerativeresponsetotraumaticeventswhich isbelievedtoleavetheindividualsensitivetoexternal cuestriggeringsporadicre-experiencing[47].
ArecentregionofinterestinPTSDtreatmentisthe therapeuticeffectsofVagusNervestimulation(VNS) inrelationtotargetingneurologicaldeficitsseenwithin PTSDaffectedindividuals.Beingthelargestnerve withinthebody’sparasympatheticnervoussystemthe vagusnervereducessympathetic(autonomicstress inducing)inputandcontributestowardsthecontrolof multiplebodilyfunctions,includingimmunity,digestion,cardiovascularregulationandmood[43].Once stimulated,eitherthroughinvasive(Figure6)ornoninvasive(Figure7)methods,thevagusnervealso modulatesfearcircuits,encouragesneuralplasticity, andenhancescognitivefunctioningandmemory[51]. Itsstrengtheningeffectsoncognitiveability,andconnectionstostresscontrollingregionsincludingthehypothalamus,amygdalaandHPAaxis[43],hasproved effectiveintreatingmultiplestressrelatedillnesses, includingdepression,panicdisorderandobsessivecompulsivedisorder[52].Thevagusnerve’scapability tomanipulatestressrelatedprocessingaswellas strengtheningmemoryfunctionhasinevitablyplacedit forefrontwithinPTSDresearch,alongsidethediscoverythatVNShasaninhibitoryeffectonthereduction ofcortisolrelease[53],whichisaneurologicaldeficit
Figure4. ExampleofinvasiveVagusnervestimulation[49]
Figure5. ExampleofNon-InvasiveVagusnervestimulation[50] correlatedwithPTSDasmentionedprior. InitialtestingofVNSinhopestotreatfear relatedPTSDsymptomswasconductedusingrats, whereVNSanditsimpactonmemoryextinction wasassessed.Memoryextinctiontakesplacewhena responsetoacertainstimulusdeterioratesorvanishes astimeprogressesduetorepeatedfutureexposure tothestimuluswithoutthefollowingpredictednegativeoutcome.Thisprocessdoesnoterasethepast memoryofwhichtheresponseisderivedfrom,howeverconsolidatesnewmemorieswhichsuppressesthe previousresponsetakingplaceuponfutureexposure. Memoryextinctionisakeyfeatureofbehavioural adaptationallowingforindividualstochangetheir reactionsbasedonmorerecentexperiences.Inrelation
toPTSDefficientmemoryextinctionisimpaired, renderingtheindividualincapableofoverridingtheir traumaticmemorieswithnewtraumarelatedmemories whichdonotneedsuchadversereactions,resultingin consistentfearresponsesbeingtriggeredinreaction tostimulithatcorrelateswiththeirtraumaticmemory. Withinthisstudyfearwasconditionedusingatone shockexperimentaldesign,wherefearwaslearned inacquisitiontrialswhereanelectricshockfollowed thepresentationofanaudiblestimuli,thereafterextinctiontrialswereconstructedbyshocksnolonger beingadministeredinconsequenttoauditorystimuli. Resultsfoundasignificantdecreaseinconditioned fearresponses(CFR)andfreezingratesinratswho receivedVNSinextinctiontrialscomparedtononstimulatorycontrolgroups,whoconsistentlydisplayed highlevelsofCFRandfreezingbehavioursinmultiple extinctiontrialsfollowingtheconditionedfearlearning [54].ThisrelationshipbetweenVNSandenhanced memoryextinctionexemplifiesthepotentialVNShas withinmemory-basedtherapeuticsinaffectingmemoryextinctionallowingtheindividualtoincreasingly adapttonewexperiencelearning.Arecentpilotstudy conductedbyWittbrodtetal[55]testedVNSinhuman applicationtoassessthepotentialneurologicalinfluenceVNSmayachieveinrelationtotheexposureof personalisedtraumascripts(Passageswhichaccurately correlated/describedpastpersonaltraumaticevents). Althoughallparticipantswerenotdiagnosedwith PTSD,eachofthemhadexperiencedtraumaticlife events-ofwhichwererepresentedinthepersonalised scripts.ResultsshowedVNSlessenedvisualisation andre-experiencingbehavioursinreactiontoscript exposure,consequenttoaVNSinducedupregulation intheirventralvisualstream.Individualswhoreceived VNSalsoexhibitedalteredactivitylevelsinstress inducingbrainareas,includingtheamygdalaandanteriorcingulatecortex,bluntingtheindividual’strauma responseonbothemotionalandneurologicallevels, highlightingVNS’sabilityinlesseningtraumainduced processinguponexposuretostimuliwhichcorrelates withthetraumaticmemory.ArecentsurgeininterestwithinPTSDresearchhasemergedfollowing theaforementionedrodentandhumanVNSstudies, showingVNSabilityinimprovingmemoryextinction, stressregulationandtrauma-relatedresponse.Such pilotstudiesandadvancementsinVNStechniques, likeelectricalearpiecestimulation[56],contributeto thedevelopmentofVNSasaviabletreatmentfor PTSD.ThisprogresspositionsVNSasapotential
methodinfuturePTSDtherapy,helpingindividuals whoareunabletorespondtocurrentPTSDtreatment.
Aswestandonthevergeofthisnewerain psychologicaltreatment,recentintegrationofclinical methodologiesandbiotechnologyechoesthenowfrequentsynergyseenamongsttechnologyandnumerous scientificdisciplines.Throughtheuseofinnovative biotechnologiesincludingDeepBrainStimulation, TranscranialMagneticStimulation,andVagusNerve Stimulationwearewitnessingthedevelopmentof moreprecise,personalisedtreatmentmethodswhich arebecomingunparallelinefficiency,hintingtowards thefuturenorminmentalhealthmanagement.Theuse ofbiotechnologyinclinicaltreatmentmostimportantly providespromisingalternativestoindividualswhodo notrespondadequatelytocurrenttreatmentmethods, usuallyrootedintalking/medication-basedpractices. Thisinterdisciplinaryapproachalsoenhancesourcurrentknowledgetowardstheneurobiologyofseveral psychiatric/psychologicalillnesses,positivelyimpactingsurroundingareasofresearch.Resultantfromthis, itisimperativethatresearchcontinuestopromote andinvesttheirtimeandmoneyintothetestingand developmentofnewtechnologiesinrelationtopsychiatrictreatment,asoutcomespossessthepotentialto changethelivesofmillions.Overall,thisexcitingnew waveapproachcannotbereducedtoamereextension ofexistingmethodsseenwithinclinicalpsychology, insteadthisinterdisciplinaryapproachisacompletely distinctfield–whichmayholdthekeytoovercoming thebiggestchallengesseenwithinclinicalpsychology today,throughtheredefinitionofpossibilityandlimitlessroomforimprovement.
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LeoElliott isa3rdyearBiologyandPsychology StudentattheUniversityofStAndrews,Contactat: le42@st-andrews.ac.uk
VioletMelcher
Bsc(Hons)Environmental&EarthSciences
LailaDeen
Bsc(Hons)Physics
SushmhitahSandanatavan
Bsc(Hons)Medicine
Abstract—Thisreportexploresthecomplexitiesassociatedwiththeelectrificationrevolutionofthe globalautomotiveindustry.Thoughelectriccarspromisefeweremissionsovertheirlifetimes comparedtotheirpetrol-reliantalternatives,thebatteryproductionprocessrequiredforsuchvehicles isbothresourceandenergy-intensive.Byexaminingcurrentmineralrequirementsforelectric vehicles(EVs)andtheprojectedmarketgrowth,thisworksuggestsatwo-foldsolutiontomeetfuture demandforelectriccars.Sodium-ionbatteriesmustcontinuetoadvancetoreducecalculated greenhousegasemissions.However,thisbatterytechnologyhasthepotentialtorelievethedemand stresscurrentlysurroundingtypicallithium-ionbatteriesduetothecrustalabundanceofsodiumand itsrelativecost.Asinnovationsaredevelopedtomitigateenvironmentaldetrimentswithinthe productionofsodium-ionbatteries,‘DirectLithiumExtraction’canactasashort-termsolutionto relievethestressorscreatedbycurrentlithiumharvestingtechniques.Electriccarsareapromising techniqueforreducingemissions,butbatteryinnovationsarerequiredtomakeatrulybeneficial impactintheyearstocome.
HEGLOBALSALEOF ELECTRIC VEHICLES (EVS) hasbeengrowingconsistentlyyearafteryear atarapidrate,withprojectionsfortheyearsto comeshowingnosignofhalting(RockyMountain Institute,2022).Projectionsfor2024indicatethat globalsalesofplug-inelectricvehiclesareanticipated togrowbymorethan21percent,totaling16.7million vehiclesworldwidebytheendofthisyear(McKerracher,2024).Manysourcesandavarietyofpublications,includingtheInternationalEnergyAssociation, emphasisethattheelectrificationoftheautomotive industryisavitalcomponentinreachingnetzero emissionsby2050(IEA,2023).However,electric vehiclesrequirecriticalmineralsandenergy-intensive practicestobeproduced,averaging173kgmoremineralsthanthepetrolalternative(IEA,2023).Minerals
suchaslithium,nickel,andcopperarefiniteand requirepracticessuchasminingforextraction,which aredetrimentaltothesurroundinghumanandnatural environments(Bealesetal.,2021).Thoughelectric vehiclebatteriesrangeinexactcomposition,allrequiresimilarmaterialsandcriticalminerals(Bealeset al.,2021).Inthepastdecade,CO2emissionsfrom themanufacturingofelectricvehicleshaveexpanded threefoldbecauseofpastmarketgrowth(Lakshmi, 2023).Evenso,ithasbeenshownthatoverthelifetime ofanEV,emissionsstilldonotreachthoseofpetrol vehicles(USEPA,2021).However,solutionsmustbe constructedanddevelopedifEVsaremeanttobea pathwaytowardsnetzeroemissions.Sodium-ionbatterieshavebeenproposedandresearchedasanalternativetocurrentbatterytechnologywithtechniquessuch asDirectLithiumExtractionasapossibleadaptationto
currentpractices.Thoughelectricvehiclesconsistently emitlessthanpetrol-reliantalternatives,theresourceheavyproductionofEVbatterieslessenspollutant reduction.AstheEVmarketcontinuesitsrapidexpansionwithnosignsofslowing,advancementsinbattery technologyarecrucialtoreducerelianceonharmful mineralextractionpractices.However,thetechnologicalbreakthroughsnecessaryforthisprogressarestill intheirearlystages.
EVsproducefeweremissionspost-manufacturing comparedtotraditionalvehicles(Moseman,2022). ThoughthemainoppositiontoEVscomesfrom criticswhoproposethatsincecriticalmineralsand energy-intensiveprocessesarerequiredforthebattery productionofEVs,theyarefarlesssustainablethan theirconventionalcounterparts,Figure1,produced byTheGreenhousegases,RegulatedEmissions,and EnergyuseinTechnologiesModel,illustratesthestark differencebetweenthetwovehicletypes(USEPA, 2021).
Figure1. LifecycleGHGsforanElectricVehicle vsaGasolineReliantCarfromtheUnitedStates EnvironmentalProtectionAgency(2021)
EVsare,andremain,thegreenestoptiontodate whenfindingthemostsustainableavenueforpersonal transportation.However,whenconsideringtherole thatEVsaremeanttoplayintheupcomingyears, asthegoalofnetzerocarbonemissionsby2050is emphasised,theresourcesrequiredtoproducesuch vehiclesmustbeconsidered.ThoughEVsarethe bestoption,thisstatementisrelativetotheoptions currentlyavailable.Asofthisyear,asinglelithium battery-poweredelectricvehiclerequires,onaverage, 53.2kgofcopper,8.9kgoflithium,39.9kgofnickel, 24.5kgofmanganese,13.3kgofcobalt,66.3kgof graphite,and.5kgofrareearths(IEA,2023).EVsare resourceheavyandglobaldemandforsuchvehicles growdaily(EPA,2023).Figure2showsthegrowthof theglobalelectricvehiclemarketinrecentyears.
Figure2. GrowthoftheChinese,European,and AmericanElectricVehicleMarketfromtheInternationalEnergyAgency(2023)
By2032,30%ofallpassengercarsworldwidewill beelectric(LievenandRietmann,2020).Additionally, by2050,thispercentageispredictedtogrowtoover 80%ofallglobalcarsales(Carlier,2022).Becauseof theproposeddemandforEVsbetween2022-2050,this transitioncouldrequireover6.5billiontonsofendusematerialssuchascopper(Mazzanti,2023).Mining isoftenutilisedtoharvestthemineralsrequiredfor EVproduction(Agusdinata,Eakin,andLiu,2022). Currently,theminingandrefiningprocessrequired forEVsaccountsforroughlyaquarterofallproductionemissions,withlithiumandnickelmakingup approximatelyhalfoftheminedresources(McKinsey &Company,2023).Lithiumextractionrequireslarge amountsofwater,creatingmineralwaste,impacting surroundingcommunities,andbeingassociatedwith over1.3milliontonsofemittedcarbonannually(Ukpanah,2024).TheMITClimatePortalcalculatesthat foreverytonoflithiummined,anestimated15tonsof CO2isemittedintotheatmosphere(Crawford,ShaoHorn,andKeith,2022).Alongsidethis,a2022report highlightsthatharvestingpracticesoftenoccurinthe GlobalSouth,whilemanyend-productsareutilised andconsumedincountriessuchastheUSandCanada (Agusdinata,Eakin,andLiu,2022).
Giventheimminentmarketgrowth,itisurgent torevolutionisetheharmfulextractionpracticesof essentialmineralsusedinEVs.Ifelectricvehicles
couldbeassociatedwithlesspollutingpracticesand haveareducedimpactonglobalcommunities,afuturedominatedbyelectriccarswouldbesignificantly lessharmful.Thisiswheretheinnovationofbattery alternativesandextractionpracticesbecomescrucial. A2017articlepublishedbytheRoyalSocietyof Chemistrysuggeststhatsodium-ionbatteriesmayhold promiseinsatisfyingincreasingdemandandlimiting thenegativeimpactsoflithiumextraction(Hwang, Myung,andSun,2017).Sodiumiswidelyavailable globallyandhasasimilarchemistrytolithium-ion batteries(Hwang,Myung,andSun,2017).Another proposedimprovementincurrentEVtechnologiesis changingcurrentlithiumharvestingtechniquestothe moredirectandenvironmentallysoundtechniqueof DirectLithiumExtraction(Veraetal.,2023).This techniquerecyclestheresourcesutilised,significantly reducingtheneedforadditionalminingwhenaccessingtheinitiallithiumbrines(Veraetal.,2023).
Thoughcurrentlyutilisedlithium-ionbatteries havebeenmeetingdemandsandreducingglobalfossil fueldependencycomparedtopriorlevels,lithiumis notregardedasanabundantelementwithinEarth systems(Yabuuchietal.,2014).
Figure3. CrustalAbundanceofCommonElements fromYabuuchietal(2014)
Figure3expressesthisrelationship,illustrating therelativeabundanceoflithiumcomparedtoother elementsintheEarth’scrust,showingacalculated abundanceof20ppm(Yabuuchietal.,2014).Additionally,lithiumproductionistiedtospecificcountries, relyingonsignificantexportsfromregionssuchas SouthAmericaasglobaldemandincreases(Berg, 2021).Lithiumextractionisresource-heavyandenvironmentallyharmful(InstituteforEnergyResearch,
2023).WithinSouthAmerica,Argentina,Bolivia,and ChilecomprisetheLithiumTriangleregion,producing morethanhalfthegloballithiumsupply(Institutefor EnergyResearch,2023).Lithiumextractionthrough brineusesover65%oftheregion’swater,harmingthe naturalenvironmentandthesurroundingcommunities (InstituteforEnergyResearch,2023).Manyrecent innovationsregardingbatterytechnologyhavebeen proposed.Sodium-ionbatteriesarealeadingcontender inthisdebate.Unlikelithium,sodiumisoneofthe mostabundantmineralsintheEarth’scrust(Yabuuchi etal.,2014).Sodiumisalsothesecondlightestand smallestalkalimetal,behindlithium(Yabuuchietal., 2014),inadditiontobeingsignificantlycheaperthan othermineralsusedinbatterymanufacturing(Rudola etal.,2023).
Figure4. PriceofCarbonate,Sodium,Cobalt,and NickelOvertheLastFiveYearsfromRudolaetal (2023)
Figure4articulatestherelationshipbetweenmineralprices,enforcingtheincreasedavailabilityof sodiumresourcescomparedtoitscounterparts(Rudola etal.,2023).Recentstudiesalsoshowthatalongsidesodium-ionbatteries’promisingperkWhstorage capacity,thecyclelifenearsthatofLi-ionbatteries (Petersetal.,2016).However,comparisonstudies betweenlithiumandsodium-ion-basedbatteriesshow thatwhenconsideringrawmaterials,energycarriers, manufacturingrequirements,andsupplychains,the greenhousegasemissionsassociatedwithsodium-ion batteriesoutrankthoseoflithiumbatteries(Schneider etal.,2019).
Figure5exemplifiesthis,notatingsodium-ionbatteriesasNIBandlithium-ionbatteriesasLIB.This researchsuggeststhatthoughsodium-ionbatteriesmay solvefuturesupplyanddemandissuespresentedby
Figure5. GHGEmissionsofSodium-IonBatteries andLithium-IonBatteriesfromSchneideretal(2019).
lithium-ionbatteries,theydonotyetsolvetheenvironmentalimpactproblemsassociatedwithlithium-ion batteries(Schneideretal.,2019).
Assodium-ionbatteriesdonotcurrentlypresent aworthwhilealternativetolithium-ionbatteries,other innovationsmustbeconsidered.Aninnovationthathas receivedrecentmediaattentionisachangeinlithium extractionmechanisms,switchingtoaprocesscalled DirectLithiumExtraction(DLE).CurrentlithiumextractionforEVbatteriesreliesonhardrockmining. Thisprocessisnotonlyassociatedwithemissions andlargeamountsofgeneratedwastebutalsocan pollutesurfacewaters,degradewetlandsandother nearbynaturalhabitats,aswellasdisruptingsurroundingcommunities(USEPA,2019).Lithiumextraction throughthebrinemethodisanotherformofextractionthathasbecomemorecommoninrecentyears. However,thisprocessrequires2milliontonsofwater usagethroughevaporationpertonoflithiumharvested whilejeopardisingmassivequantitiesofunderground freshwaterwaterreservesthroughcontaminationwith theutilisedbrine(WetlandsInternational,2023).DLE minimisesthenegativeimpactsofalternativeextractiontechniques,extractinglithiumbrinefrombasins andusingaprocessingunittoextractandconcentrate theavailablelithium(Veraetal.,2023).Insteadof evaporatingvastamountsofwater,thismechanism usesaprocessingunittoremoveonlythelithium
fromtheextractedbrinewhilereplacingthepreviously lithium-bearingbrineintobasins,recyclingthewater resourcesinsteadoflosingthemthroughevaporation (Nicolacietal.,2023).
Figure6. LithiumBrineExtractionComparedtoDLE fromNicolacietal(2023)
Figure6providesavisualforthecomparison betweentheseprocesses.Thisapproachminimizes waste,using50timeslesswaterthanthecurrentlyused brinetechnique,andshortenstheprocessingtimesof typicallithiumextractionfrommonthstoyearstodays ormonths(Cleantech,2022).Thisprocessminimizes thecurrentenvironmentalimpactoflithiumextraction whilecurbingsomeofthedemandissues.Thatsaid, thecrustalabundanceoflithiumisstillanissueon thehorizon(Yabuuchietal.,2014).Environmental degradationandmeetingever-growingdemandremain thefundamentalproblems.Thoughsodium-ionbatterieshaveyettocurbnegativeenvironmentalimpacts, multiplepublications,includingtheArgonneNational Laboratory,agroupsupportedbytheUSDepartment ofEnergy,continuetoresearchpromisedinnovations andchangestocurrentproposals(Harmon,2024).As thisbatterytechnologyhasyettobeproducedat scaleandchangesmuststillbemade,DLEactsas apossibleshort-termsolutiontocurrentdegradation causedbylithium-ionbatteries,reducingwasteand impactwhileincreasingtheabilitytomeetdemand. Asinglesolutionhasyettobeestablished,butthe futureisstillpromising.
Withthefutureholdingmanyyearsofcontinuedprojectedgrowthforelectricvehicles,innovations mustbemadeintermsofbatterytechnology.Current lithiumbatteryoptionsareenvironmentallydetrimental andarenotsustainableforthecalculatedmarket increase.FromCO2emissionstomassiveamounts ofwaterloss,variousmethodsofharvestinglithium negativelyimpactbothnaturalandhumanlife.With thatinmind,technologicalinnovationswouldbemassivelybeneficialinmanyways.However,proposed solutionshaveyettohavetheinfrastructureneededto meetsupplyanddemandrequirementswithoutfurther harmingtheenvironment.Becauseofthis,atwophasedapproachissuggestedinthisreport.Starting withswitchingtoDirectLithiumExtractionincurrent
lithiumharvestingpractices,animprovementcouldbe madeintermsoftheenvironmentalimpacts,making theprocessmoresustainable,reducingwaterwaste, landuse,timerequired,andoverallimpact.Following this,assodium-ionbatterytechnologyadvancesand solutionsareestablishedtosolvethecurrentcalculated emissionsforbatterycreation,aswitchcouldultimatelybemadetoabatterysourcethatdoesnothave asstrictresourcelimits.Ifthisoptionbecomesmore environmentallyviable,currentcomplicationscouldbe curbed.
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VioletMelcher isa2ndyearEnvironmental&Earth SciencesStudentattheUniversityofStAndrews, Contactat:vvrm1@st-andrews.ac.uk
TeddyHenderson Bsc(Hons)Biology
LailaDeen
Bsc(Hons)Physics
ThomasBurton Bsc(Hons)Mathematics
Abstract—Enhancingtheresilienceofcropstoclimatechangeiscriticalforfuturefoodsecurity,and scientistsaredevelopingmanydifferentapproachestothisissue.Technologicaladvancessuchas RNAsequencingandCRISPR-Cas9areamongmanyofthetoolshelpingresearcherstocreatecrops withenhancedtolerancetoenvironmentalstresses.Inaddition,theagriculturalsystemmustfind waystoincreaseitssustainability,withareductioninnitrogenfertiliserusageofparticular importance.Thebeneficialsymbiosisbetweencropsandarbuscularmycorrhizalfungi(AMF)could helpreachbothaims.ThetransferofwaterandnutrientsfromAMFtohostplantsmeansthatcrops havehighertolerancetoabioticstress,suchasdrought,aswellasincreasednutrientuseefficiency, minimizingtheneedforenvironmentallyharmfulfertilisers.
ANINCREASINGLYUNPREDICTABLEANDMORE EXTREMECLIMATE threatensthestabilityoflifeon ourplanet;therefore,wemusttakeactiontominimizetheconsequences.Climatechangemayhave potentiallydisastrousimpactsonouragriculturalsystem,duetoanincreasedriskofflooding,extreme temperatures,drought,pests,andpathogens,which threatenthefoodsecurityofmany.TheUnitedNationsSustainableDevelopmentGoal2isto“End hunger,achievefoodsecurityandimprovenutrition, andpromotesustainableagriculture”(Nations,2024). Toaddressthesetargets,withfutureclimateconditions inmind,scientistsareendeavoringtoimprovecrop resiliencetoclimatechange,andfarmersareadaptingtheircropmanagementpracticestohelpfarmlandbetterwithstandweatherchallenges.Inaddition, theagriculturalsystemiscontinuouslyinnovatingto improvesustainabilityandlessenitscontributionto globalwarmingandclimatechange.Inthisreview,I willinvestigatehowcollaborationsbetweenscientists andindustryarehopingtoenhancecropresilience.
EnvironmentalStress
Firstly,toenhancecropresilience,wemustunderstandplantresponsestoenvironmentalstress.Aplant’s stressresponseinvolveschangestomanyphysiological,morphological,andmolecularprocesses,which mayresultinlimitedgrowthandreducedyields.These includechangesinsignaling,grainformation,water useefficiency,rootandshootgrowth,andthesymbioticmicrobiome(Benitez-Alfonsoetal.,2023).While manyofthesestressresponsephenotypesareeasily observable,theunderlyingmolecularmechanismof thesechangesismorechallengingtouncover.
Advancesintechnologyallowtheseplantstress responsestobemeasuredholistically,fromgenotype tophenotype,helpingtoelucidatetheoriginofspecific resiliencetraits.Inparticular,theabilitytomeasure changesingeneexpressionthroughRNAsequencing hasbeenrevolutionary(Starketal.,2019).Itisnow possibletomapthe“transcriptome”ofanorganism, tissue,orcell,whichistheoveralllevelofdifferent RNAtranscripts.RNAtranscriptsarecreatedbythe cellwhenageneisexpressed(switched“on”)and arethetemplatesforproteinsynthesis.Thismeans
thatwhentwoplantsaresubjectedtodifferentenvironmentalconditions,wecanseehowtheplant respondsonamolecularlevel:thevariationingene expressionand,therefore,proteinproduction(Stark etal.,2019).Thisinformationmaythengiveclues aboutthemechanismofaspecificplantresponse, andifwecanidentifyresiliencepathways,wecan breedorengineercropstotakeadvantageofthese responses.Therearemanydifferentapproachesto improvingcropresiliencetoenvironmentalstresses. Duringthedevelopmentofimprovedcroplines,these resiliencetraitscanthenbeselectedforandenhanced throughgeneticengineeringorbreedingprograms. Someofthetraitswhichprovideplantswithenhanced resiliencetoenvironmentalstressesincludewateruse efficiency,rootmorphology,ageofmaturity,andthe soilmicrobiome(Benitez-Alfonsoetal.,2023).
CRISPR-Cas9andGeneticallyModifiedPlants
Thereisstillanongoingdebateabouttheethics anddangersofgeneticallymodified(GM)plantsand theirconsumption,andvariationworldwideinthe technology’sacceptanceandlegalstatus.Whilehumanshavebeenselectivelybreedingcropplantsover thousandsofyears,itisonlyrecentlythatresearchers havebeenabletogeneticallyengineerplantsfor desiredcharacteristics.CRISPR-Cas9hasadvanced manyareasofresearch,withplantscienceexperiments benefittingfromthisnovelmethodforpreciselyalteringandremovinggenes(Belhajetal.,2015).The “knockout”ofageneisacommonapplicationof CRISPR-Cas9andprovidesaneffectivewaytostudy thefunctionofageneifyoucanlinkittochanges inthephenotypeofthemutantplant.Furthermore, CRISPR-Cas9hasbeenusedtosuccessfullyimprove cropresilienceandyieldsinavarietyofcropplants byalteringthegenometoincludeoptimumgenes fordesiredtraits(Yuanetal.,2023).Thismethod ofgenomeengineeringispromisingduetoitsrapid resultscomparedtotraditionalbreedingandselection methods.
Recentstudiesondroughtresiliencehavebeen investigatingawidelybeneficialsoilfungus,arbuscularmycorrhizalfungi(AMF),anditssymbiotic relationshipwitharound80%oflandplants.AMF
infectsplantroots,initiatingamutuallybeneficial relationshipwhereAMFprovidesnutrientsandwater totheplantandreceivescarbonfixedbytheplant throughphotosynthesisinreturn.Thereisevidencefor thissymbiosiswithAMFincreasingplanttoleranceto droughtbyhelpingtheplantadapttowaterdeficiency andincreasingitsaccesstowaterandnutrients(Cheng etal.,2021).Whilewaterdeficitconditionscanlimit thediversityanddevelopmentofAMFsymbiosis, someAMFspecieshavedevelopedadaptationsto theseconditionsandarestillabletothrive.
InoculationofplantswithAMFhasbeenshown toincreasedroughttolerancethroughacomplexmix ofmechanisms(Chengetal.,2021).Underdrought conditions,theairspacesinsoilincrease,making watertransferuptakemorechallenging.AMFaids theplantinovercomingthischallengebyfacilitating thepassageofwaterfromthesoilthroughtheAMF andtotherootsthroughaquaporins(AQP),thereby improvingwateruptake.Furthermore,AMFisableto inducechangesinrootmorphology,whichimprove soilwaterretentionandnutrientacquisition.AMF induceschangesingeneexpressionofnutrientand watertransporterstopromotewaterandnutrientacquisition.AnotherwaythatAMFcontributestodrought toleranceisthroughtheformationofsoilaggregates duetothesecretionofglomalin,whichisabletobind soilparticlestogetherandimprovesoilstructureand waterretention.AMFalsoreducestheairgapbetween soilandplantroot,whichallowsmoreefficienttransfer ofnutrientsandwater.AMFsymbiosisalsoenhances droughttolerancethroughimprovedphotosyntheticcapacity,enhanceddefenseagainstantioxidants,osmotic regulation,polyamineandfattyacidmetabolism,as wellasregulationofendogenoushormones(Chenget al.,2021).
Furthermore,harnessingAMFsymbiosishasthe potentialtoreducerelianceonnitrogenfertiliser, whichcausesharmtotheenvironmentduetoassociatedgreenhousegasemissionsfromproduction, aswellaspollutionafterapplication(Robertson& Vitousek,2009).Theuseofnitrogenfertiliserisvital toproducethehighyieldsseenacrosstheglobein ourcurrentagriculturalsystem.However,withashift towardsustainability,thereareincreasingeffortsto reduceitsapplication.Instead,researchersarehoping toimprovethenutrientuseefficiencyofcrops,sothey
makethemostofthenitrogenalreadyavailablein thesoilorrequirelessnitrogenfertilisertoachieve thesameyields(Anasetal.,2020).Itisthoughtthat AMFcouldalsobehelpfulinimprovingthenitrogen useefficiencyofplantsduetoitsroleinsupplyingthe hostplantwithnutrients(Xieetal.,2022).
ThesymbiosisbetweenAMFandplantsisan exampleofoneofmanydifferentinteractionsatplay betweenmicroorganismsinthesoilandplants,which togetherformtheplants’microbiome(phytomicrobiome).Onewayinwhichindustryistranslatingthis researchintoinnovationtoimprovecropresilience andagriculturalsustainabilityisthedevelopmentof biostimulantswhichpromotethegrowthofbeneficial microorganismsinthesoil(Alahmadetal.,2023). InoculationofplantswithAMFhasbeenshownto actasabiostimulantandisapromisingalternativeto nitrogenfertilisers(Rouphaeletal.,2015).
Insummary,technologicaladvancesinRNAsequencingareallowingustoinvestigatethegenetic basisforenvironmentalstressresponsesandresilience. Withthisknowledgeofkeygenesinmind,CRISPRCas9allowsustorapidlydevelopplantswithprecise mutations,eithertoinvestigateaphenotypefurther ortocreateacropwithincreasedresiliencedueto theinsertionofanoptimizedgeneintothegenome. IfwearetoachievetheUnitedNationsSustainable DevelopmentGoals,theremayneedtobewideracceptanceoftheuseoftechnologylikeCRISPR-Cas9 tocreatecropsabletowithstandthechallengesof climatechange.However,theethicsbehindgenome editingandconsumptionmustbediscussedwithcare andclearpubliccommunication.
Thisreportalsooutlinedthepotentialadvance incropresiliencethatcomesfromoptimizingcrop plants’symbiosiswithAMF,duetoitsroleinwater andnutrientuptake.Toachievethis,theagricultural industryisdevelopingbiostimulantsthatharnessthe benefitsofthesoilmicrobiomeforcropsbycreating productsthatpromotethegrowthofmicroorganisms
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TeddyHenderson isa3rdyearBiologyStudentat theUniversityofStAndrews,Contactat:teh8@standrews.ac.uk