Brain Medicine (Genomic Press) 2025 issue-1-1 by genomicpress

The Changing Brain

August 18 – 20, 2025 Irvine, California, USA

• The Evolving Brain

• The Learning Brain

• States of the Brain

• The Developing Brain

• The Dynamic Brain

• The Disordered Brain

Paola Arlotta, Harvard University

Xiangmin Xu, University of California, Irvine

Confirmed Speakers: Conference Organizers:

Ishmail Abdus-Saboor, Columbia University

Paola Arlotta, Harvard University

Carlos Brody, Princeton University

Beth Buffalo, University of Washington

Edward Chang, UCSF

Anne Churchland, UCLA

Yang Dan, University of California, Berkeley

Catherine Dulac, Harvard University

Guoping Feng, MIT

Zhigang He, Harvard University

Hailan Hu, Zheijang University, China

Josh Huang, Duke University

Sten Linnarsson, Karolinska Institutet, Sweden

Liqun Luo, Stanford University

Hongkui Zeng, Allen Institute for Brain Science

Guillermina López-Bendito, UMH-CSIC, Spain

Liqun Luo, Stanford University

Michelle Monje, Stanford University

John Ngai, National Institutes of Health

Tom Nowakowski, UCSF

Vanessa Ruta, Rockefeller University

Bernardo Sabatini, Harvard University

Nelson Spruston, Howard Hughes Medical Institute

Karel Svoboda, Allen Institute for Neural Dynamics

Li-Huei Tsai, MIT

Pierre Vanderhaeghen, Leuven Brain Institute of Technology

Hongkui Zeng, Allen Institute of Brain Science

Larry Zipursky, UCLA

Editor-in-Chief

JulioLicinio, StateUniversityofNewYork,UpstateMedicalUniversity,Syracuse,NewYork13210,USA

PublishingManager

Ma-LiWong, StateUniversityofNewYork,UpstateMedicalUniversity,Syracuse,NewYork13210,USA

EditorialBoard

SchahramAkbarian, IcahnSchoolofMedicineatMountSinai,NewYork,NewYork10029,USA

DanielBarbosa, MedicalUniversityofSouthCarolina,Charleston,SouthCarolina29425,USA

TatianaBarichello, TheUniversityofTexasHealthScienceCenteratHouston,Houston,Texas77054,USA

HilaryBlumberg, YaleSchoolofMedicine,NewHaven,Connecticut06510,USA

StefanR.Bornstein, TUDDresdenUniversityofTechnology,01307Dresden,Germany

EmilianaBorrelli, UniversityofCalifornia,Irvine,California92697,USA

PaoloBrambilla, UniversitàdegliStudidiMilano,20122Milan,MI,Italy

JoshuaC.Brown, HarvardMedicalSchoolandMcLeanHospital,Belmont,Massachusetts02478,USA

AnnamariaCattaneo, UniversitàdegliStudidiMilano,20133Milan,MI,Italy

UdoDannlowski, UniversityofMünster,D-48149Münster,Germany

HamedEkhtiari, UniversityofMinnesotaMedicalSchool,Minneapolis,Minnesota55454,USA MassimoFilippi, Vita-SaluteSanRaffaeleUniversity,20132Milano,MI,Italy

KostasN.Fountoulakis, SchoolofMedicine,AristotleUniversityofThessaloniki,Thessaloniki,Greece SamGandy, IcahnSchoolofMedicineatMountSinai,NewYork,NewYork10029,USA

RubenGur, UniversityofPennsylvania,Philadelphia,Pennsylvania19104,USA

CaseyH.Halpern, PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,Pennsylvania19104,USA

AlanG.Harris, NewYorkUniversityGrossmanSchoolofMedicine,NewYork,NewYork10016,USA

IanB.Hickie, UniversityofSydney,BrainandMindInstitute,Camperdown,NewSouthWales2050,Australia

AtsushiKamiya, JohnsHopkinsSchoolofMedicine,Baltimore,Maryland21287,USA

KeithM.Kendrick, UniversityofElectronicScienceandTechnologyofChina,Chengdu,China

RonaldC.Kessler, HarvardMedicalSchool,Boston,Massachusetts02115,USA

AdrienneCarolLahti, UniversityofAlabamaatBirmingham,Birmingham,Alabama35294,USA

TatiaM.C.Lee, TheStateKeyLaboratoryofBrainandCognitiveSciences,UniversityofHongKong,HongKongSAR JohnMantsch, MedicalCollegeofWisconsin,Milwaukee,Wisconsin53226,USA

ValeriaMondelli, InstituteofPsychiatry,PsychologyandNeuroscience,King’sCollege,London,SE59RT,UK

RuthO’Hara, StanfordUniversity,Stanford,California94305,USA

AnilkumarPillai, UniversityofTexasHealthScienceCenteratHouston,Houston,Texas77054,USA

JelenaRadulovic, AlbertEinsteinCollegeofMedicine,Bronx,NewYork10461,USA

GavinReynolds, Queen’sUniversityBelfastandSheffieldHallamUniversity,UK

MarisaRoberto, TheScrippsResearchInstitute,LaJolla,California92037,USA

IsabelleM.Rosso, HarvardMedicalSchoolandMcLeanHospital,Belmont,Massachusetts02478,USA

ZoltanSarnyai, MargaretRoderickCentreforMentalHealthResearch,JamesCookUniversity,Townsville,Queensland4811,Australia

JonathanSavitz, LaureateInstituteforBrainResearch,Tulsa,Oklahoma74136,USA

AkiraSawa, JohnsHopkinsSchoolofMedicine,Baltimore,Maryland21287,USA

HelenBlairSimpson, ColumbiaUniversityandNewYorkStatePsychiatricInstitute,NewYork,NewYork10032,USA

NunoSousa, SchoolofMedicine,UniversityofMinho,4710-057Braga,Portugal

WeihongSong, WenzhouMedicalUniversity,Wenzhou,325015,ChinaandUniversityofBritishColumbia,Vancouver,BritishColumbiaV6T1Z3,Canada Li-HueiTsai, PicowerInstitute,MassachusettsInstituteofTechnology,Cambridge,Massachusetts02139,USA

KueiY.Tseng, UniversityofIllinoisChicago–CollegeofMedicine,Chicago,Illinois60612,USA

LucinaUddin, UniversityofCalifornia,LosAngeles,California90095,USA

GuidovanWingen, UniversityofAmsterdam,Amsterdam,1100DD,TheNetherlands

RogerWalz, UniversidadeFederaldeSantaCatarina,Florianópolis,SantaCatarina88040-970,Brazil

YunleiYang, AlbertEinsteinCollegeofMedicine,Bronx,NewYork10461,USA

Wei-DongYao, StateUniversityofNewYork,UpstateMedicalUniversity,Syracuse,NewYork13210,USA

KeqiangYe, ShenzhenInstituteofAdvancedTechnology,ChineseAcademyofSciences,Shenzhen,518055,China

AllanH.Young, InstituteofPsychiatry,PsychologyandNeuroscience,King’sCollegeLondon,London,SE58AF,UK

TifeiYuan, ShanghaiMentalHealthCenter,BrainHealthInstitute,200030Shanghai,China

MoneZaidi, IcahnSchoolofMedicineatMountSinai,NewYork,NewYork10029-5674,USA

BrainMedicine ispublishedbyGenomicPress.

SCOPE: Thescopeof BrainMedicine startswithfundamentalneuroscience,extendstotranslationalinitiatives,andthentoallbrainbaseddisorders.Weareequallyinterestedinspecificdisordersaswellasincross-disciplinaryinterfaces,includingareassuchas neuropsychiatryandneuropsychology.Wepublishworkthatutilizesarangeofapproaches,includinggenetics,cellularandmolecularneuroscience,the“-omics,”neuroimaging,neuropsychopharmacology,functionalneurosurgery,brainstimulation,microbiology includingthemicrobiome,psychoneuroimmunology,psychoneuroendocrinology,analysesof“bigdata,”computationalapproaches includingartificialintelligence(AI),environmentalcontributions,digitalhealth,e-health,allthewaytothesocietalimpactofbrain disorders,includingepidemiologyandpublichealth.

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BrainMedicine

Volume1 Number1 January2025

BrainMedicine:Exceptionalscience,nofiefdoms,andabettertomorrow

INNOVATORS&IDEAS:RISINGSTARS

RuthM.Barrientos:Vulnerabilitiesassociatedwiththeagingbrainthatmakeitmoresusceptibletoinflammatorychallengesleading tomemorydysfunction

NathanielG.Harnett:Identifyingtheneurobiologicalmechanismsofsusceptibilitytotraumaandstress-relateddisorders

DanielH.Wolf:Understandingmotivationimpairmentfromclinical,behavioral,andneurobiologicalperspectivestopavethewayfor bettertreatments

HaithamAmal:Nitricoxideisasharedmolecularmechanismofmultipleneurodevelopmentalandneurodegenerativedisorders

NoraVolkow:Insightsintothefunctionofourbrainsthroughthescienceofdrugsandaddiction

EdytheLondon:Translatingknowledgefrommolecularandfunctionalimagingstudiestonewpharmacologicalandbrainstimulation treatmentsforaddiction

AlyssonMuotri:Modelingthehumanbrainwithstemcellsandorganoids,fromdiseaseparadigmstoneanderthoids,spacebrains, andbeyond

KimQ.Do:Antioxidantsspecificallytargetedatmitochondria:Anoveltherapeuticapproachtoschizophrenia

Theassociationofdifferentacutemanifestationsofmultiplesclerosisonfunctionaloutcome JoãoPedroF.Gonçalves,AlexC.S.Figueiredo…PedroA.P.deJesus

Thecoverillustratesthecomplexrelationshipbetweenenvironmentalairpollutionandbraindevelopment.Achildlooksupwardagainstabackdropofanurbanskyline shroudedinindustrialpollution,whileconstellation-likeneuralnetworksemergefromthechild’shead,suggestingtheintricateinterplaybetweenenvironmentalexposures andneurologicaldevelopment.Thegradientfromwarmsunsettonestocoolbluesrepresentsthetransitionfromenvironmentalhazardstotheirneurobiologicalimpacts. Thecoverartemphasizesthejournal’sfocusonbrainmedicine“fromneuronstobehaviorandbetterhealth.”Furtherinformationonthistopiccanbefoundinthearticles “HaithamAmal:Nitricoxideisasharedmolecularmechanismofmultipleneurodevelopmentalandneurodegenerativedisorders”byHAmal(pages16–18)and“Airpollution: anemergingriskfactorforautismspectrumdisorder”bySKOjhaandHAmal(pages31–34)inthisissue.

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Thisissueisnowavailableat https://genomicpress.kglmeridian.com/view/journals/brainmed/brainmed-overview.xml

EDITORIAL

BrainMedicine:Exceptionalscience,nofiefdoms,andabettertomorrow

©TheAuthor(s),underexclusivelicencetoGenomicPress2024

BrainMedicine January2025;1(1):1–2;doi: https://doi.org/10.61373/bm024d.0007

Weareembarkingonanexcitingjourneywiththelaunchofthefirstissue of BrainMedicine:FromNeuronstoBehaviorandBetterHealth.Thisis notjustanotherjournal;itisaleapintounchartedterritory,bridgingall ofneurosciencewithclinicalknow-howacrossdistinctbutbrain-focused medicalspecialtiesinwayswehavenotseenbefore.Wegobeyondthe traditionalfiefdomsthathaveshackledthecross-disciplinaryintegration ofneuroscience,translationalscience,andclinicalpractice.Thinkofitas drawingnewstarpatternsintheacademicsky,notjusterasingoldboundarylines.

Whatisthebigdealaboutthisjournal?Well,itiswherethecuttingedgescienceofbraincellsmeetstranslationalneurologyandpsychiatry, nottomentionalltheotherfieldsthattouchonourbrainsandmental health.Wearetalkingbigpicturehere–howallthisplaysintopublicpolicyandthebiggerworld(1–3).Butbecertainthatwearenotjustfollowingthelatestfads.Weareheretoshakethingsupinbrainscience,from thenutsandboltsofneurotransmitterstothebigquestionsinneuroethics(4).

Now,youmightbethinking,“Whatmakes BrainMedicine anydifferent fromotherjournals?”Weareallaboutpushingboundariesandthinking outsidetheboxwhenitcomestothebrain.Thisisnotaboutplayingit safeorstickingtothetrends;weareheretochallengethestatusquoin brainsciencewithrealinnovativethinking,fromtheneurochemistryright downtotheethicaldilemmaswefaceinthisfield(4).

Thisisnota20th centuryneurologyorpsychiatryjournal.Thepast20 yearshavegeneratedexplosiveknowledgeinneuroscience.Wenowknow somuchmoreaboutthebrain.Thankstounprecedentednewtechnologiesandsmarterwaysofdoingresearch,wearegettingahandleonhow thebrainworks,fromthinkingandfeelingtounravellingdiseasestates. Andthisisnotjustacademicivorytowernarcissism–itisashakingup ofpsychiatryandneurologyinbigways.Thearticlesyouwillreadin BrainMedicine aregoingtobeatawholeotherlevel–thinkcutting-edge techniqueslikeimagingandgenetics,broughttogetherbyadvancedartificialintelligence(AI)toadvanceprecisionmedicine.Wehavemovedpast description;now,wearefiguringoutcircuitsandmechanismsinthebrain andhowwecanusethatknowledgetomakepeople’slivesbetter.Itisa wholenewballgame,andourjournalwasspecificallycreatedtoberight inthethickofit,bringingyouthelatestandgreatestinbrainresearch that’snotjustsmartbutexceptionallyrelevantandgame-changing(5).

Oneofourbigfocusesin BrainMedicine istacklingthetoughstuff, likeAlzheimer’sdisease(AD).SiddharthaMukherjeecalledcancer“The EmperorofAllMaladies”(6).GiventhefactthatADcanbefarmoredevastatingthancancer,whatshallwecallit?Whoismightierthantheemperor?Godzilla?ADisindeedabeastthatisdestroyingthelivesofmillions,anditisoneofthegnarliestpuzzlesinallofmedicinetoday.But weareonit–publishingthehottestresearchonADandotherdementias, andhuntingdownnewwaystobeatthesecalamitousdiseases(5).

Andletusnotforgetaboutthecuttingedge;e.g.,deepbrainstimulation,especiallywhenothertreatmentsarenotcuttingit.Thisisnextleveltreatmentformultiplebraindiseasesandpsychiatricdisorders,and itcouldtotallyflipthescriptonhowwehandletheseconditions. Brain Medicine willbringyouthelatestresearchondeepbrainstimulation

Received:19January2024.Accepted:23January2024. Publishedonline:25January2024.

andotherbreakthroughtreatmentsthatarechangingthegameinbrain medicine(7,8).Thisfundamentalareaof BrainMedicine isaddressedin ourGuestEditorialledbyJoshBrown(9).

Thereisalsothewholefascinatingworldofthemicrobiome–microorganismsinourgutsthathavealottosayaboutourbrainhealthand moods.Wearejustscratchingthesurfacehere,but BrainMedicine isdivingdeepintohowourgutmicrobesaffectwhoweare(10,11).

WecannotignorethewildworldofAI–especiallywhenitcrossespaths withbrainscienceandmentalhealth.Ifyouarewrestlingwithbigquestionsaboutmachinelearning,digitalhealth,theuseofAItoolsfordiagnosisandprecisiontreatments,ande-health, BrainMedicine iswhereyou wanttobe(12–17).

Atitsheart, BrainMedicine isallaboutbeingtop-notchinscience, stickingtothefacts,andalwaysonthelookoutforthose“aha!”moments thatflipeverythingupsidedown.Whenyousendusyourpaper,itisgettingassessedbysomeofthesharpestmindsaroundtheworld.

Butitisnotjustaboutbeingsmart.Wegetthattheworldhasgone digital,andwearenotjustsittingonourlaurels.Weareshoutingyourresearchfromthedigitalrooftops,doingeverythingpossible–fromtraditionalpressreleasestoX,Insta,Facebook,andLinkedInposts,andgetting yourresearchhighlightsonYouTube,narratedbynoneotherthanyou.

BrainMedicine isnotjustanotherjournal;itisarevolution.Weare rallyingeveryonewhoisreadytostepupandchallengetheoldwaysof thinkingaboutthebrain.Withadreamteamofrenownededitorialboard membersfromallovertheglobe,wearebridgingeverythingfromneurosciencetoneurology,psychiatry,andmore.Threeboardmembershave alreadycontributedtoour InnovatorsandIdeas sectionthatspotlights individualswhohavemadenoteworthycontributionstothefield.These innovatorsincluderisingstarRuthBarrientos(neuroinflammationand aging)(18)andresearchleadersEdytheLondon(drugabuseandbrain imaging)(19)andKeqiangYe(ADandParkinson’sdisease)(20).

Wearelightingthiscandle,andwewantyoutobepartofthisepic journey. BrainMedicine isheretoturnheads,stirupnewideas,andadvancebrainhealthandmentalwell-being.

JulioLicinio1

1 Editor-in-Chief,BrainMedicine,GenomicPress,NewYork, NewYork10036,USA e-mail: julio.licinio@genomicpress.com

References

1.LevittS,Henri-BhargavaA,HoganDB,ShulmanK,MitchellSB.TheBrainMedicine Fellowship:ACompetency-BasedTrainingProgramtoTreatComplexBrainDisorders.Academicmedicine:journaloftheAssociationofAmericanMedicalColleges. 2023;98(5):590-594.DOI: 10.1097/ACM.0000000000005156 PMC10121366

2.SaraviSFB,MitchellSB,LevittS.TheBrainMedicineClinic:twocaseshighlightingthe advantagesofintegrativecare.BJPsychOpen.2023;9(3):e92.DOI: 10.1192/bjo.2022. 631 PMC10228218

3.BrownJC,Dainton-HowardH,WoodwardJ,PalmerC,KaramchandaniM,WilliamsNR, GeorgeMS.TimeforBrainMedicine.TheJournalofneuropsychiatryandclinicalneurosciences.2023:appineuropsych21120312.DOI: 10.1176/appi.neuropsych.21120312

4.SontateKV,RahimKamaluddinM,NainaMohamedI,MohamedRMP,ShaikhMF,Kamal H,KumarJ.Alcohol,Aggression,andViolence:FromPublicHealthtoNeuroscience. FrontPsychol.2021;12:699726.DOI: 10.3389/fpsyg.2021.699726 PMC8729263

5.WilsonH,deNataleER,PolitisM.RecentAdvancesinNeuroimagingTechniquestoAssistClinicalTrialsonCell-BasedTherapiesinNeurodegenerativeDiseases.StemCells. 2022;40(8):724-735.DOI: 10.1093/stmcls/sxac039

6.MukherjeeS.TheEmperorofAllMaladies.London:FourthEstate;2011.ISBN:978-000-725091-2.

7.RemoreLG,TolossaM,WeiW,KarnibM,TsolakiE,RifiZ,BariAA.DeepBrainStimulationoftheMedialForebrainBundleforTreatment-ResistantDepression:ASystematic ReviewFocusedontheLong-TermAntidepressiveEffect.Neuromodulation.2023.DOI: 10.1016/j.neurom.2023.03.011

8.HaberSN,LehmanJ,MaffeiC,YendikiA.TheRostralZonaIncerta:ASubcorticalIntegrativeHubandPotentialDeepBrainStimulationTargetforObsessiveCompulsiveDisorder.Biologicalpsychiatry.2023;93(11):1010-1022.DOI: 10.1016/j. biopsych.2023.01.006

9.NuthalapatiP,PalmerC,BarbosaD,BrownJC.InterventionalBrainMedicine: Medicine’snewestfrontier.BrainMed.2024.DOI: 10.61373/bm024g.0013

10.ZhengP,YangJ,LiY,WuJ,LiangW,YinB,etal.GutMicrobialSignaturesCanDiscriminateUnipolarfromBipolarDepression.AdvSci(Weinh).2020;7(7):1902862.DOI: 10.1002/advs.201902862 PMC7140990

11.ZhengP,ZengB,LiuM,ChenJ,PanJ,HanY,etal.Thegutmicrobiomefrom patientswithschizophreniamodulatestheglutamate-glutamine-GABAcycleand schizophrenia-relevantbehaviorsinmice.SciAdv.2019;5(2):eaau8317.DOI: 10.1126/ sciadv.aau8317 PMC6365110

12.NwanosikeEM,ConwayBR,MerchantHA,HasanSS.Potentialapplicationsandperformanceofmachinelearningtechniquesandalgorithmsinclinicalpractice:Asystematicreview.Internationaljournalofmedicalinformatics.2022;159:104679.DOI: 10.1016/j.ijmedinf.2021.104679

13.WatsonDS,KrutzinnaJ,BruceIN,GriffithsCE,McInnesIB,BarnesMR,FloridiL. Clinicalapplicationsofmachinelearningalgorithms:beyondtheblackbox.Bmj. 2019;364:l886.DOI: 10.1136/bmj.l886

14.MuskerM,ShortC,LicinioJ,WongML,BidargaddiN.Usingbehaviourchangetheoryto informaninnovativedigitalrecruitmentstrategyinamentalhealthresearchsetting. JPsychiatrRes.2020;120:1-13.DOI: 10.1016/j.jpsychires.2019.09.012

15.TandonR.Computationalpsychiatryandthepsychopathologyofpsychosis:Promisingleadsandblindalleys.Schizophreniaresearch.2023;254:143-145.DOI: 10.1016/ j.schres.2023.02.003

16.BrucarLR,FeczkoE,FairDA,ZilverstandA.CurrentApproachesinComputationalPsychiatryfortheData-DrivenIdentificationofBrain-BasedSubtypes.Biologicalpsychiatry.2023;93(8):704-716.DOI: 10.1016/j.biopsych.2022.12.020 PMC10038896

17.KopalJ,BzdokD.EndorsingComplexityThroughDiversity:ComputationalPsychiatry MeetsBigDataAnalytics.Biologicalpsychiatry.2023;93(8):655-657.DOI: 10.1016/j. biopsych.2022.07.023

18.BarrientosRM.Vulnerabilitiesassociatedwiththeagingbrainthatmakeitmoresusceptibletoinflammatorychallengesleadingtomemorydysfunction.BrainMed.2024. DOI: 10.61373/bm024k.0004

19.LondonE.Translatingknowledgefrommolecularandfunctionalimagingstudiesto newpharmacologicalandbrainstimulationtreatmentsforaddiction.BrainMed.2024. DOI: 10.61373/bm024k.0001

20.YeK.TheC/EBPb/AEPpathwayisthekeydriverforAlzheimer’sdisease(AD)and Parkinson’sdisease(PD)pathogenesisanditsspecificinhibitorattenuatesAD/PD pathologies.BrainMed.2024.DOI: 10.61373/bm024k.0010

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GUESTEDITORIAL

InterventionalBrainMedicine:Medicine’snewestfrontier

©TheAuthor(s),underexclusivelicensetoGenomicPress2024

BrainMedicine January2025;1(1):3–5;doi: https://doi.org/10.61373/bm024g.0013

ANewJournaltoBridgeaDisadvantageousGap Dysfunctionofneuralcells,ortheirdestruction,arethecauseofmost neurologicandpsychiatricdiseases.Whichspecificnetworksareinvolved determineswhetherthereisaneurologicorpsychiatricdisease(orboth, asinmostcases).Advancesinneurosciencehaveblurredtheartificial boundariesbetweenpsychiatryandneurologyandhavecontributedto themomentumtowardalong-awaitedconvergenceofthesedisciplines. Unifiedclinicaltraininghasbeenproposed(1),butcurrenttraininginthe USandmuchofEuropecontinuestofollowthedivergentapproachestablishedinthe19thcentury.Asaresult,neurologyandpsychiatryoperate isolatedfromeachother,withoutexplicitorconsistentcriteriaforwhy adisorderisclaimedbyonedisciplineortheother.Pathologicprocesses thataffectpurely“neurologic”or“psychiatric”braincircuitsaretheexceptionandarenottherule.Thissplitapproachhindersaccesstothebest qualitycareforpatientswithbraindisorders.Anewjournalhasbeencreatedwiththisinmind(2). BrainMedicine willembraceaninclusiveway forwardthatuniquelyholdsthepotentialtoshiftcurrentparadigms(2).

AModelofConvergence:InterventionalBrainMedicine Thereareseveralareaswherethefieldsarealreadyconverging,suchas increasedneuroimagingofpsychiatricdisorders(3)orpsychotherapeutic techniquesbeingadoptedinneurologyclinics(4).Butperhapsnowhere isthewayforwardmoreapparentthanwiththerapidlyadvancingtreatmentmodalitiesofbrainstimulation.Indeed,dialoguefromexpertsata BrainStimulationSubspecialtySummit(BRASSS)heldinBostonin2023 emphasizedaninterestincross-disciplinaryimplementation. InterventionalBrainMedicine emergedastheleadingnameforapotentialnew medicalsubspecialty.Thisnameandapproachbuildonliteratureandexistingclinicsimplementing‘InterventionalPsychiatry’(5, 6)butexpands thesetreatmenttoolstoincludemodulationofanybrainnetwork.

Theprospectivesubspeciality,InterventionalBrainMedicine,representsthenewestfrontierandembodiestheaimofthenewjournal,Brain Medicine,whichwillincludepublicationsofresultsfromtherapeutic modulationofneuralcellsandcircuitsacrossthebrain.Wedonotpresent acomprehensivereviewofthesemodalities.However,wewillhighlight howthescienceandpracticebehind InterventionalBrainMedicine serve asamodelforbringingneurologyandpsychiatrytogetherandhowitfits intotheconceptofBrainMedicineasmedicine’snextfrontier.

Neuromodulation,orbrainstimulation,referstotechniquesthatuse waveformenergytodirectlyandtherapeuticallyperturbtargetedbrain regionsandnetworks.Recentadvancementsinneuromodulationmodalitiesalsoofferanovelparadigmforunderstandingthebrain.Thesemodalitiesuseelectrical,magnetic,acoustic,oropticalenergytoperturbspecificbrainregionsandnetworks.Theyalsoallowvaluableinsightsinto thecausalrelationshipsbetweenthebrainandbehavioronanindividualsubjectbasis.Neuromodulationtechniquesalsohelprefineneurobiologicalmodelsofbraindisordersandoffertherapeuticbenefitstopatients whocannotimprovewithconventionaltreatments.

Variousneuromodulationmodalitiesareavailableasclinicalorinvestigationalapproachesfortreatingneurologicalandpsychiatricconditions.Theseincludeopen-loopdeepbrainstimulation(DBS)and

Received:18March2024.Revised:21March2024.Accepted:22March2024. Publishedonline:25March2024.

responsiveneurostimulation(RNS),vagusnervestimulation(VNS),transcranialmagneticstimulation(TMS),transcranialelectricalstimulation (tES)[whichincludestranscranialdirectcurrent(tDCS),transcranialalternatingcurrentstimulation(tACS)andtranscranialrandomnoisestimulation(tRNS)],electroconvulsivetherapy(ECT),magneticseizuretherapy(MST),epiduralcorticalstimulation(ECS),spinalcordstimulation (SCS),transcranial/low-intensityfocusedultrasound(tFUS/LIFU),and temporalinterference(TI).Whilesomenovelapproacheshavepromising evidence,wewillfocusonthosealreadyinclinicalusetohighlightthe trans-disciplinaryutilityandpotentialofthetoolsoftheemergingsubspecialtyof InterventionalBrainMedicine

InvasiveModalities

DeepBrainStimulation

Perhapsthemostclassicalapproachtoneuromodulationisthedirect deliveryofelectricalstimulationtobraintissue.Deepbrainstimulation (DBS)isaninvasivetechniquethatinvolvesimplantingelectrodesinspecificbrainregionsanddeliveringelectricalpulsestomodulateactivity. Currently,DBSisprimarilyclinicallyusedformovementdisorders,includingessentialtremor,dystonia,Parkinson’sdisease(7),andepilepsy (8)and,thus,ismostoftenconsidereda“neurological”treatment.However,withinpsychiatry,italsohasanFDAhumanitariandeviceexemptionforobsessive-compulsivedisorder(OCD)(9);althoughunderutilized, ithasalsoshownefficacyinsomestudiesandcaseseriesindepression, Tourettesyndrome(10),andaddiction(11).Unfortunately,theexpansion ofDBSwithinbrainmedicineindicationshasbeenlimitedbyavailability,cost,andapprehensionofaninvasiveprocedure,especiallybypsychiatristswhoarenotfamiliarwithDBS(12).Awarenessisaparticular barrieramongpsychiatristsowing,inpart,toafragmentedfieldwhere “neurologic”treatmentsarenotwidelyconsideredforpsychiatricpatients,[althoughmanymedicationsdevelopedinitiallyforclassicalneurologicaldisorderslikeepilepsycanalsotreatdepressionandmooddisorders](13, 14).ThefutureofDBSinvolvesmorepreciseandpersonalizedcircuit-basedtargetingforabroaderrangeofneurologicaland psychiatricsymptoms,closed-loopparadigmsthatadjuststimulationparametersbasedondiseasebiomarkers,andcombinationtherapiesthat integrateDBSwithpharmacological,behavioral,orcognitiveinterventions(15).WhileinterestinusingDBSacrossthespectrumofBrain Medicinecontinuestogrow,thebenefitsfromtheseadvancementsin clinicalpracticeremainmostlylimitedtopatientswith“neurological”disease.Notwithstanding,DBShasthepotentialtoofferpowerfulandtransdiagnosticalternativesforpervasivesymptomsofbraincircuitdisorders.

ResponsiveNeurostimulation

Responsiveneurostimulation(RNS)alsoinvolvesimplantingelectrodes inspecificbrainregions,butunlikeDBS,itdeliversstimulationonlywhen abnormalactivityistrainedanddetectedinaclosed-loopfashion.RNS wasapprovedbytheFDAin2013forthetreatmentoffocalepilepsy thatdoesnotrespondtomedicationorsurgery(16).RNSdisruptsthe synchronizationofepilepticneuronstorestorenormalactivitypatterns (17).WhilecurrentlyonlyFDA-clearedforepilepsy,thereisresearch

underwaytoexpandtheindicationsforotherbrainmedicinedisorders, suchasParkinson’sdisease,essentialtremor,anddystonia,andinvestigatethelong-termeffectsonneuralconnectivityandplasticity(18, 19). Promisingly,similarsystemsarealsobeingevaluatedforpsychiatricdiseasesusingclosed-loopstimulationfordepression,bingeeatingdisorder, andOCD(17, 20, 21).

VagusNerveStimulation

Vagusnervestimulation(VNS)deliverselectricalpulsesinvasivelyornoninvasivelytotheneckortoabranchofthevagus,activatingbrainstemnucleiandcausingwidespreadneurotransmitterrelease(22).VNSwasinitiallydevelopedinthe1980sasatreatmentforrefractoryepilepsy(23) butwasalsofoundtohaveantidepressanteffectsandwasFDA-cleared forthetreatmentofmajordepressivedisorderin2005(24, 25).Itispredominantlystillusedforrefractoryepilepsy.However,theemergenceof noninvasivesystemshasledtoevaluationforotherneuropsychiatricconditions,suchasAlzheimer’sdisease,post-strokerecovery,post-traumatic stressdisorder,autism,andaddiction,aswellasforenhancingcognitive performance,learning,andmemory(26).Despiteitsrelativelylowrisk, alongwithregulatoryapprovalsfordepression,itsadoptioninclinical practicefordepressionremainslimited.Thisislikelyduetothelackofa convincingClass1evidenceclinicaltrialofefficacyindepression,andat leastinpartduetoproviderawareness,access,andtraininginprogrammingthedevice.Notwithstanding,ithascreatedsomeinroadsinthinking aboutthebrainholistically,especiallyinguidingtreatmentforpatients withbothepilepsyandprominentmoodsymptoms.Thisshouldserveas apatternforusageasevidencemountsforitsefficacyinaddressingspecificsymptomsofbraincircuitdisorders.

Noninvasivemodalities

ElectroconvulsiveTherapy

Electroconvulsivetherapy(ECT)involvestheinductionofabriefgeneralizedseizureunderanesthesiabyapplyinganelectricalcurrentthrough thescalp.WhileECThasbeenusedforover80years,itremainsthemost effectiveandfast-actingtreatmentforsevereandtreatment-resistant depression,aswellasothermooddisorders,catatonia,andpsychosis (27).Whilenottypicallyusedinclinicalneurology,ECTdoeshaveevidenceforsafetyandefficacyintreatingParkinsonism(28)aswellasstatusepilepticus(29).ThefutureofECTmayinvolveimprovingitssafety andtolerability,refiningelectrodeplacementandstimulationparameters,combiningitwithothertherapies,suchastranscranialmagnetic stimulation(TMS)andketamine,andbetterelucidatingitsmechanisms ofaction(30–32).Similarlytoothermodalities,ECTisalmostexclusively usedby“oneside”ofBrainMedicine;mostneurologistshaveverylittle awarenessorcomfortwithusingthispotentiallylife-savingtherapyin timesofneed,suchasrefractorystatusepilepticus.

TranscranialMagneticStimulation

Moderntranscranialmagneticstimulation(TMS)wasinventedin1985 andapprovedfortheacutetreatmentofdepressionin2008(33).Itisa noninvasivetechniquethatcreateselectricalactivityinthebrainviamagneticwavesthroughanelectriccoilpositionedonthesurfaceofthescalp. Throughmanipulationofstimulationparameters,itcaninducelong-term potentiation(LTP)ordepression(LTD)-likeeffects,whicharethoughtto exertatop-downeffectfromcorticalareasthroughthediseasenetwork (34, 35).Innovationssinceitsconceptionhaveincludedmoreefficientdeliverysystems,variouscoildesignstoshapetheinducedfieldtoactivate specificbrainnetworks,targetingvianeuronavigation,anddifferentprotocolstodelivermorerapidoreffectivetreatment(36–38).Clinically,TMS ismainlyusedforFDA-clearedpsychiatricindications,includingdepression,OCD,andsmokingcessation.However,single-pulseTMSisalsoFDAclearedformigraine,andTMSwasjustrecentlyclearedforpain. Further,thereisevidenceforitsuseinneurodegenerativediseases, movementdisorders,epilepsy,andmultiplesclerosis(39).Infact(and caseinpointtohighlightourargument),TMSwasoriginallyandexclusivelyusedbymotorneurophysiologists(40).Butapotentiallyimportant momentinthedevelopmentofTMSasanantidepressantoccurredwhen adual-trained(neurologyandpsychiatry)physician(M.S.G.,author)was

exposedtoTMSinaneurology/psychiatryfellowshipand“borrowed”this technologyforanewareaofresearchandeventuallyleadingtoFDAapprovedindication.Withademonstratedabilitytomodulatecorticaltissueandwithagoodsafetyandtolerabilityprofile,itissurprisingthat TMShasnotbeenadoptedforadditionalindications,especiallyinneurology.Perhapstoolittlecross-disciplinarythinking,whichthejournal Brain Medicine aimstoaddress,haslimitedTMSexpansion.

Conclusion

ThesecurrentFDA-clearedbrainstimulationmodalitieswilllikelysoonbe joinedbyothers(e.g.,low-intensityfocusedultrasound,transcranialdirectcurrentstimulation).However,ifbrainmedicinephysiciansarenot exposedtothesemodalitiesbycross-disciplinarytraining,willtheybe utilizedbythe“other”specialty(evenwhenFDA-cleared)?HowmanypsychiatristsconsiderDBSforOCD?HowmanyneurologistsconsiderTMS formigraine?Inourexperience,theanswerisveryfew.Wehavehighlightedthesetoolswithindicationsacrossbrainmedicine,althoughthey arealldominatedbytheuseofthespecialtyinwhichtheywerefirstdeveloped.Importantly,thisemergingfieldisjustbeginning,andmanyother investigationalindicationshavegoodevidenceandwilllikelybeFDAcleared.Notallphysicianstreatingbraindisordersneedtobecomeexpertsinbrainstimulationmodalities.However,theyneedtobeawareof thesemodalitiestoreferpatientswhoarerefractorytotreatmentormay prefernon-medicationtreatmentapproaches.Theymaybetailoredtoindividualpatientsandintegratedintoacomprehensivetreatmentalgorithmforpatientswithdifferentbraincircuitdisorders.Byincreasingthe exposureandawarenessofdifferentbrainstimulationmodalities,physicianscangenuinelyoperatewitha“fulltoolbox”fortreatmentacrossthe spectrumofBrainMedicine.Untilwebringthesefieldstogether,weare limitinghowmuchwecanhelppatientswithnovelbrainstimulationapproachestobraindisease.Indeed,wesee InterventionalBrainMedicine, withitscurrentandrapidlyemergingpotentialforuseacrossdisciplines, asatypeforotherbrainsubspecialties,wherephysiciansapproachdiagnosticsandtreatmentswithoutanarbitraryborderthatinevitably leavesthe“other”affectedbraincellsandcircuitsunderrecognizedand undertreated.

Acknowledgements

JBissupportedbytheBrain&BehaviorResearchFoundation(#31748) andbytheMcLeanHospitalCenterofExcellenceinDepressionandAnxietyDisordersandbytheDepartmentofDefenseAdvancedResearch ProjectsAgency(HR00112320037);Theviews,opinionsand/orfindings expressedarethoseoftheauthorandshouldnotbeinterpretedasrepresentingtheofficialviewsorpoliciesoftheDepartmentofDefenseorthe U.S.Government.

PoojithNuthalapati1 ,CharlesPalmer2 ,DanielA.N.Barbosa2 , MarkS.George2 , 3 ,andJoshuaC.Brown4 , 5 1 DepartmentofNeurology,ComprehensiveEpilepsyCenter,YaleUniversity SchoolofMedicine,NewHaven,Connecticut; 2 DepartmentofPsychiatryand BehavioralSciencesandDepartmentofNeurology,MedicalUniversityofSouth Carolina,Charleston; 3 RalphH.JohnsonVAMedicalCenter,MedicalUniversityof SouthCarolina,Charleston; 4 PsychiatricNeurotherapeuticsProgram,Divisionof DepressionandAnxietyDisorders,McLeanHospital,Belmont, Massachusetts; 5 DepartmentofPsychiatry,HarvardMedicalSchool,Boston, Massachusetts

e-mail: jbrown@mclean.harvard.edu

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Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutralityregardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliationsofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors,withouteditingthem.Suchusesimplyreflectswhattheauthorssubmitted tousanditdoesnotindicatethatGenomicPresssupportsanytypeofterritorial assertions.

INNOVATORS&IDEAS:RISINGSTAR

RuthM.Barrientos:Vulnerabilitiesassociatedwiththeagingbrainthatmakeitmore susceptibletoinflammatorychallengesleadingtomemorydysfunction

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):6–8;doi: https://doi.org/10.61373/bm024k.0004

Keywords: Aging,Alzheimer’sdisease,brain,neuroinflammation, neuroimmunomodulation,cognition,womeninscience

Dr.RuthBarrientosisanassociateprofessor(withtenure)inthe InstituteforBehavioralMedicineResearchandtheDepartmentof PsychiatryandBehavioralHealthintheCollegeofMedicineatThe OhioStateUniversity.Shecurrentlyservesasassociateeditorof Brain,Behavior,andImmunity,theflagshipjournalforthe PsychoneuroimmunologyResearchSociety.Herresearchaimsto uncoverthevulnerabilitiesassociatedwiththeagingbrainthatmake itmoresusceptibletoinflammatorychallengesresultinginmemory dysfunction,rangingfrommildcognitiveimpairmentstoAlzheimer’s Disease;andtodiscoverinterventionstoimprovethese vulnerabilitiesandpreventmemorydegradation.Weconductedan interviewwithDr.Barrientos,askingquestionsaboutherlifeand scientificcareerandfinishedupwithselectedquestionsfromthe ProustQuestionnaire.

TheGenomicPressInterviewPart1:RuthBarrientos:Lifeandcareer Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

IwasborninBolivia,SouthAmerica,andimmigratedtotheUnitedStates withmyfamilyattheageof3.WesettledintheWashington,DC/Northern VirginiaareawhereIstayedthroughgraduateschool.IattendedGeorge MasonUniversityasanundergraduatestudentanditwastherethatIwas firstexposedtotheexcitingworldofpreclinicalneuroscienceresearch. Iwasavolunteerresearchassistantinalaboratorythatstudiedthebehavioraleffectsofcocaineandopiatereceptorblockade.Iwassofascinated andintriguedtounderstandthebrainmechanismsunderlyingbehavior, thatIabandonedmyoriginalplansofpursuingadegreeinclinicalpsychologyandinsteadpursuedacareerinNeuroscience.Duringgraduate schoolattheGeorgeWashingtonUniversityinWashington,DC,Iapplied forandwasselectedforapredoctoralSummerIntramuralResearchTrainingAwardattheNIHandjoinedDr.EstherSternberg’slaboratory.Itwas therethatIwasfirstexposedtotheburgeoningfieldofpsychoneuroimmunologyandIwasimmediatelyhooked.Itjustmadesensetomethatthe brainandtheimmunesystemworkedinconcertandthatthisrelationship manifestedvariousbehavioraloutputs.Followingasuccessfulsummerinternship,IwasfortunatetohaveDr.Sternbergextendmystayinherlaboratorylongenoughtoallowmetocompletemydissertationresearch. Thiswasacriticaltimeinmylifethatenabledmetodeepenmyknowledgeaboutthebidirectionalcommunicationbetweentheimmunesystem andthebrain,andhonevariousresearchskillsincludingbrainsurgeries, dissections,andcognitivebehavioraltasks.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis leadershipresponsibility?

AfterobtainingmyPh.D.,IsecuredajointpostdoctoralpositionattheUniversityofColorado(CU)Boulder,inthelaboratoriesofDr.StevenMaier

Received:11January2024.Accepted:12January2024. Publishedonline:25January2024.

andDr.JerryRudy.UndertheirsupervisionIcontinuedtohonemyskills andfocusmyinterestinpsychoneuroimmunologytoanswerquestions abouthowchronicneuroinflammationmightimpairmemoryfunction,especiallyduringaging.Following5yearsasapostdoctoralfellow,ItransitionedtoanAssistant,thenAssociateResearchProfessorpositionatCU Boulder.Duringthistime,Ireviewedmanymanuscriptsfordozensofjournalsandhaveservedontheeditorialboardsofseveralkeyjournalssuchas BrainBehaviorandImmunity,theflagshipjournalforthePsychoneuroimmunologyResearchSociety.Infact,Iwonthecoveted“BBIReviewerofthe Year”awardin2013and2016.In2018,Iwasrecruitedtojointhefaculty atTheOhioStateUniversity,apremierhubforpsychoneuroimmunology research.Soonthereafter,IwasinvitedtobecomeanAssociateEditorof BBI.ThisexperiencehasallowedmetolearnandgrowwithregardtoPNIrelatedscienceaswellastheworldofpublishing.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteareaofresearchorprofessionalfocus Inthemid-1990s,itwasnotaswell-knownasitistodaythattheimmune systemcouldsignalthebrainandthatthebraincouldsignaltheimmune system.Itmadesomuchsensetomeanditwasexcitingtodiscoverthe manypathwaysthroughwhichthesesystemswerecommunicatingwith

Figure1. RuthM.Barrientos,PhD,TheOhioStateUniversity,USA.

eachother,andtoidentifyhowtheirinteractionsmightmanifestintovariousbehavioraloutcomes.

Whatkindofimpactdoyouhopetoachieveinyourfieldthroughyour focusonyourspecificresearchtopics?

Ihopetodiscoveraninterventionthatwillameliorateexaggerated neuroinflammation-inducedmemoryimpairmentsinolderindividuals, withthehopeofpreservingoldmemoriesandtheabilitytoformnew ones.

Couldyoutellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?

Mylaboratoryfocusesonthevulnerabilitiesofthenormalagingbrain that,whenchallenged,leadtolong-lastingmemorydeficits.Mylaboratoryhasexaminedvarioustriggerssuchasbacterialinfection,surgery, andhigh-fatdietthatinduceexaggeratedandprolongedneuroinflammationindiscreteregionsoftheagedbrain.Wehaveidentified sensitizedmicrogliaasplayingakeyroleinthisexaggeratedresponse. Thispotentiatedneuroinflammatoryresponsecausesrobustinhibition ofbrain-derivedneurotrophicfactor(BDNF)andlong-termpotentiation (LTP)inthehippocampusandotherregions,twomechanismscriticalto forminglong-termmemories.Furthermore,wehavedemonstratedthat behavioralinterventionssuchasexerciseandreducingsaturatedfats fromthedietcandesensitizemicroglia,normalizetheinflammatoryresponseinthebrain,andprotectmemoryfunction.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour ownresearchenvironment?

Experimentalorganization(keepingverydetailednotesoneverythingI havedonesothatitcanberepeatedexactlythesamewayeverysingle time)andteamworkaretwoofthemostimportantskillsandvaluesthat IdevelopedduringmyacademictrainingandthatIcontinuetoupholdin mylaboratory.

AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?

Iagreewiththisstance.Thereisnoroominscienceforinfluencebased ontheprestigeoftheinstitution,thenumberofgrantsawardedtothePI, orhowbiganametheyhave.Scienceshouldbeevaluatedonitsinherent merit,rigorousapproach,andfairinterpretation.Howtoensurethishappensineveryreviewsituationrepresentsoneofthebiggestchallenges forsciencetoday.

Whatdoyoumostenjoyinyourcapacityasanacademicandresearch leader?

Iloveitwhenmytraineesshowmenewdata.Igetasexcitedfornewdata asakidonChristmas.Ialsoverymuchenjoyseeingmytraineesshine,in anycontextorcapacity.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Iprefertospendmyleisurelymomentsoutside,innature.Duringtheday, Ilovehikinginthewoods.Atnight,Ienjoystargazing.

TheGenomicPressInterviewPart2:RuthBarrientos–Selected questionsfromtheProustQuestionnaire1 Whatisyourideaofperfecthappiness?

Beingphysicallyandmentallyhealthy,neverworryingaboutmoney,and spendinglotsofqualitytimewithmyfamily.

Whatisyourgreatestfear?

Tohaveregretsof“livingtowork”ratherthan“workingtolive”laterin life.Itrytostrikeagoodbalance,butdon’talwaysgetitright.

Whichlivingpersondoyoumostadmire? BarackandMichelleObama.

Whatisyourgreatestextravagance? Ihaveagreenhouseattachedtomyhouse.

Whatareyoumostproudof? Mychildren.Theyareamazing.

Whatisyourgreatestregret? Notsellingsomestockatitspeakprice.

Whatisthequalityyoumostadmireinpeople? Kindness,becausethisqualityisoftenmisinterpretedasaweakness.In fact,ittakesastrongandconfidentpersontobekindinthefaceofachallengingsituation.

Whatdoyouconsiderthemostoverratedvirtue? Acceptance.

Whatisyourfavoriteactivity(physicalorpsychological)? Myfavoriteactivityishikingthroughnaturallandscapes.

Wherewouldyoumostliketolive? Colorado.

Whatisyourmosttreasuredpossession? Myphotoalbums.

Whenandwherewereyouhappiest?Andwhyweresohappythen? Duringmypostdocyears.Icouldfocussolelyondoingresearch,withoutworryingaboutgrantfunding,andIwasinthebestshapeofmylife, spendingeveningsandweekendsinthegreatoutdoors.

Whatisyourmostmarkedcharacteristic? Mygritandperseverance.

Amongyourtalents,whichonegivesyouacompetitiveedge? Myorganizationalskills.

Whatdoyouconsideryourgreatestachievement? EarningaPh.D.despitestrugglingwithdyslexia.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwouldn’tchangeanythingbecauseevenmyflawsorchallengingtraits haveallowedmetolearn,grow,andadapt.

Whatdoyoumostvalueinyourfriends? Theirwillingnesstogiveittomestraight.

Whoareyourfavoritewriters? KhaledHosseini,BarbaraKingsolver,KathrynStockett.

1 Inthelate19thcenturyvariousquestionnaireswereapopulardiversiondesigned todiscovernewthingsaboutoldfriends.Whatisnowknownasthe35-question ProustQuestionnairebecamefamousafterMarcelProust’sanswerstothesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice, atages14and20.MultipleotherhistoricalandcontemporaryfigureshaveansweredtheProustQuestionnaire,suchasOscarWilde,KarlMarx,ArthurConanDoyle, StéphaneMallarmé,PaulCézanne,MartinBoucher,HughJackman,DavidBowie,and Zendaya.TheProustQuestionnaireisoftenusedtointerviewcelebrities:theidea isthatbyansweringthesequestionsanindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightlyrewordingsome.Thesecuratedquestionsprovideinsightsintothe individual’sinnerworld,rangingfromnotionsofhappinessandfeartoaspirations andinspirations.

Whoisyourherooffiction? Idon’thaveone.

Whoareyourheroesinreallife?

Mymomanddad.Theysacrificedsomuchcomingtoaforeigncountry, havingtolearnanewlanguage,anewculture,andbasicallystartfrom scratch,togivetheirchildrenmoreopportunitiesforabetterfuture.

Whataphorismormottobestencapsulatesyourlifephilosophy? Yourtriumphswilldothetalkingforyou.

RuthM.Barrientos1

1 CollegeofMedicine,TheOhioStateUniversity,Columbus,Ohio43210,USA e-mail: Ruth.Barrientos@osumc.edu

withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.

OpenAccess. The“GenomicPressInterview”frameworkiscopyrightedtoGenomicPress.Theinterviewee’sresponsesarelicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercialNoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates: (1)Attribution:Creditmustbegiventotheoriginalwork,withalinktothelicense andnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3)NoDerivatives:Modifiedversionsoftheworkcannotbedistributed.(4) Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotential rights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Thirdpartycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunless otherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RISINGSTAR

NathanielG.Harnett:Identifyingtheneurobiologicalmechanismsofsusceptibilityto traumaandstress-relateddisorders

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):9–11;doi: https://doi.org/10.61373/bm024k.0052

Keywords: Trauma,posttraumaticstressdisorder(PTSD),Neuroimaging, Stress,imaging

Dr.NathanielHarnettisDirectoroftheNeurobiologyofAffectiveand TraumaticExperiencesLaboratoryatMcLeanHospitalandAssistant ProfessorofPsychiatryatHarvardMedicalSchool.Hisresearch investigatestheneuralsubstratesthatmediateindividualvariability insusceptibilitytotraumaandstress-relateddisordersusinga multidimensionalapproachthatincorporateshumanbrainimaging, psychophysiology,psychometrics,andbehavior.Further,his laboratoryexamineshowpre-,peri-,andposttraumatic environmentalfactorsmaymodulatetheefficacyofneuralsignatures ofposttraumaticstressdisorder(PTSD).Ultimately,thegoalofhis researchistoadvanceourunderstandingofhowweidentifyuseful, effective,andgeneralizableneuralpredictorsofPTSDtofacilitate precisionmedicineapproachesthatmightmitigatethesocialand emotionalburdensoftraumaandstress-relateddisorders.Weare delightedthatDr.HarnettengagedintheGenomicPressInterview, enrichingourreadershipwithperspectivesonhislifejourneyand professionaltrajectory.

Part1:NathanielHarnett–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

Ioriginallyneverwantedtobeascientist.IwasconvincedIwouldbecome,andoriginallyappliedtoschooltobe,aclassicalmusician.However,Iwasworriedaboutmarketabilityandthoughtadualmajorinpsychologywouldbeasmartmoveformycareeroptions.Itturnedouttobe agreatchoice,though,asearlyonin“PSYC101,"wehadourmoduleon behavioralneuroscience,andIwashooked.Theunderstandingthatthe entiretyofourexperiences–whatwehavebeenthroughandwhatwe willgothrough–areallprocessedbyasquishyorganinourskullswas fascinating.Ifullycommittedtostudyingpsychologyandneuroscience, anddidsomeundergraduateresearchatmyalmamater(IthacaCollege) andtheUniversityofMaryland.Myundergraduateresearchwasfocused onemotionalmemoryprocessingandbehaviorinhumans.Ithinkthose earlyexperienceshelpedintroducemetothejoyofdoingresearch–of knowingsomethingforabriefperiodthatnooneelsedoesandbeingable toshareitwiththeworld.Ithenappliedtograduateprogramsandmade itintotheBehavioralNeuroscienceprogramattheUniversityofAlabama atBirmingham(UAB).

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?

Mostofthedefiningmomentsofmycareerwerewhenmymentorstook achanceonme.Iappliedtograduateschoolwithsomeresearchexperience.However,Ineededtraininginmagneticresonanceimaging,coding, orothertechnicalskillsthatwouldhavebeenhelpfulinthelabIjoined. Still,mygraduatementor–DavidKnightatUAB–tookachanceandacceptedmeintohislaboratory.Daveandhislabwerehighlysupportiveof Received:3May2024.Accepted:5May2024. Publishedonline:10May2024.

me,andthereweremanyopportunitiestolearnthefundamentalsofMRI research,rangingfromrecruitment,collection,analysis,andinterpretation.WiththeworkweweredoingandtheskillsIwaslearning,Iwasfortunateenoughtogetsomeindependentfundingandstartadissertation projectthatIwaspassionateabout.Ialsomanagedtogetanawardthat wouldcovermytimeasapostdoc.So,whenitwastimetocompletepostdoctoraltraining,IreachedouttoKerryRessleratMcLeanHospital,andby coincidence,theprojecthewasworkingonwastightlylinkedtomydissertation.Kerryisaphenomenalmentorandhasalsobeengreatathelping meunderstandthe“hiddencurricula”inscience,enablingmetonavigate thefield.Fromthere,thevastnetworkofcollaborationsandexperiences helpedaccelerateandexpandmywork.Imanagedtomovetoassistant professorandestablishmylaboratoryatMcLeanHospital,whereIgetto askthequestionsIammostpassionateabout:trauma,stress,andpsychiatricdisordersusceptibility.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea. Forwhateverreason,Iwasalwaysprofoundlyfascinatedwithpersonal accountsofhowpeopledealtwithhighlystressfulexperiences.Inhigh school,IwouldsitinthelibraryandreadpersonalaccountsfromVietnam Warsoldiers(e.g.,“Nam:TheVietnamWarintheWordsoftheMenand WomenWhoFoughtThere”byMarkBaker),tryingtounderstandmore abouthowtheirideasoftheworldandthemselveschangedaftertraumaticexperiences.Ithinkthataspect–ofthedramaticshiftinpeople

Figure1. NathanielHarnett,PhD,McLeanHospitalandHarvardMedical School,USA.

afterstress–stuckwithmeandpushedmetothinkmoreabouthowtraumaticstressandthebrainareinterlinked.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Thereisalottolearnabouthowwecanusebrainimagingtounderstand whoismostinneedofresourcesafteratraumaticeventtohelpmitigate potentiallong-termpsychiatriceffects.Ideally,Iwouldlikemylabtocontributetonovelwaystoincorporatebrainimagingintoprecisionmedicine orprovideinsightintowhysomeneuralsignaturesmightbemorepredictiveforsomepeoplecomparedtoothers.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

Mylaboratorytriestoleveragemultiplewaysoflookingatthebrainto understandtwoquestions.First,howdowecombinedifferentmodalitiesofbrainimagingtocomeupwithpredictiveneuralmodelsoftransitiontoPTSDaftertrauma?ThatpartoftheresearchofteninvolvesusingMRItolookatthebrainsofrecenttraumasurvivorsandseeifthere areparticularneuralsystemsormultivariatepatternsthatareassociated withfuturePTSDdevelopment.Thesecondquestionis:Howdoinequities inpre-traumaticexposuresimpactthegeneralizabilityofneuroimaging findings?Weknowthatthereisawiderangeofsystemicorstructuralissues(e.g.,racism,sexism)thatimpacthowpeoplerespondtolaterevents, andwethinkdelvingintohowthesemayhavealongitudinalimpactonthe brainandrelevantbiologycanhelpunderstanddisparitiesinpsychiatric disease.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Curiosityandanopennesstoexplorehavealwaysbeenthemostsignificantthing.MRIresearchoftengeneratesagoodamountofdata,andwe areconstantlylearningnewwaystoanalyzeandlookatit.Ithinkawillingnessandinteresttoasknewanddifferentquestionsandpushyourself outofyourcomfortzonetoanalyzedatainanewway–whilealsodiggingintothefundamentalsabout why wemightlookatthedataacertain way–helpswithgrowthasascientist.

Itisacomplexquestion,butIthinkitisworthmakingsurewedefinewhat wemeanby“merit.”Nottocompletelyendorsestandpointepistemology, butconsidering who definesmetricsand why wedefinethemthatwayis importantforadvancingscienceforwardinanunbiasedway.Muchofthe issue(aroundbias)isstructuralorsystemic,andIaminterestedinhowwe mightchangethestructureofsciencetobreakdownbarriersthatmight dissuadeparticularpeopleorimportantresearchapproaches.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?

ItisstilltheflexibilityofhowIgettoweavethroughmycareerandthe restofmylife.Ionlysometimesstriketherightbalance,butbeingable tohavetheoptionisnice.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Thereisagoodmixofthingstokeepmymindoffscience.Iusuallyfind somethingtodobetweengaming,musicpractice,aerialstraining,or naturewalks.

Part2:NathanielHarnett–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness? Retirement.

Whatisyourgreatestfear? Failingtoliveuptomypotential.

Whatisyourgreatestextravagance? Entertainmenttech.Iownfartoomanyscreens.

Whatareyoumostproudof? Mytrainees.

Whatisyourgreatestregret? Notstartingahobbyforfearoflookingstupid.

Whatisthequalityyoumostadmireinpeople? Understanding.

Whatisthetraityoumostdislikeinpeople? Arrogance.

Whatdoyouconsiderthemostoverratedvirtue? Faith.

Whatisyourfavoriteoccupation(oractivity)? Myfavoriteactivityisprobablygaming.

Wherewouldyoumostliketolive? Someplacewithactualseasons.

Whatisyourmosttreasuredpossession? Mydata.

Whenandwherewereyouhappiest?Andwhywereyousohappythen? Wow,thisisatoughone.Mymomrecentlymovedtoafarmupstate(an actualfarm),andIgottospendafewdaysontheproperty.Itwasoneof themostpeacefulandserenetimesIhavehadawayfromeveryonewith lovedones.

Whatisyourcurrentstateofmind? Attheintersectionofstressed,content,andfocused.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003,Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Whatisyourmostmarkedcharacteristic? Myheight.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Empathy.

Whatdoyouconsideryourgreatestachievement? Managingtomakeittoassistantprofessor.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwouldnotchangeanythingatthispoint.

Whatdoyoumostvalueinyourfriends? Theirhonesty.

Whoisyourfavoritewriter? BrianJacques.

Whoisyourherooffiction? Spiderman.

Whoisyourheroinreallife? Mymother,handsdown.

Whataphorismormottobestencapsulatesyourlifephilosophy? IthinkCalvinfromCalvinandHobbes(BillWatterson)saiditbestin responseto“Lifecouldbeworse:”“Lifecouldbealot better,too!”

NathanielG.Harnett,PhD1

1 McLeanHospitalandHarvardMedicalSchool,Belmont,Massachusetts 02478,USA e-mail: nharnett@mclean.harvard.edu

INNOVATORS&IDEAS:RISINGSTAR

DanielH.Wolf:Understandingmotivationimpairmentfromclinical,behavioral,and neurobiologicalperspectivestopavethewayforbettertreatments

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):12–15;doi: https://doi.org/10.61373/bm024k.0058

Keywords: Psychosis,negativesymptoms,amotivation,ventralstriatum, decision-making

Dr.DanielWolfgrewupinLosAngeles,completedhisBAatHarvard College,MD-PhDatYaleUniversity,psychiatryresidencyat MGH-McLean,andneuropsychiatryfellowshipatUPenn.Heisan AssociateProfessorofPsychiatryatUPenn’sPerelmanSchoolof Medicine.AsheadoftheLaboratoryforMotivationinPsychiatry, Dr.Wolfusesfunctionalneuroimagingtostudytheneural mechanismsofamotivationandothersymptomdimensionsin psychosisandat-riskstates,aimingtodevelopnovelassessment biomarkersforearly-stagedrugdevelopment.Dr.Wolfalsoprovides outpatientcaretoindividualswithpsychosiswhilesupervising clinicaltrainees.AsDirectoroftheClinicalNeurosciencesTraining ProgramandCo-DirectorofthePsychosisT32,heprovidesseminars andmentoringtomedicalandgraduatestudentsandpostdoctoral fellows;heearnedtheSchoolofMedicine’steachingawardsinboth BasicScienceandTranslationalScience.HeisalsoanACNPFellowand memberofthe Neuropsychopharmacology editorialboard.Dr.Wolf answeredtheGenomicPressInterview,providingourreaderswith reflectionsonhislifeandcareer.

Part1:DanielWolf–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

Asachild,Ilovedlearningaboutanimalsfrommyextensivecollectionof JungleSafariCards,andmymotherandfatherenthusiasticallyencouragedthispassion,alongwithallotherintellectualpursuits(seeFigure 2).Myfatherisaclinicalandacademicneurologist(stillpracticingand teachingat90).Hewouldentertainuswithmedicalmysteriesatthedinnertable,whichinspiredmylifelongfascinationwiththebrainandthe tragedieswroughtbyitsmalfunction.Thejoyandmeaninghesoobviouslyfoundinhisworkalsogavemeanimplicitbeliefthatoneshould findacareeronetrulyloved.Myfirstrealexposuretoscientificresearch camewhenIspenta“gapyear”afterhighschoolandworkingatUSCinthe laboratoryofDr.DavidGalas,apioneeringmolecularbiologistwhopassed awaylastyearafteranillustriouscareerspanningacademia,government, andindustry.Dr.Galaswasaninspiringrolemodel–abrilliantphysicstrainedinterdisciplinarian,aloverofliteratureandphilosophy,andanincrediblykindpersonwhopopulatedhisgroupwithextremelykindpeople.Inhislab,IpouredPetridishes,andmouth-pipettedE.Colicultures andtyped(twicetocatcherrors)thousand-basepairDNAsequencesinto databases.Healsohandedovertomyinadequatedirectiononeofthe firstPCRprojectsintheworld–Ihavevividmemoriesofstandingona bridgebetweentwobuildings,carefullypipettingsmallvolumesofDNA templatestakenfromarefrigeratorinonebuildingintoatubecontaining DNAprimersolutiontakenfromanotherbuilding,toavoidcontamination andfalsepositives.TheprojectaimedtoidentifyrarespontaneousDNA mutationhotspots,withtheideathatPCRproductswouldonlybegeneratedwhenadeletioneventbroughttheprimerscloseenoughtogether.

Received:25June2024.Accepted:11July2024. Publishedonline:16July2024.

Ifailedtocarryhiscreativestrategytofruition,butothergroupspublishedsimilareffortsinNatureafewyearslater.

Incollege,whileIflirtedwiththeideaofbecomingatranslatorof Spanishnovels,myloveforscience,coupledwithapragmaticstreak,led metomajorinbiology.Myblood-needlephobiasuppressedanydesireto followinmyfather’sphysicianfootstepsuntilIdevelopedamorecounterphobicphilosophylateincollege.Atthatpoint,IdecidedtopursuecombinedMD/PhDtraining.Startingmylastyearofcollegeandextending intoafullyearafterward,IworkedwithDr.BruceSchnapp,whowas thenatHarvardMedicalSchool.Anotherbrilliantandnurturingscientist, Dr.Schnapp,gavemetheprojectoffluorescentlylabelingXenopusmRNA sothatthemechanismsofintracellularmRNAtranslocationbymotorproteinscouldbestudiedinreal-timeunderthemicroscope.Itackledthis effortwithgustoandutterlyfailedtomakeanmRNAthatshowednormal translocation(however,helpingCharlotteVinesonadifferentproject,I becameanexpertatrunningDNAsequencinggels).AlthoughIdidn’trealizeitatthetime,beingentrustedbyDr.GalasandDr.Schnappwith

Figure1. DanielWolf,MD,PhD,UniversityofPennsylvania,USA.

Figure2. AyoungDanWolfpeeringintohisfather’smicroscope.

scientificprojectsthatwereambitious,evenunattainable,gavemethe feelingthatIcouldandshouldtacklequestionsthatwereimportanteven ifsuccesswasuncertain.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?

IstartedtheYaleMD-PhDprogramknowingIwasinterestedinneuroscience,butIneededmorespecificity,soImetwithvariouspotentialadvisers.AsIenteredtheConnecticutMentalHealthCentertomeetwith Dr.EricNestler,therewasasignIcanstillpictureinmymind’seyeonthe walloutsidehislab:“LaboratoryofMolecularPsychiatry”–athrillwent throughmeasIrealizedthatthisfieldIneverimaginedexisted,wasinits earlydays,andIcouldbecomepartofit.ThefactthatDr.Nestler’swork inaddictioninvolvedunderstandingthebasicmechanismsdrivingmotivationsealedthedeal–theideaofhelpingunravelthemysteriesofsuch afundamentalpartofhumanexperiencewasincrediblycompelling.My PhDthesiswithDr.NestlerandDr.DavidRusselldidnotentirelysolvethe mysteriesofmotivation,butIdidgetpermanentlyhookedontrying.Iwas abletomakeconcreteprogressinidentifyingmorphine-inducedchanges inneurotrophicfactorsignalingpathwayproteinlevelsandactivityinthe mesolimbicdopaminesystemandlearnedalotofmolecular,cellular,and behavioralmethods.Ialsodiscoveredthatratswerefrustratinglysimilar tohumansinsomewaysandyetfrustratinglydis-similarinothers,which laterledmetoswitchmyfocustoresearchwithhumans.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.

Inmyearlyclinicalexposurestopsychiatry,Ihadfabulousexperiences workingwithindividualswithschizophreniaininpatientandoutpatient settings,especiallyasChiefResidentoftheMcLeanBipolarandPsychosis

program.Dr.StephanHeckerswastheinspirationalleaderofthatprogram,embodyingasynergisticfocusonpsychopathologyandneuroimaging.Myneuroimagingworkstartedhumbly,manuallyoutliningthehippocampusonmanyMRIimages.Still,itwasinhisgroupandwithhis encouragementthatIfirstdevelopedtheideathathypofunctioninbrain motivationcircuitrylikelyplayedasignificantroleinthepathophysiology ofnegativesymptomsofschizophrenia.Mytraininginaddictionneuroscienceplacedmeintheearlyvanguardofpursuingthisidea.Withinthe addictionfield,itwasintuitivethathypofunctionofsubcorticalbrainrewardregionsliketheventralstriatumshouldberelatedtolowmotivation. However,intheschizophreniafieldatthetime,thedopaminehypothesisonlylinkedtheventralstriatumtohyperfunctionandpositivesymptomswhileconnectingmotivationimpairmenttohypofunctioninthe prefrontalcortex.Thishypothesizednexusbetweensubcorticaldopaminergicbraincircuitry,motivationdisturbance,andschizophreniaperfectly connectedmyscientificandclinicalinterests.Mydesiretopursuethis questionledmetoPennandmywonderfulmentorsRaquelandRuben Gur,andIhavebeentravelingthatpatheversince.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Motivationimpairmentisoneofthemostsignificantdriversoflong-term disabilityinschizophreniaandinmanyotherneurologicalandpsychiatric disordersaswell.Ihopethatmyresearchwillhelpquantitativelyparse heterogeneityinmotivationimpairmentandlinkparticulartypesordimensionstospecificbraincircuits.Then,theseassessmentscanbeused inearly-stagedevelopmentofnoveltreatmentsandinstratifyingparticipantsintosuchinterventionstudies.Ultimately,Ihopemyresearchwill “placeabrick”inthewallofscienceandalsohaveasignificantimpacton clinicalcare,alleviatingsomeofthesufferinganddisabilitysocommon inschizophrenia.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?

Methodologically,mystrategyinvolvesaboot-strappingtriangulationof clinicalinterviewsandself-reports,laboratorybehavioraltasks,andfunctionalbrainimagingtounderstandcoreaspectsandheterogeneityof motivationanditsimpairment.MyinitialworkdemonstratedtherelationshipIexpectedbetweenventralstriatumhypofunctionandglobal negativesymptomseverity.Isubsequentlydemonstratedmorespecific relationshipsofventralstriatumhypofunctiontobehavioralmotivation usingaprogressiveratiotaskIadaptedbasedonrodentaddictionmethodsandthentoreward-efforttradeoffdecisionsinaneffortdiscounting taskIadaptedfromthehumandelaydiscountingworkofcollaboratorJoe Kable.Althoughthereremainmanydetailstobeworkedoutandsome controversiestobesettledinthisarea,Ibelievetheventralstriatumamotivationrelationshipisnowoneofthemostwell-establishedfindings inthepsychosisfunctionalneuroimagingliterature,observedbymany groupsacrossmanyparadigms,notonlyinschizophreniabutasatransdiagnosticdimension.

Iamcurrentlypursuingseveraldifferentavenueswithinmybroad focusonmotivation.Oneavenueistofurtherparsemotivationimpairmentinwaysthatmapontodifferencesinbiologyandtreatment:intrinsic versusextrinsic,approachversusavoidance,andsocialversusnonsocial. Developingbehavioral/fMRIparadigmsandself-reportmeasuresthat captureimportantdomain-specificcomponentsandthesizeabledomaingeneralcomponentofmotivationhasbeenexcitingandchallenging.Anotherfocusisonunderstandinghowthesamebraincircuitscanexhibit hypofunctionconnectedtomotivationimpairmentbutaberranthyperfunctionconnectedtoparanoiaandotherpositivesymptoms.Thesetwo majorsymptomdomainsoftenco-occurinthesameindividualsaspartof theschizophreniaandpsychosis-risksyndromes,butatleastsuperficially, theproposedabnormalitiesseemincompatible.Inthefuture,IamespeciallyinterestedindevelopingfMRItasksoptimizedforwithin-individual reliabilityandinterpretabilityforuseinsmall-sampleproofofprinciple pharmacologicalchallengestudies,indevelopingfMRImethodstoexaminetheinterplayofdirectandindirectbasalgangliapathwaysinhumans, andindevelopingapproachestoexplorehowneuralplasticityinthese

systemscontributestobothpositiveandnegativesymptomsofpsychosis andriskstates.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

OneessentialhabitIdevelopedearlyonisreadingconstantlyandwidely; anotherisquestioningeverything;andanotheristryingtoseeconnectionstobuildacoherentunderstandingofcomplexphenomena.Starting inmypostdocandcontinuingtoday,theGurshaveprovidedrolemodels fortakingthesehabitsandpersistentlyaimingthemtowardsworkthat movessteadilytowardsultimateclinicalapplicationtoimprovethelives ofthosewithpsychoticdisorders.

Itmaysoundlikeacliche,butfindingoutthetruthis,andshouldbe,the corecauseofscience.Thatneedstoalignwithothercriticalvalues,butit shouldnotcomeinsecondtoanythingelse.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?

Allthefreetime.Butseriously,whileIamalwaysbusy,myacademiccareer hasprovidedmetheflexibilitytopursuethethingsIammostinterested inandcombinethedifferentrolesIenjoy,includingresearch,teaching, andcaringforpatients.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ireadpsychiatryandneurosciencearticlesforfun,soitishardtotell whetherIamatleisure.Ialsoenjoyhangingoutwithmywifeandkids, watchingmovies(ideallyinthemovietheater)andgoodTVshows,readingnonfictionandfictionbooks,andgoingoutfordrinksanddinner.

Part2:DanielWolf–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness?

Idon’thaveoneofthose.

Whatisyourgreatestfear?

Saying/writingsomethingembarrassinginresponsetoaninterviewquestion?Idonotfeelanxiousaboutthethingsthatwouldbeobjectivelymost terrible(forexample,nuclearwar)althoughIspendalotoftimetrying tolearnaboutsystemsandpoliciesthatmightpreventthem.Igetmost anxiousaboutobjectivelyminorthingsthatimpactme,particularlyinmy

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

relationshipswithothers.Iwasashykid,andIhaven’tentirelyoutgrown that–Iconsidermyselfanintrovertwholikesotherpeoplealot.

Whichlivingpersondoyoumostadmire?

Itishardtopickone,butWillMacAskillisagoodcandidate.Hecombines intellectualdepthandrigorwhileintentionallyprioritizingasuccessful goalofmassivepositivereal-worldimpact.Healsoseemsnice,thoughI onlyknowhimviapodcasts.

Whatisyourgreatestextravagance?

Ihighlight/underlineextravagantlywhenIreadarticles…Idon’tdomuch inthewayoffinancialextravagance.

Whatareyoumostproudof?

Mywifeandchildrenareawesome,objectivelyandsubjectively,andIget totakealittlebitofcreditforfacilitatingthat.

Whatisyourgreatestregret?

Iamnotmuchforregret,andIhavebeenenormouslyfortunate,soI don’thaveanymajorregrets.Thebiggestoneisnotspendingasignificantamountoftimelivingabroad.MaybesomedayIwill.

Whatisthequalityyoumostadmireinpeople? Wisdom.

Whatisthetraityoumostdislikeinpeople? Sociopathy.

Whatdoyouconsiderthemostoverratedvirtue? Brevity.

Whatisyourfavoriteoccupation(oractivity)?

Arguingwithfriendsaboutphilosophy,publicpolicy,orscience.

Wherewouldyoumostliketolive? InthehillsofTuscany.

Whatisyourmosttreasuredpossession?

Familyphotographsandwritings.

Whenandwherewereyouhappiest?Andwhyweresohappythen? Idon’thaveanobjectiveanswer,butinmymemory,itis4thgrade,age9. Iamnotsurewhy,Ijustlikedalmosteverythingaboutmylifethen,and didn’thavemuchthatIworriedabout.

Whatisyourcurrentstateofmind?

Abitpreoccupied,butansweringthesequestionsisawelcomeopportunitytothinkaboutotherthings.

Whatisyourmostmarkedcharacteristic?

Mysnazzywardrobe?Butseriously,probably“thoughtfulness”.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Thoughtfulnesshasmixedeffects,butoverallIthinkithashelpedme succeed.

Whatdoyouconsideryourgreatestachievement? Myfamily.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwouldprefertobelessgood-looking;Ifindthatitprovestoodistracting toothers.Butseriously,Iwouldprobablyliketobeabitlessrisk-averse andabitlessself-deprecating.

Whatdoyoumostvalueinyourfriends?

Loveandtoleratingmylimitedskillinstayinginclosetouch.

Whoareyourfavoritewriters?

KurtVonnegut,ToniMorrison,VladimirNabokov…

Whoareyourheroesoffiction?

TheGreatBrain,EncyclopediaBrown,themembersoftheMadScientist Club…forsomereason,onlychildhoodfictionheroescometomind;Ihave sinceadmiredmanyheroicfictionalcharacters,butnonethatstandout inmymemorylikethoseearlyones.

Whoareyourheroesinreallife?

IadmiremanypeopleIdonotknowpersonally,whoarebrilliantand/or braveandchangingtheworld,butthemostimpactfulheroesinmyown lifearemyparents,andmywife,whosustainlove,family,work,andtrying todotherightthing,overthelonghaul.

Whataphorismormottobestencapsulatesyourlifephilosophy?

CanIhavetwo?Moderationinallthings,includingmoderation.And,The wiselearnmorefromfoolsthanfoolsfromthewise.

DanielWolf1

1 UniversityofPennsylvania,PerelmanSchoolofMedicine,Departmentof Psychiatry,Philadelphia,Pennsylvania19104,USA e-mail: danwolf@pennmedicine.upenn.edu

INNOVATORS&IDEAS:RISINGSTAR

HaithamAmal:Nitricoxideisasharedmolecularmechanismofmultiple neurodevelopmentalandneurodegenerativedisorders

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):16–18;doi: https://doi.org/10.61373/bm024k.0118

Keywords: Autism,Alzheimer’sdisease,nitricoxide,proteomics, behavior,brain

HaithamAmalisaninternationallyrecognizedexpertincellsignaling andbraindisorderswhoheadstheLaboratoryofNeuromics,Cell Signaling,andTranslationalMedicineattheHebrewUniversityof Jerusalem.Hisresearchprogramintegratesproteomicswithsystems biology,combiningbiochemical,pharmacological,andbehavioral approaches.CurrentlyaVisitingProfessoratBostonChildren’s HospitalandHarvardMedicalSchool,Dr.Amalpreviouslyconducted hispostdoctoralstudiesattheMassachusettsInstituteofTechnology (MIT),whereheservedasaSeniorPostdoctoralAssociateinthe BiologicalEngineeringDepartmentandwasaffiliatedwiththe StanleyCenterforPsychiatricResearchattheBroadInstituteofMIT andHarvard.Hisinnovativeresearchhasbeensupportedbynumerous competitivegrants,includingawardsfromtheGermanDFG,Israel ScienceFoundation,andtheUSDepartmentofDefense,withhis contributionsrecognizedthroughtheKrillPrizefromtheWolf FoundationandtheEaglesAutismFoundationResearchGrantasits firstinternationalrecipient.Hisresearchestablishedessential connectionsbetweennitricoxideandautismspectrumdisorder (ASD),whilealsorevealingsignificantpathologicaloverlapsbetween ASDandAlzheimer’sdisease.Buildingonthesediscoveries,Dr.Amal hasco-foundedPoint6BioLtd,developingbiologicaldiagnostictools forASD,andNeuroNOSLtd.,focusedonnitricoxidesynthase inhibitorsfortreatingneurologicaldisorders.InthisGenomicPress interview,Dr.Amalshareshisinsightsonthepathtothesediscoveries andhisvisionforadvancingourunderstandingofneurological disorders.

Part1:HaithamAmal–LifeandCareer Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?

In2007,Ibeganmyjourneyintoneurosciencewithamaster’sdegreeat TelAvivUniversity,whereIbecamecaptivatedbythefieldwhileresearchingthelong-termeffectsoflow-doseTHConcognitivefunction.Thisexperiencesparkedadeepinterest,leadingmetofurthermystudieswith aPhDattheTechnion,whereIfocusedonidentifyingdisease-specific chemicalsignatures.Followingthis,IcompletedapostdoctoralfellowshipintheDepartmentofBiologicalEngineeringattheMassachusetts InstituteofTechnology(MIT),exploringproteomicsandsystemsbiology inautismandAlzheimer’sunderthementorshipofProfessorStevenTannenbaum.Thispathhascontinuallydeepenedmycommitmenttounderstandingthebiochemicalunderpinningsofneurologicaldisorders.My workatMITledtotheestablishmentofmylabattheHebrewUniversity,whereIestablishedandledalargegroupofscientistswiththeultimategoalofdevelopingadrugforautismspectrumdisorder(ASD)and Alzheimer’sdisease(AD).

Received:3November2024.Accepted:4November2024. Publishedonline:12November2024.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.

MeetingfamiliesandchildrenwithautisminBostonduringmytimeatMIT inspiredmetofocusonasinglegoal:tohelpdevelopbiologicaldiagnosticsandtreatmentforautismspectrumdisorder(ASD).Theseencounters reinforcedmycommitmenttoaddressingtheunmetmedicalneedsofindividualswithASDandshapedmyresearchpathtowardcreatingtools andinterventionsthatcouldimprovetheirqualityoflife.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Asapharmacologistandneuroscientist,myuniqueexpertiseinunderstandinghowdrugsimpactthebrainisinstrumentalinachievingmygoal ofdevelopingtreatmentsforneurologicaldisorders.Myapproachcombinesinsightsintomolecularprocessesandsynapticbehavior,whichallowsmetounravelcomplexbrainmechanisms.Byfocusingonbiochemicalandbehaviorallevels,Iaimtobridgethegapbetweenmolecular changesandobservableoutcomes,ultimatelycontributingtoadeeper understandingofthebrain’s"blackbox"andadvancingthedevelopment ofeffectivetherapies.

Figure1. HaithamAmal,BScPharm,PhD,HebrewUniversityofJerusalem, Israel.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?

Mylab’sworkhasgarneredinternationalrecognition,exemplifiedbyarecentpublicationonanovelmechanismunderlyingautismpathogenesis. Wewerethefirsttoshowthatnitricoxide(NO)playsacrucialroleinASD. Thisstudy,usingsamplesfromlow-functioningchildrenwithASD,transgenicmousemodels,andin-vitrohumanplatforms,achievedwidespread interest.Ithinkthisworkwillshapeperspectivesonthebiologicalmechanismsofotherneurologicaldisorders.Furthermore,wehavepublished severalpapersonthelinkbetweenneurodevelopmentaldisordersand neurodegenerativediseases.Wealsomadesignificantcontributionsto sexdifferencesinthebrain,publishingthreeimpactfulpapers.Inmylab, weconductexperimentsonbothsexesequally.Wehaveastronginterest inagingmechanismsandhavepublishedanotherpaperonthistopic.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Ihavedevelopedthehabitofdivingdeeplyintothedataandlearning fromfailures,astheyareinvaluablegrowthopportunities.Additionally, serendipityoftenplaysacrucialroleinresearch,leadingtounexpected discoveriesandinsights.

Promotingdiversityandinclusivityinthescientificcommunityisessential forfosteringinnovationandcreativity.Culturalfacetssuchasrepresentationinresearch,accesstoopportunitiesforunderrepresentedgroups, andcollaborativeapproachesacrossdisciplinesdeservetransformative scrutiny.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?

IenjoyparticipatinginconferenceswhereIcanmeetpeoplefromallover theworldandshareideas.Additionally,mentoringmygreatstudentsis incrediblyfulfillingandrewardingforme.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ienjoystudyingnewlanguages,watchingsports,andswimming.During myschooling,Ilearnedfivelanguages:English,Arabic,Hebrew,French, andItalian.Theseinterestsandlanguageskillsallowmetoconnectwith diverseculturesandpeople,enrichingmypersonalandprofessionallife.

Part2:HaithamAmal–Selectedquestionsfromthe ProustQuestionnaire1 Whatisyourideaofperfecthappiness? Thehealthandwell-beingofmyfamily.

Whatisyourgreatestfear? None.

Whichlivingpersondoyoumostadmir MymentoratMIT,ProfessorStevenTannenbaum,whoinspiredmeto valueeverydetailinscientificdataandfosteredmyappreciationforthe nuancesofresearch.IbelievethathedeservedtheNoblePrizeforthe discoverythatnitricoxideisproducedinamammaliancell.

Whatisyourgreatestextravagance? Travelwithmyfamily.

Whatareyoumostproudof? Mytwokids.

Whatisyourgreatestregret? None.

Whatisthequalityyoumostadmireinpeople? Resilience—thestrengthtoovercomechallengesandkeepmoving forward.

Whatisthetraityoumostdislikeinpeople? Dishonesty—theinabilitytobetruthfulandtransparent.

Whatdoyouconsiderthemostoverratedvirtue? Patience–Inexcess,patiencemightdelaynecessaryactionorchange.

Whatisyourfavoriteoccupation(oractivity)? Traveling.

Wherewouldyoumostliketolive? Boston,Massachusetts,USA

Whatisyourmosttreasuredpossession? Thegiftofunconditionallovegivenbymyparents,wife,andkids.

Whenandwherewereyouhappiest?Andwhyweresohappythen? WhenIfirstmetmywifeRagedaandwhenmytwokids,SamaandAdam, wereborn.

Whatisyourcurrentstateofmind? IamcurrentlyonsabbaticalatHarvardUniversityandenjoynetworking, collaborating,anddiscussingsciencewithgreatpeople.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,Arthur ConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Figure2. HaithamAmalandhisdedicatedteamattheirlabinJerusalem.

Whatisyourmostmarkedcharacteristic? Mymainobsessionismyintensedrivetocompleteeverythingaheadof schedule.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Motivation.

Whatdoyouconsideryourgreatestachievement? Discoveringthatnitricoxideplaysakeyroleinautism.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Itwouldbetoworryless.

Whatdoyoumostvalueinyourfriends? Loyalty.

Whoareyourfavoritewriters? Toomanytolisthere.

Whoareyourheroesoffiction? HarryPotter.

Whoareyourheroesinreallife? Mydadandmom.

Whataphorismormottobestencapsulatesyourlifephilosophy? “Inthemiddleofdifficultyliesopportunity"(AlbertEinstein).

HaithamAmal1 , 2 1 InstituteforDrugResearch,SchoolofPharmacy,FacultyofMedicine,The HebrewUniversityofJerusalem,EinKarem,Jerusalem9112102, Israel; 2 RosamundStoneZanderTranslationalNeuroscienceCenterand DepartmentofNeurology,BostonChildren’sHospital,HarvardMedicalSchool, Boston,Massachusetts02115,USA e-mail: Haitham.amal85@gmail.com

OpenAccess. The“GenomicPressInterview”frameworkiscopyrightedtoGenomicPress.Theinterviewee’sresponsesarelicensed toGenomicPressundertheCreativeCommonsAttribution-NonCommercialNoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates: (1)Attribution:Creditmustbegiventotheoriginalwork,withalinktothelicenseandnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercial purposes.(3)NoDerivatives:Modifiedversionsoftheworkcannotbedistributed. (4)Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthose stipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutory exceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotential rights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Thirdpartycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunless otherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RESEARCHLEADER

NoraVolkow:Insightsintothefunctionofourbrainsthroughthescienceof drugsandaddiction

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):19–21;doi: https://doi.org/10.61373/bm024k.0109

Keywords: Addiction,dopamine,reward,stigma,mentalhealth, treatment

Dr.NoraD.VolkowisDirectoroftheNationalInstituteonDrugAbuse (NIDA)attheNationalInstitutesofHealth,whereshehasservedsince 2003asthefirstwomanandfirstHispanicpersoninthisrole.NIDAis theworld’slargestfunderofscientificresearchonthehealthaspects ofdruguseandaddiction.Dr.Volkow’sgroundbreakingworkhasbeen instrumentalindemonstratingthatsubstanceusedisorderisabrain disorder,revolutionizingourunderstandingofaddiction.Asa researchpsychiatristandpioneerinthefieldofneuroimaging, Dr.Volkowtransformedtheuseofbrainimagingtoinvestigatehow substanceuseaffectsbrainfunctions.Inparticular,herstudieshave documentedhowchangesinthedopaminesystemaffectthefunctions ofbrainregionsinvolvedwithrewardandself-controlinaddiction, leadingtofundamentalshiftsinhowaddictionisviewedandtreated. Shehasalsocontributedtounderstandingtheneurobiologyof obesity,attention-deficit/hyperactivitydisorder(ADHD),andaging. InthisGenomicPressInterview,Dr.Volkowsharesinsightsintoher remarkablejourneyfromamedicalstudentinMexicotobecoming oneofthemostinfluentialfiguresinaddictionresearchwhile discussingherperspectivesonthecurrentchallengesinaddressing substanceusedisorders,includingtheongoingopioidcrisis.

Part1:NoraD.Volkow–LifeandCareer1

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

Iwasstruckearlyonbyhowwe,ashumans,canbesovulnerabletothe effectsofaddictivedrugs,howtheycanchangeusinsuchprofoundways, andleadsomepeopletodesperationanddespairwhilepromptingothers aroundthemtoisolateandevenrejectthem.ThefirstexamplethatIexperiencedofthisphenomenonhappenedinmyownfamilywhenIlearned thatmyunclesufferedfromalcoholusedisorder.Yearslater,asamedical student,Iwouldalsoseepatientscomingintothehospitalwithcirrhosis, collapsedveins,orcancerbecausetheyhavebeendrinkingorsmoking throughouttheirlives.Theseaccumulatedexperiencesreinforcedinmea sensethatthestudyofaddictionwasanimportantgoal,mainlybecause itwassodevastatingtopeopleyetpreventable.Hence,ithadaprofound impactonmyfuturecareerchoices.1

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

IwasborninMexicoandearnedmymedicaldegreefromtheNational Universityin1980,alongwiththeRobinsAwardforthebestmedicalstu-

1 Thecontentofthisarticleissolelytheresponsibilityoftheauthoranddoesnot necessarilyrepresenttheofficialviewsoftheNationalInstitutesofHealth.

Received:30October2024.Accepted:1November2024. Publishedonline:7November2024.

tutesofHealth,USA.

dentofmygeneration.Mykeeninterestinresearchandbrainpathology startedearlyinmymedicalcareer.Someofthecriticallabexperiences thatshapedmypathduringmedicalschoolincludeworkingasaResearch AssistantintheelectronmicroscopydepartmentofpathologyattheRegistroNacionaldeAnatomiaPatologicaandlaterintheMilesLaboratory ofExperimentalTherapeutics,bothinMexicoCity.

NotlongafterIgotmydegree,IheadedtoFranceforaninternship rotationattheCentredesMaladiesetdel’EncephaleatSainte-AnnePsychiatricHospitalinParis.Afterthat,IcametotheUSforafour-yearresidencyfellowshipinPsychiatryatNewYorkUniversity,whereIearneda LaughlinFellowshipfromTheAmericanCollegeofPsychiatrists.By1984, IwasanAssistantProfessorintheDepartmentofPsychiatryandBehavioralScienceattheUniversityofTexasMedicalSchool.

Figure1. NoraD.Volkow,MD,NationalInstituteonDrugAbuse,NationalInsti-

MuchofmyprofessionalcareerwasspentattheUSDepartmentof Energy’sBrookhavenNationalLaboratoryinUpton,NewYork,whereI heldseveralleadershippositions,includingDirectorofNuclearMedicine, ChairmanoftheMedicalDepartment,andAssociateLaboratoryDirector forLifeSciences.IwasalsoaprofessorintheDepartmentofPsychiatry andAssociateDeanoftheMedicalSchoolatTheStateUniversityofNew YorkatStonyBrook.

SinceMay2003,IhavebeentheDirectoroftheNationalInstitute onDrugAbuse(NIDA)attheNationalInstitutesofHealth(NIH).Iam proudtobethefirstwomanandthefirstHispanicpersontoserveasNIDA Directorsincetheinstitute’screation.

Asmentionedbefore,myspecificresearchinterestsbeganwithadesiretobetterunderstandhowadrugcanhinderaperson’sabilitytostop itsuse.Iwantedtoknowwhatdrugsdotothebrainwiththehopethatthe knowledgewegleanedfromsuchstudiescouldonedayhelpthosewhose liveshavebeenalteredbythedevastatingeffectsofaddictivedrugs.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.

Asamedicalstudent,Ivolunteeredinalaboratorywhosepurposewasto discoveramedicationforpainbasedonopioidsthatwouldnotbeaddictive.SinceIwasworkingwithopioiddrugs,Ibecameimmediatelyfascinatedwiththeobservationofanimals(ratsandmonkeys)workingcompulsivelytoobtainaminimalamountofdruginjectedintothemandhow theanimalwouldforgoeverythingelseintheprocess.Iwasamazedby theabilityofasimplechemicalcompoundtosorapidlyandprofoundly derailadaptivebehavior.

AsImentionedbefore,Ihavedevelopedakeeninterestinhowthis phenomenonmanifestsitselfintheformofvarioussubstancesandcompulsivebehaviorsamongpeople.However,whatbecamebothfrustrating andpivotalformewastoseehowmuchstigmasurroundedpeoplelivingwithanaddiction:doctorsdidnotwanttotreatthem,theydismissed them.ThatbotheredmebecauseitwasantitheticaltowhatIhadlearned inmymedicaltraining:tohaveempathyandcareforallthoseinvulnerablecommunities.

Lookingback,theseweresomeoftheexperiencesthatmotivatedme toworkintheaddictionfield.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Ihopethatthisresearchwillallowustobetterunderstandtheimpactof druguseonbrainstructureandfunctionsoweareinabetterposition toidentifytherapeutictargetsorstrategiesandhelpthosewhomaybe athigherriskforaddiction.Thishopeisanchoredinmyfirmconviction thatthebettertheknowledge,thebetterthepreventionandtreatment interventionswecandevelop.Inthelongterm,Ibelievethisresearchwill improvethepervasivestigmaseenincommunitiesacrosstheUS,which hasmadeanalreadychallengingrecoveryprocessevenmoreofanuphillbattle.Fortunately,wearealreadyseeingencouragingsignsinthis regard,forexample,intheslowbutgrowingacceptanceofaddictionasa biobehavioraldisorder(oneinwhichgenetic,social,environmental,and otherfactorsinteracttoaffectmeasurableandstereotypicchangestothe brain)andofmultiprongedtreatmentinterventions,inthespreadofnew approachestodealwithindividualswithaddictionwhoarealsoinvolved withthecriminaljusticesystem(e.g.,drugcourts),andinthesteadyadoptionofharmreductionstrategiesthataresocriticaltosavinglivesand nudgingpeopleintoapathforlongtermrecovery.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

Ioftenpositionmyworktomakeitrelevanttoapublichealthquestion orchallenge.ThisiswhyIhavestudiedtheeffectsofacutecellphoneradiofrequencyexposureonbrainglucosemetabolism,theneurobiological overlapsbetweensubstanceusedisorder(SUD)andobesity,andtheimpactofstimulantmedicationsinchildrenwithADHD.

Atpresent,alingeringopioidcrisiskeepschallengingourabilityto tackleadevastatingandconstantlyevolvingpublichealththreat.Drug overdosefatalitiesintheUnitedStatesremainhigh,withanestimated

107,543deathsin2023,mostlyfromopioids.Despitetheeffectivenessof medicationsforopioidusedisorder(OUD)inpreventingoverdoses,only anestimated25%ofindividualswithOUDreceivethem,andcloseto50% discontinuetreatmentwithin6months.ThereisanurgentneedforalternativetreatmentsforOUD.So,spurredfurtherbytheopioidcrisis,the closingoftheaddictiontreatmentgapandthediscoveryofnew,moreeffectiveaddictionmedicationshavebecometoppriorities.Basedonanecdotalreportsofreduceddrugcravinginindividualsusingsemaglutide, anewgenerationofGlucagon-likepeptide-1receptoragonists(GLP1RAs),alongwithempiricalstudiesshowingitstherapeuticbenefitsinalcoholandnicotineusedisorders,rigorousinvestigationsofthepotential ofGLP1-RAmedicationstotreatSUDshasbecomeaparticularlysalient researchinterest.ThisiswhyIwasheartenedtolearnaboutthelatest studyshowingthattheprescriptionofGLP1-RAappearstobeassociated withsignificantlylowerratesofopioidoverdoseinpatientswithOUD;if confirmedbyfurtherstudies,thiscouldbeagamechanger.

Inthemeantime,andrespondingtotheimperativeofsavinglives,I havebecomeanadvocateforthedeploymentofevidence-basedharmreductionpracticesthatfocusonminimizingthenegativeeffectsofdrug useforthosealreadystruggling,suchasbyprovidingsaferenvironments andreducingtheriskofoverdose.

Nevertheless,inthelongrun,effectivepreventionisperhapsoneof themostimpactfulprioritiesbecauseitallowsustointerveneearly,reducingthelikelihoodthatindividualswilldevelopsubstanceusedisordersinthefirstplace.Byfocusingontherootcausesofsubstance use-suchasstress,trauma,mentalillness,andsocialandcommercial determinants-wecanfocusonat-riskpopulationsbeforedrugusestarts orescalates.Effectivepreventionstrategiesnotonlyprotectindividuals butalsoreducethebroadersocietalandeconomiccostsassociatedwith addiction.Investinginpreventionultimatelycreateshealthiercommunitiesandamoresustainablepublichealthsystem.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

OneofthemostfundamentalcodesofconductIhaveadheredtoover theyearsis"listeningandstickingtothedata."Ibelievethatprofessing thehighestlevelofrespectfortheavailableevidenceandviewingitas aguidingprincipleisa "sinequanon"requirementforsuccessfullynavigatingwhatisoftenacomplexandchallengingscientificandpolicyenvironment.Thisstancehasservedmewellovertheyears,combinedwith anon-negotiablecommitmenttoduediligence,respectforothers,and leadingbyexample.

Ithinkboth.ThreeofthemostcriticalaspectsoftheconditionIhave decidedtodevotemyprofessionallifetoarethatitisaglobalphenomenon,personallydevastating,and100%preventable.Fromapublichealthstandpoint,thiscombination,inmyview,affordsaddictionresearchanincrediblyhighreturnoninvestmentpotential,whichiswhyI amsopassionateaboutourmission,albeitwithahealthydoseofhumilityandcommitmenttoempowerandcollaboratewithotherresearchers, partners,andsectors.Iseemyselfasapublicservantandaclinician guidedbyaphilosophyofpragmatismandempathy.Myvisionforthe futurereliesheavilyonthegenerationofdatathatcandrivepolicyand healthcarepracticeandtherebysignificantlyreducethemortalityand othermedicalconsequencesfromsubstanceuseandSUDs.Atthesame time,Iamincreasinglycognizantoftheimportanceofpromotingresearch thatconsiderstheneedsandcomplexcircumstancesofthosemostimpactedbySUDs.Thismeansmakingsurethatanynewsolutionswegeneratereachthoseindividualsandthattheyarepartofthatsolutionby

facilitatingtheirparticipation,wheneverfeasible,atvariouspointsalong theresearchdesignandimplementation.

Whatdoyouenjoymostinyourcapacityasanacademicorresearch leader?

Becauseofmyinnatecuriosity,Iderivegreatjoyandintellectualreward fromanyactivitiesthatadvancescientificunderstandingabouttheworld andtheinnerworkingsofthebraininparticular.Theseactivitiescantake differentforms;thefeelingcanbeelicitedbyadiscovery,afertileexchangewithayoungmenteeorestablishedcollaborator,oralectureto raiseawarenessandeducatethepublicandpolicymakersabouttheimportanceofneuroscienceresearchtounderstandingthecomplexitiesof addiction.Myprimarysourceoffulfilmentflowsfromanintensedesireto makescientificcontributionsthatcandirectlybenefitsociety.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ilovetostayactive:exerciseisessentialtome.Ienjoyrunningandcycling becauseitclearsmymindandhelpsmerecharge.Beingoutinnatureis somethingIvalue,asitgivesmespacetothinkandreflect.Ialsohave apassionforreading,especiallyliteratureandhistory.Itisanexcellent wayformetodisconnectfromtheintensityofmyworkwhilestillstimulatingmycuriosity.Spendingtimewithfamilyisanotherpriorityforme. Althoughmyworkkeepsmebusy,Itreasuremomentswithlovedones, whethersimplyhavingaconversationorsharingameal.

Part2:NoraVolkow–SelectedquestionsfromtheProust Questionnaire2

Whenandwherewereyouhappiest?Andwhywereyousohappythen? HikinginNepalduringmyhoneymoon.Iwassurroundedbyastonishing landscapesandinlove.

Whatisyourcurrentstateofmind? Excitedbutconcerned.

2 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003,Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,Arthur ConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Whatisyourmostmarkedcharacteristic? Courage.

Amongyourtalents,whichonegivesyouacompetitiveedge? Passion.

Whatdoyouconsideryourgreatestachievement? Providingevidenceofaddictionasabraindisease.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Obsessiveness.

Whatdoyoumostvalueinyourfriends? Kindness.

Whoareyourfavoritewriters?

MichaelLewis,IanMcEwan,OrhanPamuk,SiddharthaMukherjee,Toni Morrison,andLionelShriver.

Whoareyourheroesoffiction? Odysseus.

Whoareyourheroesinreallife? AlbertEinstein.

Whataphorismormottobestencapsulatesyourlifephilosophy? Don’tevergiveup.

NoraD.Volkow1

1 NationalInstituteonDrugAbuse,NationalInstitutesofHealth,Rockville, Maryland20852,USA e-mail: nvolkow@nida.nih.gov

OpenAccess. The“GenomicPressInterview”frameworkiscopyrightedtoGenomicPress.Theinterviewee’sresponsesarelicensed toGenomicPressundertheCreativeCommonsAttribution-NonCommercialNoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates: (1)Attribution:Creditmustbegiventotheoriginalwork,withalinktothelicenseandnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercial purposes.(3)NoDerivatives:Modifiedversionsoftheworkcannotbedistributed. (4)Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthose stipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutory exceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotential rights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Thirdpartycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunless otherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RESEARCHLEADER

EdytheLondon:Translatingknowledgefrommolecularandfunctionalimaging studiestonewpharmacologicalandbrainstimulationtreatmentsforaddiction

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):22–24;doi: https://doi.org/10.61373/bm024k.0001

Keywords: Brainimaging,addiction,researchtraining,womeninscience EdytheLondon,Ph.D.,isadistinguishedprofessor-in-residenceinthe DepartmentsofPsychiatryandPharmacologyattheUniversityof California,LosAngeles(UCLA),wheresheholdstheThomasP.and KatherineK.PikeChairinAddictionStudies.Shechaired(2010–2014) andlaterco-chaired(2015–2022)UCLA’sIntegrativeCenterfor Addictions(2010–2014).BeforecomingtoUCLA,shewasactingchief oftheNeuroscienceBranchandChiefoftheNeuropharmacology LaboratoryintheIntramuralResearchProgramoftheNational InstituteonDrugAbuse,USA.There,sheestablishedandwasthe DirectorofNIDA’sBrainImagingResearchCenter(1992–1999).Inher engagementwiththeGenomicPressInterview,ProfessorLondon offeredinsightsintoherlifeanddistinguishedcareer,enrichingthe serieswithheruniqueperspectives.

TheGenomicPressInterviewPart1:EdytheLondon–Lifeandcareer Couldyougiveusaglimpseintoyourpersonalhistory, emphasizingthepivotalmomentsthatfirstkindledyourpassion forscience?

Igrewupinthe1950sand1960s—thetimeofthepost-WorldWarIICold War,whentheUnitedStatesandtheirrespectiveallieswerecompeting withRussia,andwhenscienceandtechnologywereemphasized.Aspart ofanimmigrantfamily,Iwaspatriotic,andthiszeitgeistaffectedme.The launchofSputnik,whenIwasachild,gavemethesensethatsciencecan opentheuniverseandchangetheworld.Iwashookedontheideathata careerinsciencewouldbeanexcitingandrewardingpath.WhenIwentto college,Itookadvantageofaneducationalopportunitygrantprovidedby theNationalDefenseAct,whichprovidedforscholarshipsandloansfor studentsofmathematics,science,andengineering.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

Mypostdoctoralfellowship,intheDivisionofPsychopharmacologyat theJohnsHopkinsSchoolofMedicine,wasatransformativeexperience.Thedivisionwassmallandwascreatedtorecognizeanew field.LedbySolomonSnyder,thefacultywereyoungandwerecreativelyexploitingnewtechniques,suchasreceptorpharmacologyand autoradiography,whichultimatelyhadamajorimpactondrugdevelopmentandtherapeuticregimendesign.Ididoneofthefirst characterizationsofaglutamatereceptor,thekainatereceptor,and workedamongothertraineeswhobecameleadersinthepharmacology industry.

Atthattime,positronemissiontomography(PET)wasbeingdevelopedfornoninvasivemolecularimagingofthebrain.ThefirstPETscanner cametotheNationalInstitutesofHealth(NIH),whenImovedtherefrom JohnsHopkins,andIwasabletousethisnewtechnologyinhumanstudies.Isawthevalueofmappingbrainfunctioninstudiesofdrugactionand addiction.

Received:11January2024.Accepted:12January2024. Publishedonline:25January2024.

Shortlythereafter,thecocaine/crackepidemicledtoanawardfrom theOfficeofNationalDrugControlPolicy,whichfundedmyproposal tobuildtheBrainImagingCenterintheIntramuralResearchProgram oftheNationalInstituteonDrugAbuse.Thissupportallowedmetodo somefundamentalstudiesofhumandrugaddiction.Mylaboratorydevelopednewprobesformolecularneuroimaginginhumansandmappedthe braincircuitrythatsupportsdefiningfeaturesofdrugaddiction,suchas craving.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteareaofresearchorprofessionalfocus. WhenIstartedmydoctoraltraininginpharmacologyattheUniversityof Maryland,myintentionwastostudydrugmetabolism,aresearcharea thatwasemphasizedinpharmacologyatthattime.Icompletelychanged directionbecauseofrecentdevelopmentsinpharmacology.TheseincludedtheNobelPrizeaward-winningworkofJuliusAxelrod,myscientificgrandfather,ontherelease,storage,andreuptakeofepinephrineand norepinephrine;andthediscoveryoftheopiatereceptorbyCandacePert inSolomonSnyder’slaboratoryatJohnHopkins.Learningmoreabout howneurotransmittersaffectbehaviorbecameacareer-longpassion.

Figure1. EdytheLondon,PhD,UniversityofCalifornia,LosAngeles(UCLA), USA.

Whatkindofimpactdoyouhopetoachieveinyourfieldthroughyour focusonyourspecificresearchtopics?

Ihopetoadvanceourunderstandingofthebraincircuitsthatpromote andmaintainaddiction,providingknowledgetodevelopmoreeffective treatments.Withover100,000overdosedeathsinayearduetodrugoverdoseandaccidentalpoisoning,reducingaddictionbyguidingthedevelopmentofmoreeffectivetreatmentsisanimportantmission.

Couldyoutellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?

Iamfocusingonclarifyingtheneuralvulnerabilitiestoaddiction,with aneyetowardusingtheknowledgegainedtodeveloptreatmentsusing targetedbrainstimulationaswellasmedications.Wenowhavepublicly availabledataonbrainfunctionandgenomicsofchildrenbeforetheyexperimentwithdrugsandultimatelybecomeaddicted.Atthistime,noninvasivebrainstimulationtechniquesarebeingdevelopedtoalterpathologicalfeaturesofbraincircuitry.Iamespeciallyinterestedintranslating knowledgefrommolecularandfunctionalimagingstudiestothedesign andconductofclinicaltrialsforaddictionusingmedicationsandtargeted brainstimulation.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour ownresearchenvironment?

Ihavelearnedtofocusonproblemsthathavepotentiallyhighimpact— thosethatarenotonlyofinteresttome,butthatcaninfluencehowresearchisconductedwithrelevancetoclinicalpractice.Ialsohavelearned thatscienceflourishesinanenvironmentofcollegialityandsharing.Itry toengraintheseprinciplesinmytrainees.

Sciencehasopeneduptowomenoverthecourseofmycareer.Despite somepersistentinequities,womenarecomingintothefieldandaretakingleadershippositions.Yet,westillfacethechallengeofincreasingrepresentationbyraciallyminoritizedgroupsinthescientificcommunity. Althoughourprofessionalsocietiesandacademicinstitutionshavedevelopedattitudesandprogramsthatbringmembersofthesegroupsinto science,itisnotenoughtobeincluded,butweneedtochangethecultureofsciencetomakethemcomfortableandtohave“aseatatthe table.”

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch leader?

Mygreatestpleasureinmyprofessionallifeisseeingthedevelopment andsuccessofmytrainees.Anothersourceofgreatsatisfactionisseeing thatmyworkhasanimpactonhowresearchinmyfieldisdone.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Mypriorityisfamily.Ilovetotravelwithmyhusbandandtospendtime withmychildrenandgrandchildren.

TheGenomicPressInterviewPart2:EdytheLondon–Selected questionsfromtheProustQuestionnaire1

Whatisyourideaofperfecthappiness?

PerfecthappinessformewouldbethesatisfactionthatIhavegivenmy besttomyfamilyandhavedonesomethingthatmadeadifference.

Whichlivingpersondoyoumostadmire?

IhavegreatadmirationforJenniferDoudna.

Whatisyourgreatestextravagance?

Onemightconsidermyinvestmentinpersonaltraininganextravagance. Iseeitassomethingtogivemeahealthybreakfrommyacademic endeavors.

Whatareyoumostproudof?

Iammostproudofhelpingyoungerpeopledeveloptheircareers,serving asarolemodel,andencouragingthem.

Whatisthequalityyoumostadmireinpeople? Generosity.

Whatdoyouconsiderthemostoverratedvirtue?

Rawtalentisoverrated.Withoutdedicationandresilience,itdoesnot leadtosuccess.

Whatisyourfavoriteintellectualactivity?

Developinganewproject:Iseeitasanartformtopackageanewideafor presentationandtothinkthroughthetechnicalissuesofmakingitwork.

Wherewouldyoumostliketolive?

IwouldmostliketolivewhereverIcanworkonsomethingexcitingand benearfamily.Iamacityperson,sothatplaceideallyisabustling metropolis.

Whatisyourmosttreasuredpossession?

Mycollectionoffamilyphotos.

Whenandwherewereyouhappiest?Andwhyweresohappythen?

Ofallthetimesofmylife,Iamhappiestnow.Ihavesurvivedtheuncertaintyandstressofbuildingacareer,andnolongerfacetheantifemale discriminationIsawasayoungscientist.Ienjoythecollaborationand friendshipandevenhavesomerecognitionfromvaluedcolleagues.On apersonallevel,itisajoytoseemychildrensuccessfulandhappy,andto beinalovingmarriage.

Whatisyourmostmarkedcharacteristic?

Ithinkthecharacteristicthatmostledtomysuccessisresilience.

Amongyourtalents,whichonegivesyouacompetitiveedge? Myabilitytoviewthebiggerpictureinselectingaresearchdirectionhas givenmeanextraedge.

Whatdoyouconsideryourgreatestachievement?

IcamefarinlifefromwhereIstarted.Iwasborninarefugeecampafter theWWII,andmyparentsstruggledasimmigrants.Buildingarewarding careerinscienceagainstthoseoddsandinanenvironmentthatwasunfriendlytowomenscientistswasanimportantachievement.Iamgrateful andproudofit.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwouldbeevenmoreself-confident.

Whatdoyoumostvalueinyourfriends?

Loyalty.

Whoareyourfavoritewriters?

SiddharthaMukherjeeandAbrahamVerghese.

Whoisyourherooffiction?

ElizabethBennettfrom PrideandPrejudice:Iadmireherintelligence, courage,andrecognitionoftheimportanceoflove.

Whoareyourheroesinreallife?

ThefiremenwhoranintosavepeopleattheTwinTowersoftheWorld TradeCenteron9-11.

Whataphorismormottobestencapsulatesyourlifephilosophy?

Ibelievethatweareonearthtobekindtooneanotherandtomakethe worldabetterplace.Thisviewguidesmylifeinthelaboratoryandinmy personallife.

EdytheLondon1

1 DavidGeffenSchoolofMedicine,UniversityofCaliforniaLosAngeles, LosAngeles,California90024,USA e-mail: elondon@mednet.ucla.edu

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutralityregardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliationsofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors,withouteditingthem.Suchusesimplyreflectswhattheauthorssubmitted tousanditdoesnotindicatethatGenomicPresssupportsanytypeofterritorial assertions.

INNOVATORS&IDEAS:RESEARCHLEADER

AlyssonMuotri:Modelingthehumanbrainwithstemcellsandorganoids,from diseaseparadigmstoneanderthoids,spacebrains,andbeyond

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):25–27;doi: https://doi.org/10.61373/bm024k.0082

Keywords: Braindevelopment,stemcells,organoids,evolution,autism Dr.AlyssonMuotriisaProfessorattheUniversityofCalifornia,San Diego(UCSD),holdingappointmentsinboththeDepartmentof PediatricsandtheDepartmentofCellular&MolecularMedicine.His leadershipextendsacrossseveralcutting-edgeresearchinitiativesat UCSD,whereheservesasDirectoroftheSanfordStemCellEducation program,theIntegratedSpaceStemCellOrbitalResearch(ISSCOR) center,theArchealizationCenter(ArchC),andtheGeneTherapy Initiative,aswellasAssociateDirectoroftheCenterforAcademic Research&TraininginAnthropogeny(CARTA).Dr.Muotri’sacademic journeybeganinBrazil,whereheearnedaBScinBiologicalSciences fromtheStateUniversityofCampinas(Unicamp)in1995andaPh.D. inGeneticsfromtheUniversityofSãoPauloin2001.Hethenmovedto theSalkInstitutein2002asaPewLatinAmericaFellowfor postdoctoraltraininginneuroscienceandstemcellbiology.Atthe forefrontofneuroscienceresearch,Dr.Muotri’sworkfocusesonbrain evolutionandthemodelingofneurologicaldiseases,employing cutting-edgetechniquessuchashuman-inducedpluripotentstem cellsandbrainorganoids.WearehonoredtofeatureDr.Muotriinthe GenomicPressInterviewseries,offeringourreadersaunique opportunitytogaininsightsintobothhispersonaljourneyand professionalachievements.Hiscontributionstothefieldof neuroscienceandstemcellresearchcontinuetoshapeour understandingofbraindevelopmentanddisease,makinghis perspectivesinvaluabletothescientificcommunityandbeyond.

Part1:AlyssonR.Muotri–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience? Iwaspreoccupiedwithhowthingsworkevenasachild.Iremembermy firstdeepthoughtaroundageseven,whenItriedtofigureouthowa lightbulbworks.Myideawasthatthelightbulbwasnottheretoilluminatethingsbuttosuckupthedarkness.Itookawhiletoworkonthat hypothesis.AsateenagerinSãoPaulo,Brazil,Ioftenimmersedmyself innature,capturingfirefliesinjarssoIcouldhavelightforever.Icreatedatime-lapseseriesofphotosofflickeringlightfromfireflies—one ofmanyprojectsthatearnedthenickname‘TheScientist’frommyfamily members.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

WhenImovedfromBraziltotheUnitedStatestotrainasaneuroscientist,Iwasshockedtodiscoverthatmostofour‘knowledge’aboutthehumanbraincamefromanotherspecies:themouse.Thisstruckmeaspretty strange.Afterall,itwasnotthemousebrainthatputusontheMoonor decodedthehumangenome.Inallitscomplexity,thehumanbraingeneratedourunderstandingoflifeandthelawsthatgoverntheUniverse. Nonetheless,Ilearnedhowtodissectmousebrainsasapostdoctoral researcher.Ihopedtofindoutmoreaboutthesignificantregionsandessentialstructuresassociatedwithmentalandneurologicaldisorderssuch

Received:23September2024.Accepted:24September2024. Publishedonline:30September2024.

asautismandepilepsy—and,ultimately,howtofixthem.Ipracticedand practiceduntilIwasfinallyanexpertintheanatomyofthemousenervous system.However,itwasbloodywork,andIpaidthepriceatnight.Inmy dreams,Ireplayedthevividexperienceofremovingthebrainsfromtiny skullsandslicingthemup.Somethingaboutthesenightmareswastelling menottocontinuedownthisroad.Eventually,Imusteredthecourageto challengemycolleagues:whatifthediseaseswewanttocureandthe answerswewantwillnotbefoundinthemousebrain?ThiswaswhenI decidedtocreateahumanbrainfromscratchusinghumanpluripotent stemcells,whichcanmakealltissuesinourbody,includingthebrain.Our researchreliesonbrainorganoids,structurescreatedfromstemcellsthat canbederivedfromhumanembryosorreprogrammedfromsomaticcells obtainedfromlivingpersons.Thesebrainorganoidscapturethedevelopment invitro outsidethewombandmorecloselyresemblehumanbrain developmentthanrelyingonamousemodel.Itwasn’teasysincealmost nobodywasdoingit.However,despitethedifficultyintheearlydays,Iam gladIdid.Thisexperiencepivotedmycareerandputmeinmycurrent leadershipposition.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea. Whenwepausetothinkaboutthesignificantproblemsthattheworld facestodayorwillfaceinthefuture,theyincludeadiscouraginglymountinglistofseeminglyfar-rangingissuessuchasclimatechange,poverty, sustainabledevelopment,mentalhealth,andmanymore.Whatstrikes usfirstisnotonlytheenormityofthechallengebutalsohowdiverse theyseemtobe.Identifyingproblemsisonething,andfindingsolutions isanother.However,uponcloserinspection,itbecomesclearthatthere isonlyonesourcefortheirsolution—tousethehumanbrain,especially thecortex,withitspowersofcognition.Theproblemisthatwedonot fullyunderstandhowthebrainworksandhowitisformed.Todothat wouldrequireexaminingthebrain inutero.Unfortunately,thatisaninsurmountablebarrier.Welacksufficientnon-invasivetoolstofollowbrain developmentwithhighdefinitioninlookingfortheemergenceofthefirst

Figure1. AlyssonR.Muotri,Ph.D.,UniversityofCalifornia,SanDiego,USA.

synapses,neuronstofire,ornetworkstoform.Allthesechangesoccur withinthewomb,andourtools,suchasMRIandultrasound,lacksufficient magnificationorpowertofocusonthesestructuresorevenatthemolecularlevel.Duetotheseandotherlimitations,theprecisewayinwhich thehumanbrainformsduringgestationisablackbox.Bridgingthisgap tounderstandhumanbraindevelopmentwastheimpetustostartmylab atUCSD,focusingonhumanbrainorganogenesis.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

TheultimateimpactIhopetoachieveisonpeople’slives,bothonpatients andfamilymembers.ConditionssuchasprofoundautismorAlzheimer’s Diseasecanbedevastatingtothefamilyandsocietysincetreatmentsare highlyspecializedandexpensive.Thehumanmodelsystemwedeveloped cancomplementcurrentneurosciencetoolstoadvancetreatments.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

Iamfocusedonseveralexcitingprojects.WeareemployingstrategiessuchasASOs(allele-specificoligonucleotides),genetherapyapproaches,orevengenomeeditingcapabilitiestocorrectthemutationin thegenomeofpatient-derivedbrainorganoidstounlockthepotentialof severalgeneticconditions.Wearealsolookingatwaystotakethistechnologytootherapplications.Oneideawastogrowbrainorganoidsatthe InternationalSpaceStationtounderstandthespaceenvironment’simpactonhumanbraincells,includingradiationandmicrogravity.Weknow thatthenervoussystemhasnotevolvedtocopewiththeveryharshenvironmentofouterspace;forthatreason,findingwaystomitigatethe environmentaleffectsoncellswillbeessentialtohelpastronautswith futurelong-terminterplanetarymissionsandspacecolonization.There arealsocrucialimplicationsonEarth.Becauseorganoidsaregreatneurodevelopmentalmodels,theyarenotidealforhelpingusfindbetter treatmentsandcuresforlate-onsetdiseases.Wearelearningthatwecan leveragemicrogravityexposuretospeeduptheagingofbraincellssothat wecanmodeltheadult-agedhumanbrain,includingconditionssuchas Alzheimer’s,Parkinson’s,andDementia.

Wealsoleveragehumanbrainorganoidnetworkstoimproveartificialintelligence(AI).Basedonwhatwelearnfromorganoids,wecanproposeinnovativealgorithmstoexplainhowthebrainworks,whichwill befundamentaltocreatingamorehuman-likeAItype.Itwillbelikean organicwaytoperformAI,usingbiocomputerscreatedbystemcellsto havemorehumanizedAInetworks.Theenergycostissolowthatitis possibletoperformseveralcomputationalanalysessimultaneouslyata fractionofthepricethatwecurrentlyhavewithAI.Thisworkalsohelps usunderstandtheemergenceofconsciousnessinthehumanbrain.Finally,Iamalsointerestedintheevolutionofthehumanbrain.OurapproachistoresurrectextinctgeneticvariantsfromNeanderthalsusing genome-editingenzymestoarchealizethehumangenomeinpluripotent stemcellsandgeneratebrainorganoidsfromthem.Wenowcallthese brainorganoids’neanderthoids,’andtheyrevealunexpectedevolutionarystepsthatwouldbeimpossibletodiscoverusingfossilrecords.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Themostimportantvalueisbeinghonestwiththedataandbeingpersistent.Mostofmyessentialdiscoveriescamefromunexpecteddatathat actuallycontradictedmyinitialhypothesis.Ittakespersistencetoconvinceyourselfandothersaboutanunusualperspective.

Yes,Iaminvolvedwithtwoissues.Thefirstisdiversity,withtheinclusionofdifferenttypesofminorities.Whilethisisimprovinginscience,

Togetherwithmywithson(Ivan)andwife(Andrea)onawalktosupportbettertreatmentsandconditionsforautisticindividuals(SãoPaulo,Brazil 2024).

the“neuro”diversityisstillbehind.Iamdesigninganon-traditionalacademicpathforpeoplewithneurodiversity.Theseindividualsmightnotsit inaregularclassbutcouldsignificantlyimpactsciencebyworkingindifferentenvironmentsandwithappropriatesupport.Anotheraspectthat IenjoyismergingWesternsciencewithtraditionalsciencefromancient tribes.Thereissomuchknowledgeinthesecommunitiesthatisbeing lost,mainlyduetoprejudice.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch leader?

Ienjoyinteractingwithdifferentgenerationsofscientistsandlearning fromdifferentdisciplines.Ilovegenuinelyinterdisciplinaryresearchand leadingtrulytransformativeprojects.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Familytimeissignificantforme,especiallywhenIamdoingoutsideactivitieswithmysonandwife.Whenalone,Ienjoyyogaandsurfing,meditating,listeningorplayingmusic,andtraveling.

Part2:AlyssonR.Muotri–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness?

DoingwhatIlike,whilehelpingothersinneed.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Figure2.

Whatisyourgreatestfear? Iamfreeoffears.

Whichlivingpersondoyoumostadmire? MysonIvan.

Whatisyourgreatestextravagance? Toimagineanovelscientifichypothesis.

Whatareyoumostproudof? WitnesstheprogressofmyautisticsonIvan.

Whatisyourgreatestregret? Worryingtoomuchaboutothers’opinions.

Whatisthequalityyoumostadmireinpeople? Creativity.

Whatisthetraityoumostdislikeinpeople? Cruelty.

Whatdoyouconsiderthemostoverratedvirtue? Innateabilities.

Whatisyourfavoriteoccupation(oractivity)? Tocreateandtestthemostabsurdscientifichypothesis.

Wherewouldyoumostliketolive? SanDiego,California.

Whatisyourmosttreasuredpossession? Mymemories.

Whenandwherewereyouhappiest?Andwhyweresohappythen? Hereandnow,becauseIhaveallIneed.

Whatisyourcurrentstateofmind? Energetic.

Whatisyourmostmarkedcharacteristic? Optimism.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Creativityandmultitasking.

Whatdoyouconsideryourgreatestachievement? Tocreateandtestthemostout-of-the-boxscientifichypotheses.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Tobecomemoreself-confidentearlierinlife.

Whatdoyoumostvalueinyourfriends? Unconditionalloveandsupport.

Whoareyourfavoritewriters? MachadodeAssis,JorgeAmado,andOliverSacks.

Whoareyourheroesoffiction? MychildhoodimaginaryfriendFader,whostillvisitsmymind.

Whoareyourheroesinreallife? MywifeAndrea,mymomVitoria,andmygrammaDonaAna.

Whataphorismormottobestencapsulatesyourlifephilosophy? Theonlycertaintyinlifeismaybe.

AlyssonR.Muotri1

1 DepartmentofPediatricsandCellular&MolecularMedicine,Universityof California,SanDiego,LaJolla,California92037-0965,USA e-mail: muotri@ucsd.edu

INNOVATORS&IDEAS:RESEARCHLEADER

KimQ.Do:Antioxidantsspecificallytargetedatmitochondria:Anoveltherapeutic approachtoschizophrenia

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine January2025;1(1):28–30;doi: https://doi.org/10.61373/bm024k.0025

Keywords: Oxidativestress,antioxidant,parvalbumininterneurons (PVI),schizophrenia,biomarkers

KimQ.DowasappointedseniorlecturerattheUniversityofLausanne (CH)in2000.Overtheyears,shebecameanassociateprofessorof translationalpsychiatryin2011andattainedthepositionoffull professorin2017.In1999,sheestablishedtheUnitforResearchin SchizophreniaattheCenterforPsychiatricNeurosciencewithinthe DepartmentofPsychiatryatLausanneUniversityHospital.Sheserved astheheadofthisunitfrom1999until2022.Additionally,shewas theCenterforPsychiatricNeurosciencedirectorfrom2013to2019. SheholdsvisitingprofessorpositionsatHarvardMedicalSchoolin Boston,USA,theInstituteofPsychiatry,Psychology&Neuroscienceat King’sCollegeLondon,UK,andtheSwissFederalInstituteof TechnologyLausanne(EPFL).ProfessorDograciouslyconsentedto participateintheGenomicPressinterview,offeringinsightsintoher uniquepersonalandprofessionaljourneys.

Part1:KimDo–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

IwasbornandraisedinVietnamduringthewar,whichexposedmeto muchsufferingfromayoungage.Thisexperienceinstilledinmeadeep desiretoalleviatethepainsofothers.Myfascinationwithscienceand medicinebeganearlyon,andthankstoascholarship,Iwasfortunateto pursuemystudiesinchemistryattheUniversityofNeuchâtel,located intheFrench-speakingpartofSwitzerland.MytimeattheUniversityof Neuchâtelbeganmypassionforscientificresearchandlaidthefoundationformysubsequentcareer.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

Aftercompletingmystudiesinchemistry,IembarkedonaPh.D.thesisinmolecularbiologyattheFederalInstituteofTechnologyin Zurich,Switzerland.Thispivotalopportunityallowedmetoexplorethe enkephalinsfieldandsynthesizestableanalogs,mergingmychemistry expertisewithbiology.Itwasduringthistimethatmyfascinationwith brainresearchtookroot.IsubsequentlyjoinedtheBrainResearchInstituteattheUniversityofZurich,theonlyinstitutioninSwitzerlanddevotedtobasicneuroscienceresearch.ItwasalsowhereImetmyfuture husband,Prof.MichelCuénod,whosharesmypassionforneuroscience (figure2).

DuringmytimeattheInstitute,Icontributedtoestablishinganeurochemistrylaboratoryanddevelopedcutting-edgeanalyticalmethods toexploreglutamatefunction,athen-emergingneurotransmittercandidate.However,acollaborationwithProf.FlorianHolsboerfromMPIFrankfurttrulyredirectedmyfocus.Accesstocerebrospinalfluidsamplesfrom untreatedschizophreniapatientsledtoaseminalobservationregarding

Received:24March2024.Accepted:25March2024. Publishedonline:28March2024.

glutathionedeficiencyinschizophrenia.Drivenbythisdiscovery,Iseized theopportunitytoestablishaneurobiologylaboratoryattheCenterfor PsychiatricNeuroscienceinLausanne.Teamingupwithcliniciansdedicatedtoearlypsychosisdetectionandtreatment,alongwithagroupof talentedandmotivatedstudents,postdocs,andcollaboratorsinthefield ofbasicneurobiologyaswellaswithclinician-scientists,weachievedto createabench-to-bedmultidisciplinaryapproach.Thistranslationalapproachwasentirelyinnovativeandrepresentsthecornerstoneofmyprofessionalcareer.Ithusdevelopedaresearchprogramaimedatabetter understandingofthecausesandmechanismsleadingtoschizophrenia phenotypestoidentifymarkersforearlydiagnosis,newdrugtargets,and preventiveandtherapeuticmeasures.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.

Oneday,amotherintheaudienceapproachedmeataconference.Her thirteen-year-oldgrandsonwasshowingthesame“awkwardbehavior” thathersonwithschizophreniahadatthesameage,andsheaskedme, “Whatcanyouadvisemetodo?”.Thatwasatrigger,a“wake-upcall” formetoadoptamoretranslationalvisionandtofocusonbridgingthe

Figure1. KimQ.Do,UniversityofLausanne,Switzerland.

Figure2. KimDoonvacationwithMichelCuénod.

realmsofbasicneurosciencewithcomplexproblemsofclinicalpsychiatry. Thisencounterservedasacatalyst,drivingmetostudycausesandmechanismsinpreclinicalmodelsandvalidatethesemechanismsingroups ofpatients.Consequently,Idevelopedmechanism-basedbiomarkersto facilitateearlyinterventionandnoveltreatmentapproaches.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Inthefieldofschizophreniaresearch,myfocusisdirectedtowardaddressingthemultifacetedchallengeslinkedtothecomplexityandheterogeneityofthedisease,fromgeneticsandpathophysiologytoclinical presentationanddiseaseprogression.Centraltomymissionisdevelopingmechanism-basedbiomarkersthataccuratelycapturecircuitrydysfunction,facilitatingearlydetection,improvedpatientstratification,and effectivetreatmentmonitoring.Myresearchactivitiesarethusfocused onpavingthewayforprecisionmedicineinpsychiatry.Ultimately,Iaim tomakesignificantcontributionstoenhancingthepreventionandtreatmentofpsychosisatanindividuallevel,catalyzingbreakthroughsinour understandingofpsychiatricillnessesand,consequently,patientcare.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

Myprimaryfocusislaunchingaclinicaltrialcenteredaroundanantioxidanttargetedexplicitlyatmitochondria.Thesecellularpowerhouses arecrucialforensuringtheproperfunctioningofneurons,particularly parvalbumininterneurons(PVI),vitalforcognitive,affective,andsocial activitiesandimpairedinpatientswithschizophrenia.Thistrialrepresentstheculminationofpioneeringexperimentalworkoverthepast 25years.Ifsuccessful,administeringthisspecificantioxidanttopatientswithschizophreniacouldsignificantlyalleviatetheirsymptoms andimprovecognitivefunctions—areaswherecurrentantipsychoticsoftenfallshort.Enhancedcognitionisessentialforimprovingsocialand professionalfunctioningandoverallqualityoflife.Additionally,Iamconcentratingonstudiesaimedatidentifyingmechanism-basedbiomarkerstopredictcognitivedeficitsinindividualsatclinicallyhighriskfor psychosis.Furthermore,Iseektoadvancefunctionalmagneticresonancespectroscopytotargetneurometabolicalterationsinpsychiatric disorders.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Throughoutmyacademiccareerandpostdoctoralexperiences,Ihavealwaysadheredtoopenness,fairness,andrespect.Ifirmlybelieveinlearningfromoneanother,promotingteamwork,andnurturingmotivation amongteammembers.Additionally,Iprioritizeperseveranceasacriticalfactorinovercomingchallengesandachievingsuccessinresearchendeavors.Creatinganenvironmentwhereeveryonefeelsvaluedandsupportedisessentialforfosteringpositiveandproductivecollaborations.

AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitywarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?

Diversityisacornerstoneofmyworkingenvironment,encompassing researchersfromdiversedisciplines,countries,andcultures.However, thereisstillroomforprogressinensuringequalaccesstoscience,particularlyforwomenandindividualsfromdevelopingcountries.Additionally, Iamdedicatedtopromotingwidespreadexchangeamongresearchers fromvariousfieldstofostersynergies.Encouragingcollaborationand inclusivityenhancesthequalityofresearchandcontributestoamoreequitableandinnovativescientificcommunity.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch leader?

Oneofthemostrewardingaspectsofmyroleismentoringearlycareer researchersinbasicandclinicalresearch.Ifindgreatsatisfactioninnurturinganewgenerationofpsychiatristswithclinicalpracticeandneuroscienceexpertise.Breakingdownthetraditionalbarriersthatonceexistedbetweenbasicscientistsandcliniciansisparticularlygratifying,asit stimulatescollaborationtowardacommongoal.Witnessingthesynergy andinnovationthatarisefromthisinterdisciplinaryapproachbringsme greatsatisfactionandfulfillmentasaresearchleader.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Inmyleisuretime,Iprioritizeactivitiesthatallowmetorelax.Ienjoy practicingmeditation,walking,swimming,andcookingformylovedones. Theseactivitieshelpmerechargeandmaintainbalanceinmylife.Additionally,Ihaveapassionfororchidsandtakepleasureincaringforthem, aswellastendingtomyJapanesegarden.Aboveall,spendingqualitytime withmyfamilyandfriendsisessentialtome.

Part2:KimDo–SelectedquestionsfromtheProustQuestionnaire1 Whatisyourideaofperfecthappiness?

Idonotbelievein’perfecthappiness’;ifitexisted,itwouldlikelybefleeting.Happinessandbeautyareephemeral,andonemustrecognizewhen toseizethosemoments.Forme,perfecthappinessliesindiscoveringinnerpeace.

Whatisyourgreatestfear?

Failingtofindmyownpath.

Whichlivingpersondoyoumostadmire?

Iadmiremorethanasingleperson:theUkrainianpeople,individualswho contributetobreakingtheglassceilingforwomen,andthosewhohelp

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,Arthur ConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

toalleviatethesufferingofpeopleaffectedbypsychiatricdiseasesand theirfamilies.

Whatisyourgreatestextravagance?

Eatinganddrinkingtothepointofbeingunabletowalk;mymotherhad tocarrymeonherbacktoreachhome.

Whatareyoumostproudof?

Itakeimmenseprideinmydaughter,whohasbecomeremarkableand compassionate.Additionally,Iaspiretobeproudtocontributetoenhancingourpatients’livesthroughourresearchresults.Developingknowledgenotonlyaidsinimprovingtheirwell-beingbutalsoservestodestigmatizepsychiatricillnesses.

Whatisyourgreatestregret?

Myparentspassedawaybeforewitnessingmyprofessionalaccomplishments.

Whatisthequalityyoumostadmireinpeople?

Ivaluejustice,integrity,anddedicationtoanoblecause.Additionally,I appreciatetraitsliketoleranceandrespectextendedtoalllivingbeings, includinganimalsandplants.

Whatdoyouconsiderthemostoverratedvirtue?

Heroism!

Whatisyourfavoriteoccupation(oractivity)?

Ienjoycooking,winetasting,andtakingcareofmyorchids.Withover 30,000species,eachsurpassingtheotherinbeauty,orchidsareacaptivatingmirrorreflectingthemanyfacetsofthehumansoul.

Wherewouldyoumostliketolive?

Athome,nearalakeorthesea.Ialsoliketraveling.

Whatisyourmosttreasuredpossession?

Possessionsdonotcarryinherentvalue;thetruetreasureliesinsharing andcommunalexperiences.

Whatisyourmostmarkedcharacteristic? Resilience.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge?

Myempathyandabilitytothinkoutsidethebox,oftendescribedas ‘exotic,’contributesignificantlytomyedge.

Whatdoyouconsideryourmostoutstandingachievement?

IntegratingEasternandWesternperspectives,fosteringglobalthinking,anddelvingintotheessenceandcoreofanissue,bothinlifeand science.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Enhancemyspatialorientationskillsandtempermyemotionaloutbursts.

Whatdoyoumostvalueinyourfriends?

Loyaltyandhonesty

Whoareyourfavoritewriters?

HarukiMurakamiforhisthought-provokingandimaginativenovels.In “NorwegianWood”or“KafkaontheShore,”Ilikehowheexploresthe complexitiesofhumanrelationshipsandthemysteriesofexistence,and FrançoisChengforhisinsightsintothehumanexperienceandthequest forwisdom.

Whoareyourheroesoffiction?

A‘hero’isnotaconcept.Onecannotfindaheroinjustoneperson. Everyonehastheiryinandyang,theirpartinthelightandtheirpartin thedark.

Whoareyourheroesinreallife? Sameasabove.

Whataphorismormottobestencapsulatesyourlifephilosophy?

Breakdownbarriersbetweendisciplinesandforgeconnectionsamong people.

KimQ.Do1 1 UniversityofLausanne,Switzerland e-mail: Kimquang.Docuenod@unil.ch

EMERGINGTOPIC

Airpollution:anemergingriskfactorforautismspectrumdisorder

ShashankKumarOjha1 ,andHaithamAmal1 , 2

Theglobalsurgeinairpollutionposesanincreasinglyconcerningenvironmentalriskfactorforneurodevelopmentaldisorders,particularly autismspectrumdisorder(ASD).Recentepidemiologicalstudieshaverevealedcompellingassociationsbetweenexposuretospecificair pollutants,includingfineparticulatematter(PM),nitrogenoxides(NO,NO2 ),sulfurdioxide(SO2 )andozone(O3 ),andincreasedASDrisk.While therisingglobalASDprevalence,nowaffecting1%–1.5%ofthepopulation,partiallyreflectsexpandeddiagnosticcriteriaandenhanced screening,mountingevidencepointstothecriticalroleofgene–environmentinteractionsinASDetiology.Airpollutantscantriggermultiple pathogenicmechanisms,includingneuroinflammation,oxidative/nitrosativestress,epigeneticmodifications,andglutamatergic/GABAergic neurotransmittersystemdisruption.Thetimingofexposureappearscrucial,withheightenedvulnerabilityduringprenataldevelopmentand earlychildhoodwhencriticalneurodevelopmentalprocesses,suchasneuronalmigration,synaptogenesis,andmyelinationoccur.Research prioritiesshouldfocusonhowairpollutantsaffectbraindevelopmentingeneticallysusceptibleindividuals,especiallyduringpregnancyand earlychildhood.Betterwaysareneededtoidentifyindividualsatthehighestriskanddeveloppracticalprotectivemeasures.Giventherising globalpollutionlevels,thisknowledgewillhelpshapemeaningfulpublichealthpoliciestoprotectfuturegenerationsfromenvironmental factorsthatmaycontributetoASD.

BrainMedicine January2025;1(1):31–34;doi: https://doi.org/10.61373/bm024e.0115

Keywords: Airpollution,autismspectrumdisorder,nitricoxide,neuroinflammation,oxidativestress

AirPollutantsAssociatedwithAutismSpectrumDisorder Airpollutioncomprisesparticulatematter(PM),carbonmonoxide(CO), sulfurdioxide(SO2 ),nitricoxide(NO),nitrogendioxide(NO2 ),ozone(O3 ), andvolatilecompounds.AstudyintheUnitedStates,Israel,andTaiwan hasshownthatPM2.5(airborneparticlessmallerthan2.5 μmindiameter),NO,andNO2 arepositivelyassociatedwiththecauseofautism(1). Thestudyhasalsoshownthattheeffectofpollutantsdependsontheexposuretimeforpregnantwomenorchildrenofanearlyage.

Onewell-studiedairpollutantisPM,includingPM10andPM2.5,the latterofwhichisparticularlyhazardous.Theseparticlescanentertherespiratorysystemandthebloodstream.Theycanalsocrosstheplacenta andaffectthenormaldevelopmentofthefetalbrain.StudieswithPM10 haveshownitshightoxicityandabilitytocauseautismspectrumdisorder (ASD)inpregnantwomen.Meanwhile,PM2.5showedevendeeperpenetrationandamoreharmfuleffectduringthepreconceptionperiod,andit alsoposedanincreasedriskofASDinnewborns(2).

“NO”isacommonairpollutantproducedmainlybyvehicleemissions andthecombustionoffossilandindustrialfuels.ExposuretoNOand itsderivativeNO2 duringpregnancyandearlychildhoodcandisruptnormalbraindevelopment(1, 2).RecentbreakthroughresearchhasestablishedthefirstdirectlinkbetweennitricoxideandASDpathogenesis(3, 4).Thetimingofitsexposureiscrucial.Exposuretothesepollutantsduringpregnancyandearlypostnataldevelopmentposesasignificantrisk ofASDsincetheseperiodsareessentialforbraindevelopment,includingneuronalmigrationandmyelinization(5).Anotherhazardousfactoris ozone.O3 isahighlyreactiveoxygengas.Ground-levelO3 isproducedbya photochemicalreactionbetweentwosignificantclassesofairpollutants: volatileorganiccompoundsandnitrogenoxides.ThestudybyMcGuinn etal. hasshownanassociationbetweenO3 ,PM2.5,andASD(6).Ithas beenfoundthatO3 andPM2.5exposureduringpregnancyandtwofirst postnatalyearshasastrongassociationwiththedisorder(6).

AccumulatedevidencehasalsorevealedthatSO2 isasignificantair pollutantproducedbyvehicles,thecombustionoffossilfuelsinpower plants,andothersources.StudieshaveshownthatexposuretoSO2

duringamaternalperiodandthefirst4yearsofageincreasestherisk ofASD(7).Benzeneisavolatileorganiccompoundcommonlyfoundin vehicleemissions,industrialprocesses,andtobaccosmoke.MaternalexposuretoNO2 andbenzeneduringpregnancycanalsoincreasetherisk ofASD(8).Anotherstudyhasshownthatco-exposuretoafewairpollutantslikePM2.5andSO2 exertsynergisticeffectsleadingtoneurodegenerationatlowdoses,includingneuronalapoptosis,reductionofsynaptic structuralproteinpostsynapticdensity(PSD-95)andsynapticfunctional protein N-methyl-D-aspartate(NMDA)receptorsubunits(NR2B)(9). Figure1 depictsthepotentiallinksbetweenairpollutionandASD.

PotentialMechanismsbyWhichAirPollutantscanCauseASD NeuroinflammationandOxidative/NitrosativeStress

Neuroinflammationiswidelyrecognizedasakeyriskfactorinneurologicaldisorders.Duringpregnancy,inhaledairpollutantslikePMcaninduce asystemicinflammatoryresponseinthefetusandcauseneuroinflammationinthedevelopingbrain.Withtheblood–brainbarrierimmature,PM candirectlyenterthefetalbrain,triggeringinflammationinastrocytes andmicroglia.Thiswouldreleaseproinflammatorycytokinesandactivatekeyinflammatorypathways,suchasJNKandnuclearfactor-kappaB (NF-κ B)(10).PollutantslikeNO2 andPM2.5canstimulatetoll-likereceptors(TLRs),particularlyTLR4,directly(11)orthroughoxidativestress (12),inducinganimmuneresponse.Thisactivationleadstodownstream signalinginvolvingNF-κ B,acriticaltranscriptionfactormodulatingnumerousinflammatorygenes’expression.ChronicactivationofNF-κ Bresultsinsustainedinflammationandhasbeenlinkedtoneurodevelopmentaldisruptionsbyalteringthebalanceofpro-andanti-inflammatory mediatorsinthebrain(11).Themitogen-activatedproteinkinase(MAPK) signalingpathwayisalsohighlyresponsivetoenvironmentalstressors likeairpollutants.ExposuretoPM2.5canleadtothephosphorylationof extracellularsignal-regulatedkinase,partoftheMAPKpathway,whichis acrucialmediatorofinflammation(13).

Inthecentralnervoussystem,MAPKactivationinmicrogliaandastrocytesresultsinthesecretionofproinflammatorycytokineslikeTNF-α

1 InstituteforDrugResearch,SchoolofPharmacy,FacultyofMedicine,TheHebrewUniversityofJerusalem,EinKarem,Jerusalem9112102,Israel; 2 RosamundStoneZander TranslationalNeuroscienceCenter,andDepartmentofNeurology,BostonChildren’sHospital,HarvardMedicalSchool,Boston,MA02115,USA

CorrespondingAuthor: HaithamAmal.E-mail: haitham.amal@mail.huji.ac.il

Received:12October2024.Revised:1November2024and2November2024and4November2024.Accepted:5November2024. Publishedonline:12November2024.

andIL-6,contributingtoneuroinflammationandlikelyalteringsynapticplasticityinregionsimplicatedinASD,suchastheprefrontalcortex.Thesestressescanalsoimbalancetheexcitatory(glutamate)andinhibitory(gamma-aminobutyricacid[GABA])neurotransmittersystems,a commonoccurrenceinASD(4).Studieshaveshownthatairpollutionmediatedoxidativestresshasbeenlinkedtochangesinneurotransmitterlevels.Thelevelsofthekeyneurotransmittersofthereward processingandmotorfunction,dopamineandserotonin,canbediminishedbyairpollutantsinthestriatum(14)causingimpairmentsofthese functions,characteristicofASD.Additionally,airpollutionexposurehas beentiedtoreductionsinnorepinephrineanddopamineintheprefrontalcortex,whichmayimpairexecutivefunctionanddecision-making abilities(14).

ProlongedneuroinflammationtriggeredbyNOexposurehasbeen showntoinfluencetheactivityofbrainregionsinvolvedinsocialandcognitivefunctions,whicharecommonlyimpairedinASD(4).ExogenousNO andNO2 canincreasethebrain’sNOlevel,affectingtheNOsignalingpathways.IndividualswithageneticpredispositiontoASDmaybemorevulnerabletotheharmfuleffectsofNOexposure.Thus,ithasbeenfound thatmutationsofgenesinvolvedinthedetoxificationofoxidativestress orregulatingNOsignalingmayexacerbatetheimpactofenvironmental factorslikeairpollution,contributingtothedevelopmentofASDingeneticallysusceptibleindividuals(1).

Airpollutionexposureduringpregnancycanactivatethemother’simmunesystem,leadingtoinflammationandalteredfetalbraindevelopment.Elevatedconcentrationsofinflammation-relatedcytokinesinmaternalserum inutero andchildrenduringtheirearlylifeareassociated withworseneurodevelopmentaloutcomes(15).Maternalimmuneactivationcanleadtothereleaseofdifferentcytokines(e.g.,IL-1b,IL-6,IL-10, andTNF-α ),alteringbrainconnectivityandresultinginASD-likebehavior inoffspring(15, 16).

EpigeneticModifications

Airpollutioncancauseepigeneticchanges,suchasDNAmethylationand histonemodification,thataltergeneexpression.Thesemodificationscan affectgenesrelatedtobraindevelopmentandimmunefunction,increasingtheriskofASD(17).

GlutamatergicandGABAergicSystems

Airpollutionhasbeenshowntoaffectneurotransmittersystems,includingglutamateandGABA,whicharecrucialforneuralsignalingandsynap-

ticplasticity(18).Studieshaveshownincreasedtotalfrontalcortexglutamate,glutamine,andGABAlevelsinbothsexesafterpostnatalexposuretoairpollutants.Theyimpactbrainglutamatelevelsandaffectdevelopingandadultmicrogliawithglutamatereceptors,whichcanleadto glutamatereleaseuponmicroglialactivation(18).Thisrelease,inturn, activatesmicroglia,creatingacyclethatpotentiallydriveschronicinflammation(18).ImbalancesintheglutamatergicandGABAergicsystemsare commonlyobservedinindividualswithASD(4, 19).Airpollutantshave beenshowntodisruptthenormalformationandpruningofsynapses duringearlybraindevelopment,leadingtoalteredbraincircuitsthatare associatedwithASDsymptoms(18).

EndocrineDisruption

Someairpollutants,likePM2.5andPM10,actasendocrinedisruptors, affectinghormonelevelscriticalforbraindevelopment(20).Disruptions inhormonessuchasestrogenandthyroidhormonesduringcriticalperiodsofbraindevelopmentcanleadtoneurodevelopmentalabnormalities, includingASD(20).

TheDysregulatedMetabolicPathways

Epidemiologicalstudieshaveshownthatairpollutionexposurecancause dysregulatedmetabolicpathwaysandincreasetheriskofASD(21). Metabolicdisruptionsinfattyacids,aminoacids,neurotransmitters,and microbiomeprocesseshavebeenassociatedwithbothshort-andlongtermairpollutionexposure,increasingtheriskofASD.Studyingthese metabolicdysfunctionsoffersinsightsintoASDetiologyrelatedtoairpollution,particularlyduringtheperinatalperiodwhenneurodevelopment ishighlyvulnerabletooxidativestressandinflammation(21).

BiomarkersofAirPollutionwithHighRisktoASD

BiomarkerscouldhaveheldpromiseforearlyASDpreventionbyidentifyingindividualsathighriskduringprenatalorpresymptomaticstages. Thiswouldenableearlyinterventiontoaddressneurodevelopmentalabnormalitiesoravoidenvironmentaltriggerslikeexposuretoairpollutants.Todate,nostudieshavefocusedonbiomarkersthatspecificallyreflecttheimpactoftheairpollutantsthatposeariskofASD(22).NOis bothanendogenoussignalingneurotransmitterandapollution-related molecule.DysregulationinNOsignalingpathwayshasthepotentialtoofferearlybiomarkersforASDriskrelatedtoairpollutionexposure.One suchbiomarkercouldbe3-nitrotyrosine,whoselevelsareincreasedin thebloodplasmaofASDchildrenasaresultofnitrosativestress(23, 24). ChangesinthebloodbalanceofGABAandglutamate(19)andincreased levelsofIL-6(22),asdiscussedabove,canalsoindicateanearlyresponse toairpollution.ElevatedexpressionofC-reactiveproteinduringpregnancyappearstobesignificantlyassociatedwithneuroinflammationand anincreasedASDriskintheoffspring(25).Anotherpossiblemarkerismicronuclei.Theyindicatethepresenceofinitial(andreversible)alterations inthechromosomalstructureandoxidativedamagetoDNAcausedby airpollution(26).IdentifyingaspecificbiomarkeroragroupofbiomarkersmayofferearlyindicatorsofASDriskduetopollutionexposure. Thepathogenicmechanismslinkingairpollutantstoautismspectrum disorderriskfactorsaresummarizedin Figure2

FuturePerspectives

Numerousstudiesclearlyshowthatairpollutionplaysasignificantrole inASDandshouldbeconsideredamongtheemergingriskfactorsfor thisdisorder.Yet,themechanismsunderlyingtheinvolvementofthese factorsinASDpathogenesisarenotfullyunderstood(27–29).Fromthis viewpoint,therelationshipsbetweenairpollutantsandASDwarrantfurtherinvestigation.Sinceairpollutionisamixtureoftoxins,theyhavedifferentbiologicaleffectsonASDdevelopment.Studyingvariousairpollutants’cumulative/synergisticeffectswouldbeparticularlyinteresting. Theimpactofairpollutantsonneurogenesisandneurondevelopment atdifferenttimewindowsisalsoessential.Intheearlyprenatalstage (firstandsecondtrimester),neuralstemcellsproliferatetoformneuronsandglialcells.Themid-prenatalstage(secondtrimester)involves neuronalmigration,whereneuronsdrifttotheirdesignatedplaceand formstructures.Synaptogenesisoccursinlateprenatalandearlypostnatalneurondifferentiation(30).Airpollutantscanaffectneurondevelopment,migration,differentiation,andsynapseformationduringthese

Figure1. IllustrationofthelinkbetweenairpollutionandASD.

Figure2. MolecularandcellularpathwayslinkingairpollutantstoASDdevelopment.ThediagramillustratesthecomplexcascadeofbiologicaleventsconnectingenvironmentalairpollutantstoASDriskfactors.Beginningwithprimarypollutantsfromindustrialandvehicularsources(showninverylightsage),the pathwaytraceshowspecificcompoundsincludingPM2.5/PM10,nitrogenoxides,sulfurdioxide,ozone,andbenzene(highlightedinverylightblue)influence neurodevelopmentduringcriticalexposurewindows.Thewindows,emphasizedinsagegreen,encompassbothprenataldevelopmentandearlychildhoodperiods(verylightgreen),duringwhichthedevelopingbrainisparticularlyvulnerable.Thediagramthenrevealstheintricatepathogenicmechanisms(medium lightblue)triggeredbytheseexposures,includingneuroinflammation,oxidative/nitrosativestress,epigeneticmodifications,excitation/inhibitionimbalance, andendocrinedisruption(showninlightochre).Thesemechanismsconvergetoinducemolecularchangesthatmanifestasincreasedinflammatorycytokines, enhancedoxidativedamage,DNAmethylationalterations,andGABA/glutamateimbalance(depictedinsoftpink).Thebrightyellowheaderemphasizestheprimaryairpollutants,whilethesoftorangeendpointhighlightstheculminationinASDriskfactors,creatingavisualprogressionfromenvironmentalexposureto neurobiologicalimpact.Thecolor-codedframeworkhelpstracktheprogressionfromexternalenvironmentalfactorsthroughbiologicalmechanismstoclinical outcomes,emphasizingthemultifacetednatureofpollution-inducedneurodevelopmentaldisruption. timewindows.Airpollutantsinpostnatalorchildhoodperiodscanalso affectsynapticpruning,impairglialfunction,andcauseneuroinflammation(10, 18).

Differentconfoundingfactorsshouldbeconsideredwhilestudying thelinkbetweenairpollutantsandASD.Thesefactorsmayincludemicrobiome,nutrition,financialstate,educationlevel,socialaspects,and workplaces.Lifestylefactors,suchasactiveandpassivesmokinginpregnancy,alsoneedtobetakenintoaccount.Theycouldbepotentfactorsfor ASDpathogenesis.Itisalsoessentialtoconsidertheplaceofresidence andsocioeconomicposition,aspoorerneighborhoodsarelikelytoexperiencemorepollution,highervulnerabilitytothesefactors,andahigher riskofASD(26).Avoidingexposuretotheabove-mentionedenvironmentalriskfactorscouldpreventaconsiderablenumberofASDcases.Ultimately,mitigatingharmfulenvironmentalexposures,especiallyduring pregnancy,couldplayacrucialroleinpreventingnongeneticcasesofASD andimprovingpublichealthoutcomes.

Acknowledgments

WethankDr.IgorKhaliulinandMs.MaryamKartawyforcontributingto thediscussionofthisstudy,aswellastheSatellFamilyFoundationand theNeubauerFamilyFoundationfortheirsupport.

AuthorsContributions

SKOwroteadraftandcontributedtothediscussion.HAwasresponsible forideation,projectexecution,andsupervision.

FundingSources

ThisworkwasfundedbyaU.S.DepartmentofDefense(DoD)grant,a DFG—GermanResearchFoundationGrant,anIsraeliScienceFoundation (ISF)grant,anEaglesAutismFoundationgrant,aCaliforniaInstitutefor RegenerativeMedicinegrant,aNationalInstituteofPsychobiologyinIsrael(NIPI)grant,anIsraeliCouncilforHigherEducationMaofGrant,anda BerettlerCentreforResearchinMolecularPharmacologyandTherapeuticsGrant.

AuthorDisclosures

HAisaCSOofPoint6BioandNeuro-NOS.Nofundsfromeitherofthose twocompanieswerereceivedforthisstudy.SKOdoesnotholdanycompetinginterests.

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PERSPECTIVE

Amultimodalapproachfortreatingpost-acuteinfectioussyndrome

CharlotteSteenblock1 ,NicoleToepfner2 ,YannickP.Kok3 ,PhilipMavberg4 ,HorstBruckmoser5 ,AlfonsBreu6 ,JohannesKorth7 , HaraldHeidecke8 ,MiloA.Puhan9 ,andStefanR.Bornstein1 , 10 , 11

Long-termcomplications,suchasextensivefatigueandcognitiveissues,areknownfromvariousinfections,includingSARS-CoV-2,influenza virus,or Borreliaburgdorferi.Thepathologyismostlyunknownanddiffersbetweenpatients.Unfortunately,thereiscurrentlynocommonand effectivetreatment.Inthisperspective,weimplythatpost-acuteinfectioussyndromesareduetoavarietyoffactors,includingamongothers diminishedtissueperfusion,tissueinfiltrationbyviruses,inflammation,andoxidativestress,andthatnotonespecificbiomarkercanbeused tomeasurethesesyndromes.Thus,wesuggestthatascorebasedonanumberofcriteria/factorsshouldbeusedtoassesspost-acuteinfectious syndromes.Consequently,probablynotonesingletreatmentcanbeusedtotreatthisgroupofpatients,andwesuggestamultimodal treatmentregimencomprisingacombinationofpharmacotherapy,suchasmetforminandnaltrexonewithanti-inflammatoryeffects, alongsidephysicaltherapiessuchasextracorporealapheresisandtranscutaneousneurotherapy.Thiscombinedapproachaimstoreduce biomarkerlevelsandenhancecognitivefunctions.Thisimpliesthataresetofthesystemscanbeachievedbyamultimodalapproachbasedona scoreforpost-acuteinfectioussyndromes.

BrainMedicine January2025;1(1):35–41;doi: https://doi.org/10.61373/bm024p.0064

Keywords: Long-Covid,post-acuteinfectioussyndrome,COVID-19,SARS-CoV-2,virus,therapy

Introduction

AftertheCOVID-19pandemic,anumberofpatientsexperiencepersistentsymptomsandphysiologicalchangesevenafterrecoveringfrom theacutephaseofthedisease(1).Thepotentialsymptomscovera broadspectrum,includingfatigue,breathlessness,headaches,sleepdisturbances,difficultyconcentrating,cognitiveissues,skinrashes,diarrhea, andtinnitus(2–4).SARS-CoV-2causingCOVID-19isnotuniqueinthis abilitytocausepost-acutesequelae.Variousotheracuteinfections,includingEbola,polio,dengue,butalsoinfluenzaorbacterialinfections, suchas Borreliaburgdorferi,whichmightgiverisetoLymediseasesyndrome(5),havebeenlinkedtoanunexplainedchronicdisabilityinasubpopulationofpatients(6).Post-acuteinfectioussyndromes(PAIS)arenot new;theyusuallycometoattentionwhenmanypeopleareinfected,such asduringpandemics,andhavebeendescribedsincetheRussianflu(7). TheconsistentsymptomprofilesacrossdifferentPAIS,regardlessofthe infectingagent,alongwiththeoverlappingclinicalfeatureswithmyalgic encephalomyelitis/chronicfatiguesyndrome(ME/CFS),indicatethepotentialcontributionofasharedetiopathogenesis(8).

TheprevalenceofPAISdependsonthepathogenandvariesfromafew percentagesinpatientshavinghadinfluenza(9)toupto70%ofpatients withpersistentsymptoms2yearsafterinfectionwithWestNilevirus (10).ForLong-Covid,theevidencesuggeststhat,beforetheintroduction ofthevaccines,about20%ofpatientsdiagnosedwithCOVID-19and5–10%ofallinfectedpersonsdevelopedlong-termcomplications(11–14), whichfellbelow5%withtheintroductionofvaccinesandnewvariants likeomicron(15, 16).Interestingly,womenseemtohaveahigherprevalence(6),whichmightatleastpartlybeexplainedbythefactthatwomen aregenerallymoresusceptibletoimmune-mediatedconditions(17).The recoveryperiodforpatientswithLong-Covidmayvarysignificantlydependingontheseverityofthedisease,hospitalization,comorbidities,and age(11, 18).

ThepersistentsymptomsexperiencedbypatientswithPAIScanresultinsignificantfinanciallosses,affectingindividuals,businesses,and economiesglobally.Furthermore,syndromesfollowingacuteinfections cangreatlydiminishqualityoflife,aschronicsymptomsmayresultinlost productivity,increasedhealthcarecosts,andmentalhealthissues,allof whichcaninterferewithpersonal,social,andprofessionallife.HealthdisparitiesrelatedtoPAIShavebeenshowntoparticularlyaffectracialand ethnicminorities.Thesedisparitiesaredrivenbyfactorssuchassocioeconomicstatus,discrimination,andlimitedaccesstohealthcare.Theyare notconfinedtospecificregionsbuthaveglobalimplications(18).

FactorsResponsibleforPAIS

TheunderlyingmechanismsforPAISremainpoorlyunderstoodbutthe currenthypothesesproposedtoelucidatetheconsequencesofchronicfatigueandpost-exertionalmalaiseinpatientswithLong-Covidencompass diminishedtissueperfusion(19),viralinfiltrationoftissues,inflammationinboththebrainandperipheralorgans(20),theprolongedpresence ofSARS-CoV-2spikeproteins(21),andthereactivationofotherinfectiousagentssuchasEpstein–Barrvirus,cytomegalovirus(CMV),andvariousotherinfectiouscomponents(22–26).

Furthermore,recentfindingsdemonstratethatheightenedlipidlevelsrepresentasignificantriskfactor(27–29).Likewise,Long-Covidinducesasubstantialelevationinlipids,posingalong-termriskforcardiovasculardisease(30).Recently,itwasdemonstratedthatinpatientswith Long-Covid,apersistentdysregulationandactivationofthecomplement systemcouldbeobserved(31).Moreover,thromboinflammatoryproteins wereincreasedinLong-Covid(31).

Changesinbloodcellularcomponents(32–34)andtherarefactionof vessels(35)havealsobeenproposedaspotentialfactorscontributing totheonsetofLong-CovidsubsequenttoSARS-CoV-2infection.Interestingly,twodistinctbloodmarkerprofilesduringtheacutephaseof

1 DepartmentofInternalMedicineIII,UniversityHospitalCarlGustavCarus,TechnischeUniversitätDresden,Dresden,Germany; 2 DepartmentofPediatrics,UniversityClinic CarlGustavCarus,TechnischeUniversitatDresden,Dresden,Germany; 3 INUSLaboratoriesAG,Horgen,Switzerland; 4 AyusMedicalBaselAG,Basel,Switzerland; 5 MICROMEDICALInstrumenteGmbH,Senftenberg,Germany; 6 BREUGmbH,Putzbrunn,Germany; 7 DialysepraxisamKortumpark,Bochum,Germany; 8 CellTrendGmbH,Luckenwalde,Germany; 9 Epidemiology,BiostatisticsandPreventionInstitute,UniversityofZurich,Zurich,Switzerland; 10 SchoolofCardiovascularandMetabolicMedicineand Sciences,FacultyofLifeSciences&Medicine,King’sCollegeLondon,London,UK; 11 DepartmentofEndocrinology,DiabetologyandClinicalNutrition,UniversityHospital Zurich(USZ)andUniversityofZurich(UZH),Zurich,Switzerland.

CorrespondingAuthor: CharlotteSteenblock,DepartmentofInternalMedicineIII,TechnischeUniversitätDresden,Fetscherstrasse74,Dresden01307,Germany. Tel.: +49-351-458-16130;E-mail: charlotte.steenblock@uniklinikum-dresden.de Received:26April2024.Revised:2August2024and7August2024.Accepted:12August2024. Publishedonline:30August2024.

Figure1. Metabolicandendocrinestressactivation.Theendocrinestressaxis,whichcanbetriggeredbyvariousfactorssuchaspsychologicalstress,physical exhaustion,ormetabolicdiseases,playsapivotalroleinthebody’sresponsemechanisms.Whentheendocrinestressaxisispersistentlyactivated,thebody’s immunesystemcanbecomecompromised,leadingtoheightenedsusceptibilitytoinfections.Chronicorexcessiveinflammationcanleadtotissuedamageand celldeath,whichmightaggravateorinitiatemetabolicandendocrinedisorders,thusperpetuatingaviciouscycle.Createdwith BioRender.com

COVID-19havebeenassociatedwithcognitivedeficitsupto1yearafter theacuteinfectionwithSARS-CoV-2.Oneiselevatedfibrinogenandthe otheriselevatedD-dimer,bothinrelationtoC-reactiveprotein(36). Otherstudieshaveshownthatplasmasamplesfrompatientswithboth acuteCOVID-19andLong-Covidcontainlargeanomalous(amyloid)deposits(microclots)thatareresistanttofibrinolysis(37).

TheemergenceofautoantibodiesagainstG-proteincoupledreceptorshasraisedconcernsabouttheirpotentialinvolvement,giventheir pathogenicroledemonstratedinvariousautoimmunedisorders(38).Particularlynoteworthyistheimplicationofautoantibodiestargetingneurotransmitters,suchas β -adrenergicreceptors,whichhavebeensuggestedtoimpacttheseverityofCOVID-19andcontributetoLong-Covid (6, 39).Furthermore,increasedlevelsofautoantibodiesagainstproteaseactivatedreceptor-1(PAR-1),whichpromotesplateletactivation,has beenlinkedtosevereCOVID-19(40–42),suggestingthattheseautoantibodiescouldalsoplayaroleinLong-Covid.

Ithasbeenspeculatedthattheactivationofinterferon(IFN)signalinglinkedtoSARS-CoV-2couldtriggertheproductionofautoantibodiestargetingtypeIIFNs(17)andexacerbatelocalinflammation(18, 19), therebypossiblycontributingtothemanifestationofPAIS.

Nonetheless,ourresearch,alongwithothers’,suggeststhatfunctionalautoantibodiesagainsttypeIIFNsareunlikelytocontributetothe pathogenesisofLong-Covid(43, 44).Additionally,weobservednocorrelationbetweenLong-CovidfatiguescoresandIFN-stimulatedgenesignatures(43).

TheEffectofMetabolicandEndocrineDiseasesonPAIS

Metabolicandendocrinedisorders,aswellaschronicstress,cantriggeractivationofthehypothalamic-pituitary-adrenal(HPA)axis,resultingindysregulatedcortisolrelease.Moreover,theymayimpactthe

renin-angiotensin-aldosteroneandthesympatho-adrenomedullarysystem(45).Additionally,stimulationoftheneuroendocrinestressaxiscould resultinpersistentlow-gradeinflammationthroughoutthebody(45). Forinstance,bothstressandobesityappeartoexertcomparableeffectsonbrainfunction,attributedtothepresenceofneuroinflammationobservedinbothcircumstances(46, 47).Chronicinflammationand imbalancebetweenproinflammatoryandanti-inflammatoryfactorsin endocrineandmetabolicdiseasesandinstressincreasesthesusceptibilityforadditionalpathogenicinfections,whichmayleadtoanabnormalimmuneresponsereachingpathogeniclevels(48),whichinturnincreasestheriskofexperiencingPAIS.Thedirectinfectionofendocrine organs,suchaspancreaticislets(49–52),adipose(53–56),oradrenaltissue(57)mayleadtonewonsetofendocrinediseases(58).Moreover, theinitialviralentryandreplicationincellsofmetabolicandendocrine organscaninducedirectdamage,ultimatelyresultingincelldeath,eitherthroughtheimmunesystem’sactivationortheinitiationofcellautonomousdeathsignalingpathways(Figure1).Additionally,immune cellsactivatedtoproduceantibodiesorcytokines,alongwithinfected cellsreleasingbiomolecules,mayalsoaffectnoninfectedcellslocallyand indistanttissues(59).

Inconclusion,PAISimpactsvariousorgansystemsandmultiplemutuallynonexclusivebiomedicalexplanationsforthepathogenesisofPAIS canbehypothesized(60),whichaloneorincombinationmightberesponsibleforthedevelopmentofPAIS.Theyprobablyinvolveunregulatedimmuneresponse,persistentgenerationofproinflammatorycytokines(chronicinflammation),autoimmune-likereactions,persistent viralreplication,andmicroclotformation(61).Thus,managingPAIS involvesaddressingarangeofsymptomsthatincludephysical,cognitive,andpsychologicalaspects.Consequently,werecommendmeasuringapanelofbiomarkerstoobtainaclinicalindicationfortreatment

inpatientsseverelyaffectedbyPAIS.Furtherresearchinvolvinglarge groupsofpatientswithandwithoutPAISisneededtodetermineexactly whichbiomarkersshouldbeincludedinsuchascoreandtheirrespective weights.

PotentialTreatmentsofPAIS

SeveralpotentialtreatmentsforLong-Covidhavebeenexplored(62)and recently,asystemicreviewofallregisteredclinicaltrialsfortreatment ofPAISwasconducted(63).Thisstudyshowedthatwhilemostresearch focusesonmonotherapies,acombinationofinterventionsisalsobeingexamined.Bothpharmacotherapiesandrehabilitativeapproachesbut alsopsychotherapyorcomplementaryandalternativemedicineisbeing tested(63, 64).Mostofthesestudiesarestillrunningandbecauseofthe heterogeneityamongthestudies,itisextremelydifficulttodrawaconclusionatthispoint.BecauseofthecomplexityofsymptomsofPAIS,also thetreatmentischallengingandprobablynotonesingletreatmentcan beusedforallpatientsexhibitingPAIS.Here,wewilldiscusssomeofthe treatmentsthathaveshownapositiveeffectonLong-Covid.Currentor emergingtreatments,suchasnutritionalsupplementsorrestorationof thegutmicrobiota,willnotbediscussedhereastheyhavebeenrecently describedelsewhere(62).

Metformin

OneofthepharmaceutictherapiesthatshowsapositiveeffectonLongCovidisthetreatmentwithmetformin.Worldwide,metforministhefirstlinedruginthetreatmentoftype2diabetesmellitus(65)duetoits effectiveness,safety,andaffordability(66).

Apartfromitsabilitytoinhibitgluconeogenesisandenhanceinsulin sensitivity,metforminhasbeenrecognizedasapowerfulsuppressorof thechronicinflammatoryresponseinmacrophages.Inacuteinflammation,metforminreducesthetranscriptionofinterleukin(Il)1b and Il10 by activatingAMP-activatedproteinkinase(AMPK)(67),whereasinchronic inflammation,itreducestheproductionofreactiveoxygenspecies(ROS) bymitochondria,whichleadstoareductioninthelevelsofHIF1-α and resultsindecreasedexpressionof Il1b,whereasexpressionof Il10 isenhanced(68).RecentstudiesdemonstratedthattheSARS-CoV-2spike protein1induces α -synucleinopathythroughmicroglia-mediatedinflammationandmitochondrialROS,whichcanbesuppressedbymetformin (69).Thisabilityofmetformintoreducethelevelsofinflammatorymarkershasledtothehypothesisthatmetformincouldbeusedforthe treatmentofLong-Covid.Furthermore,targetedmachinelearninganalysisindicatedthatmetforminuseisassociatedwithareducedriskof post-infectionmortalityinCOVID-19–positivepatients(70).Indeed,ina double-blindtrial,adultswithoverweightorobesityandSARS-CoV-2infectionwhotookmetforminfor2weekswerelesslikelythanthosewho tookaplacebotolaterreportadiagnosisofLong-Covid(71).Similarfindingswereobservedinastudyassessingthe3-monthand6-monthriskof PAISinpatientswithtype2diabetesmellitus.Thisstudycomparedmetforminuserswiththoseusingsulfonylureasordipeptidylpeptidase-4inhibitorsandfoundthatmetforminusershadalowerriskofPAIS((72). TheseresultssuggestthatadditionalinterventionsaimedatreducingmitochondrialROSproductionshouldbeidentifiedandsubjectedtofurther investigation.

Low-doseNaltrexone

Anotherpromisingtherapyislow-dosenaltrexone(LDN)(73).Naltrexone isanoral μ-opioidreceptorantagonist.ItisFDAapprovedforthetreatmentofopioidandalcoholdependencestandardlyinhighdosesof50–150mg/day.Inlowdosesof1–5mg/day,opioidreceptorsignalingisnot completelyblocked,whichleadstoendogenousproductionofopioidsand opioidreceptors.TheseendogenousopioidsmodulatetheimmunesystembyinhibitingtheproliferationofBandTcells(74).Furthermore,on immunecells,LDNisaspecificantagonistforToll-likereceptor4,thereby inhibitingtheproductionofproinflammatorycytokines(75).

Theanti-inflammatoryeffectsofLDNhavebeenwidelyusedoff-label forthetreatmentofautoimmunediseasesandpainindiseasessuchas multiplesclerosis,Crohn’sdisease,andfibromyalgia(73, 76–78).Inaddition,LDNhasbeenappliedforthetreatmentofME/CFS(79, 80).Recently, LDNwastestedfortreatmentofLong-Covid,whereitdemonstratedto

haveapositiveeffectonclinicalsymptomsandself-reportedmeasures offatigue(81–84).

ExtracorporealApheresis

Apheresisinvolvestheextracorporealextractionoftargetedbloodconstituents,suchasparticularcellsorspecificplasmacomponents.Originallydevisedforeliminatinglipidstoaddressseveredyslipidemias andautoantibodies,methodsforremovingvariouspathogenicmolecules fromplasmahaveyieldedsurprisingadditionalbenefits.Subsequentresearchrevealedthecapacitytoenhancebloodviscositybyeliminatinghighmolecularweightproteins,reduceoxidativestressbyremoving oxLDL,mitigateinflammationbyextractingcytokinesandinflammatory lipidsandeliminateautoantibodies(85–88).

Upto70%ofpatientswithME/CFS,includingpatientswithLongCovid,reportedasignificantimprovementintheirsymptomsafterextracorporealapheresis(89).Wedemonstratedthatpatientswhoreported significantimprovementaftertwocyclesoftherapeuticapheresisshowed asubstantialreductioninneurotransmitterautoantibodies,lipids,andinflammatorymarkers.Additionally,weobserveda70%decreaseinfibrinogenlevels,anddarkfieldmicroscopyrevealedthaterythrocyterouleaux formationandfibrinfiberslargelydisappearedpost-apheresis(90).However,randomized,sham-controlledtrialsthataresufficientlypowered andincludepsychologicalandphysiologicaloutcomesarestilllacking.

TranscutaneousElectricalNerveStimulation

Fornontranspondersofpharmacotherapy,alternativestrategiesareimportant.Asmentionedabove,PAISisacomplexconditioncontaininga neurologicaldimensionbutalsocognitiveandaffectivesymptomsthat mightnotbepharmacologicallytreated.Fortreatmentofthesepatients, noninvasivebrainstimulation,andinparticularauriculartranscutaneous nervestimulation(atVNS)hasbeensuggested(91).atVNSisabrainstimulationtechniqueprimarilyusedasatreatmentforepilepsyanddepression,butitisalsobeingexploredforotherconditionslikemigrainesand Alzheimer’sdisease(92).

TheexactmechanismofhowVNSworksisnotfullyunderstood,but it’sthoughttomodulatebrainactivityandthereleaseoftheneurotransmittersgamma-aminobutyricacidandnoradrenaline(93).Furthermore, HPAaxisactivationisinhibited(94–96).Inaddition,anti-inflammatory effectsofatVNSaremediatedviathe α 7nicotinicacetylcholinereceptor (97),whichleadstomodulationofcholinergicanti-inflammatorypathwaystherebyinhibitingthereleaseofcytokines,suchasTNF-α intheprefrontalcortex,hippocampus,andhypothalamus,thussuppressingneurologicalinflammation(98).

ApilotrandomizedcontrolledtrialofatVNSshowedatrendsuggestingthatatVNSmayhavemildtomoderateeffectinreducingmentalsymptomsinasubsetofpatientswithLong-Covid(99).Another pilotstudyinvolving24femalepatientswithLong-Covidshowedsignificantimprovementsinvariouscognitivefunctions,anxiety,depression, andsleepimmediatelypost-intervention,withbenefitspersistingorincreasingatthe1-monthfollow-up.Improvementsinfatigueweredelayed,achievingstatisticalsignificanceatthe1-monthfollow-upcomparedwithbaseline(100).Thesefindingssupportallocatingresourcesto conductfurthertrialsandadvancetheunderstandingofatVNSasapotentialtreatmentforLong-Covid.

MultimodalTreatment

GiventheabsenceofasingledefinitivebiomarkerforPAIS,andrecognizingthesignificantheterogeneityamongpatientswithPAIS,wepropose apragmatictreatmentapproach.Ourrecommendationinvolvesamultimodaltreatmentregimencomprisingacombinationofpharmacotherapy,suchasmetforminandnaltrexonewithanti-inflammatoryeffects, alongsidephysicaltherapiessuchasrehabilitativemeasures,extracorporealapheresisandtranscutaneousneurotherapy.Thiscombinedapproachaimstoreducebiomarkerlevelsandenhancecognitivefunctions. Selectioncriteriaforthistreatmentshouldbebasedonpresentingsymptomsandabiomarkerpanelscore(Figure2).Asmentionedabove,additionalresearchisnecessarytoidentifythespecificbiomarkersthatshould bemeasuredandtoestablishthethresholdscoresfordiagnosingLongCovidorotherPAIS.

Figure2. MultimodalstrategyfortreatingPAIS.AsPAISappearstobemultifactorialinnaturewithawidevarietyofsymptoms,weproposeanapproachinvolving themeasurementofapanelofbiomarkerssuchasdifferentbloodparameters,complementfactors,inflammationmarkers,orneurotransmitterautoantibodies. Iftwoormoreofthesebiomarkerstestpositive,werecommendimplementingacombinedapproachcomprisingbothpharmaceutical(e.g.,metforminornaltrexone)andphysicalinterventions(e.g.,extracorporealapheresisorauriculartranscutaneousnervestimulation).Furthermore,rehabilitativemeasuresaddressing bothphysicalandpsychologicalneedsshouldbeconsidered.Createdwith BioRender.com

Ideally,thesuggestedmultimodaltreatmentshouldbeaccessibleto everyone.Sincebothmetforminandnaltrexonearerelativelyinexpensive,providingthepharmaceuticalcomponentshouldbefeasible.However,accesstospecialistsofferingextracorporealapheresisoratVNSis limited,makingthesecomponentschallengingtoimplement.Thisunderscorestheneedforinclusivehealthcarestrategiesandsupportforall communitiesworldwide.

Conclusion

Long-termcomplicationsareknownfromvariousinfections.Thepathologyismostlyunknownanddiffersbetweenpatients.Unfortunately,currentlythereisnocommonandeffectivetreatment.Limiteddataonthe prevalenceandoutcomesofunexplainedPAISmakeinterpretationdifficult.Theabsenceofcomprehensive,prospectivestudieswithlongtermfollow-ups,objectivemeasures,andappropriatecontrolgroups, alongwithsmallsamplesizes,obscurescaseoutcomes.Methodologicaldifferencesandvariedsymptomcriteriafurtherhindercomparisonacrossstudies,makingitchallengingtodrawdefinitiveconclusions aboutprevalenceaccuracyandlong-termprognosis.Thisdatagapunderminesfoundationalknowledgefordesigningclinicalstudiesandassessinginterventions’impactonpost-infectiouschronicdiseaseanddisability management.

TodevelopaclinicalscoringsystemforPAIS,multicenterstudiesinvolvingalargerpatientcohort,inclusiveofthosewhohavenotresponded totreatment,willbeimperative.Thesestudieswillaimtocorrelateindividualbiomarkerswithtreatmentoutcomes.Specifically,multivariable analysiswillbeessentialforestablishingapracticalclinicalscoringsystemtomonitorbothshort-termandlong-termtreatmentefficacy.Moreover,amorecomprehensiveexplorationofdiseasemechanismsunderlyingLong-CovidandotherPAIScouldenhanceorsupplementtheexisting panelofclinicalbiomarkers.Furthermore,inthefuture,modernartificial

intelligence-basedtechnologies,particularlythoseemployingmachine learning,willbeideallysuitedtotailoranddefineindividualizedtreatmentprotocolsbasedonspecificmarkersforvariouspatientsubgroups afflictedwithpost-infectioussyndromes.

Inconclusion,acomprehensiveapproachisneededtoaddress globalhealthdisparitieswhilealsoencouragingspecialiststocombine well-establishedtreatmentswithpotentiallylesser-knowntherapiesto achieveoptimalresults.

AuthorContributions

CSandSRBwrotetheinitialdraftofthepaper.NT,YPK,PM,HB,AB,JK, HH,andMPwrotesmallersectionsoftheperspective.CSpreparedthe figures.AllauthorsreviewedsuccessivedraftsoftheReview.Allauthors approvedthefinalsubmittedversionandhadfinalresponsibilityforthe decisiontosubmitforpublication.

Acknowledgments

ThisworkwassupportedbytheGermanResearchFoundation(DFG, projectno.314061271andprojectno.288034826).

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Theassociationofdifferentacute manifestationsofmultiplesclerosison functionaloutcome

JoãoPedroF.Gonçalves1 ,AlexC.S.Figueiredo1 ,GabrielS.M.Nunes1 , CatarinaS.T.deAraújo1 ,MarivaldoY.S.Leal1 , # ,LuísaD.M.Aravena1 , # , FelipeA.B.Millard1 , # ,andPedroA.P.deJesus1 , 2

1 BiomorphologyDepartment,HealthSciencesInstitute,Federal UniversityofBahia,Salvador,Bahia40110-100,Brazil 2 CerebrovascularDivision,DepartmentofNeurology,RobertoSantos’ GeneralHospital,Salvador,Bahia40301-110,Brazil # Theseauthorscontributedequally.

CorrespondingAuthor: JoãoPedroFernandesGonçalves;Av.Reitor MiguelCalmon,S/N–ValedoCanela,Salvador–BA,40110-100,Brazil Phone: +55(71)98512-7890.E-mail: joaofernandes@ufba.br

BrainMedicine January2025;1(1):42–45; doi: https://doi.org/10.61373/bm024r.0073

Multiplesclerosis(MS)isanautoimmunedemyelinatingdiseaseof thecentralnervoussystem(CNS),typicallypresentinginyoungadults (20–50yearsold).Clinicalmanifestationsareheterogeneous,dependingonwhichpartoftheCNSdemyelinationoccurs.Therefore,this studyaimstoassesswhetherdifferentsymptomsatfirstacutemanifestationofMSareassociatedwithworsefunctionaloutcomes.We enrolledallpatientswithaconfirmeddiagnosisofMS,regardlessof thesubtype,solongasitfulfilledtheMcDonald’s2017criteria.Astepwisemultiplelinearregressionmodelincludedstatisticallysignificant (p < 0.05)variablesintheMann–WhitneyUtest.Atotalof195patientswithMSwereincludedinthefinalanalysis,ofwhich140(78.5%) werefemale.Acuteblurryvision,acuteparalysis,acutehypoesthesia, autonomicsyndrome,andLhermitte’ssignatdiseaseoutbreakwere foundtobeassociatedwithworseEDSS(ExpandedDisabilityStatus Scale)inunivariatetests.Inadjustedanalysis,theindependentpredictorsofworseEDSSwereacuteblurryvision(Beta = 0.183; p = 0.010) andautonomicsyndrome(Beta = 0.219; p = 0.003).Theseresultsmay helpbetterunderstandtherelationshipbetweenMSsymptomatology, functionality,andpatientprognosis,potentiallyassistingphysiciansin determiningMSpatient’sinitialtreatment.

Keywords: Multiplesclerosis,prognosis,functionaloutcomes.

Introduction

Multiplesclerosis(MS)isanautoimmunedemyelinatingdiseaseof thecentralnervoussystem(CNS),typicallypresentinginyoungadults (20–50yearsold).MSaffectsaroundtwotothreetimesmorewomenthan men.Thereare2.8millionpeopleintheworldlivingwithMS,withahigher prevalenceinNorthAmericaandEurope.ClinicalmanifestationsareheterogeneoussincedemyelinationcanhappeninanypartoftheCNS(1).It maycausephysicalandcognitiveimpairmentduringthedisease’sdevelopment,suchasfatigueandlossofself-efficacy.Therefore,MSprovokes significantdisabilityandharmfullyaffectspatients’functionalindependence.

Thecurrentliteraturelacksstudiesregardingclinicalfactorsassociatedwithpatients’personalexperienceswiththedisease.Therefore, healthprofessionalscoulddirectcaretominimizetheimpactofMSsymptomologyonthepatient’slifeandimprovefunctionality.Dataregarding theeffectofspecificsymptomsonfunctionalityandoutcomesareoften controversial,forexampleregardingtheeffectofparalysisandhypoes-

Table1. Demographicandclinicalcharacteristicsofthestudy population,includingdataregardingclinicalcourse,EDSSat admission,andnumberofrelapses.Thetablealsodetailsthe prevalenceofsymptomsatdiseaseonsetandtheirassociation withtheEDSSintheunivariateanalysis

Variables

Demographics

Age(mean;sd)39.89(11.57)

Sex

Male45(28.2%)

Female140(71.8%)

Race

Black44(22.6%)

Mixed90(46.2%)

White58(29.7%)

Clinicalcharacteristics

Clinicalcourse

Relapsing-remitting173(88.7%)

Primaryprogressive19(9.7%)

Unknown3(1.6%)

EDSSatadmission(median,IQR)2(1–4)

Numberofrelapses(median,IQR)2(1–4)

Yearssinceonset(median,IQR)8(5–13)

Symptomsofonset p-value

Acuteblurryvision77(39.5%) <0.001

Acuteblindness17(8.7%)0.257

Acuteparesis122(62.6%)0.167

Acuteparalysis22(11.3%)0.021 Acuteparesthesia131(67,2%)0.139

Acutehypoesthesia106(54.4%)0.005 Autonomicsyndrome71(36.4%) <0.001 Nausea34(17.4%)0.656 Vomiting22(11.3%)0.984 Ataxia107(54.9%)0.471 Cranialnervesdysfunction92(47.2%)0.993 Headache93(47.7%)0.659 Lhermittesign57(29.2%)0.017

SD = StandardDeviation;IQR = Interquartilerange.

thesiainfunctionality(2–4).Thus,thisstudyaimstoclarifytheassociationbetweentheseclinicalfeaturesandpatients’functionaloutcomes, evaluatedthroughtheExtendedDisabilityStatusScale(EDSS).

Results

Atotalof195patientswerediagnosedwithrelapsing-remitting(173patients,88.7%)andprimaryprogressiveMS(19patients,9.7%)andincludedinthefinalanalysis.Three(1.6%)patientshadtheclinicalcourse ofMSthatwasstillunderinvestigationatadmissiontothestudy.A totalof140patientswerewomen(71.8%),andtheaverageagewas 39.89 ± 11.57years.TheirmedianEDSSatadmissionwas2points(IQR 1–4)(Table1).Generalinformationaboutthesymptomsofthefirstacute manifestationofthediseaseisalsodescribedin Table1

Anunivariateanalysiswasperformedusingthesymptomsofthefirst acutemanifestationofthedisease,aswellasdemographicinformation suchassexandage.Fromthese,fivevariablesshowedstatisticallysignificantcorrelationwithworseEDSSatadmission,werethey:acuteblurry vision(U = 3204.5; p < 0.001; r =−0.251),acuteparalysis(U = 1326.5; p = 0.021; r =−0.165),acutehypoesthesia(U = 3444.5; p = 0.005; r =−0.204),autonomicsyndrome(U = 2696.5; p < 0.001; r =−0.325),

Received:20April2024.Revised:14August2024and6September2024.Accepted:10September2024. Publishedonline:24September2024.

Table2. MultiplelinearregressionanalysisshowingtherelationshipbetweensymptomsatonsetandtheEDSS.Thetableincludes unstandardized(B)andstandardized(Beta)coefficients,t-statistics,p-values,95%confidenceintervals,andoddsratios(OR)foreachpredictor

Acuteblurryvision0.8910.3410.1832.6140.0100.2191.5631.201

Acutehypoesthesia 0.0130.018

Acuteparalysis0.3910.5450.0520.7180.474

Autonomicsyndrome1.0880.3640.2192.9910.0030.3711.8061.245

Lhermittesign0.5230.3640.1001.4380.152

Std. = Standard.

andLhermittesign(U = 2617.5; p = 0.017; r =−0.181).Allvariables showedasmalleffectsize,excludingtheautonomicsyndrome,which showedamoderateeffectsize.

Thelinearregressionmodelincludedthefivevariablesthatshowed acorrelationwiththeEDSS.Thefinalmodelwasstatisticallysignificant (R2 = 0.117; p < 0.001),althoughwithalow R2 ,indicatingpoormodel fittodata.Twovariableswereshowntobeindependentpredictorsof worseEDSSatadmission:acuteblurryvision(Beta = 0.183; p = 0.010; IC95% = 0.219–1.563;OR = 1.201)andautonomicsyndrome(Beta = 0.219; p = 0.003;IC95% = 0.371–1.806;OR = 1.245).Therefore,patients withacuteblurryvisionorautonomicsyndromeatpresentationhave,respectively,20%and24.5%morechanceofdevelopingworsefunctional status.Theteststatisticsforeachvariableandthemodelaredescribed in Table2

Discussion

Thisstudyhighlightshowsomesymptomsatdiagnosisareassociated withworseprognosisbasedonEDSS,suchasacuteblurryvision,acute paralysis,acutehypoesthesia,autonomicsyndrome,andLhermittesign, althoughwithasmalleffectsize,exceptforautonomicsyndrome,which showedamoderateeffectsize.Inmultivariateanalysis,acuteblurryvisionandautonomicsyndromewereshowntobeindependentpredictors ofworseprognosis.

Asexpected,allsymptomsatfirstpresentationassociatedwithhigher EDSSareevaluatedbythescale,exceptfortheLhermittesign.Lhermitte’s signtypicallypresentsincervicalspinelesionsorlowbrainstemlesions (5).Thiscouldhelptoexplainwhythissignmightbeassociatedwith worseoutcomeswhileotherbrainstemsigns(suchascranialnerveimpairments)arenot.ApreviousstudytriedtoassessthecorrelationbetweenLhermitte’ssignandprognosticfactorsbutbaredunfruitfulresults (6).However,themaindifferencebetweenthepresentingstudyandthe previousisthemomentwhenLSwaspresent,whichinthelatterwasin anymomentofdisease.

AcuteblurryvisionatpresentationwasconsideredtobeanindependentpredictorofworseEDSSinourstudy.Besidesvisualacuitybeing evaluatedinEDSS,blurryvisionisasymptomdirectlyrelatedtopossible affectioninpathways,suchastheopticnerve.Somestudieshaveassociatedalterationsintheretinaandopticnerve,andevenacuity,withworse functionallymeasuredbyEDSS(7, 8).Thiscanbeexplainedbytheassociationofthesefeatureswithcentralinflammation,whichplaysasignificantroleinthepathophysiologyofMS(9).Furthermore,astudyshowed thatincreasingannualratesofatrophyoftheinnerretinallayersareassociatedwithworseningambulation,significantlyincreasingtheEDSS score(10).

Ourstudydefinesautonomicdysfunctionasurinaryorfecalincontinence/retention.Thesesymptomsarealsocorrelatedwithspinalsymptoms,whichcanalsobeassociatedwithgaitdisturbances,pyramidal, andsensitivesymptomsthusresultinginhigherEDSS(11–14).Another importantfeaturewhileinterpretingthisfindingisthatEDSSitself measuressphinctericdysfunctionsinceitisagreatcauseoffunctional

dependence,especiallybothfecalandurinaryincontinence(15).Moreover,urodynamicdysfunctionsignsareassociatedwithhigherEDSSin previousstudies(16–19).AlterationsintheanalsphincterwerenotassociatedwithdifferencesinEDDSinpreviousstudies(2).However,some olderstudiessuggestanassociationofsphincterinvolvementwithunfavorableprognosis(3).

Theeffectsofacuteblurryvisionandautonomicdysfunctionarenot tobetakenlightly.Theyshowed20%and24.5%increasedoddsofworse functionaloutcomes,respectively.Forinstance,manyclinicalvariables suchassex,ageatonset,andfamilyhistoryofMShavenosignificant effectonfunctionaloutcomes.Moreover,knownpredictorssuchasthe numberofrelapseshavesimilarorevenlowereffectsizesonlong-term disability(4).

AlthoughhypoesthesiaandparalysiswereassociatedwithworseEDSS intheunivariateanalysis,theireffectswerenotsignificantinthemultivariateanalysis.Asforhypoesthesia,thismayberelatedtoapossible relationshipbetweenhypoesthesiaanddynamicposturalcontrol(20), maybeleadingpatientstosubjectivelyassociatehypoesthesiaandataxia. AsataxiaisevaluatedintheEDSS,theeffectofhypoesthesiaintheunivariateanalysismaybeexaggeratedbyapossiblecorrelationwithataxia. Inapreviousstudy,sensorysymptomsdidnotaffectlong-termdisability outcomes(4).

Asforacuteparalysis,theevidencesupportingthisfindingiscontroversialintheliterature(3, 4).Weseeitascounterintuitivesincemotor functionisevaluatedthroughtheEDSS,andseveremotorimpairment hashigherpunctuationonthescale(15).Therefore,weexpectedpatients withacuteparalysistohaveworsefunctionaloutcomes.Morestudiesare neededtoconfirmordiscardthiscorrelationandtohelpunderstandwhy itmayhavehappened.

Inthissetting,thefindingsofourstudymaypotentiallyhelpphysiciansindefininginitialdisease-modifyingtherapies(21).Forexample, severemotororcerebellarinvolvementisconsideredacriterionofseverityofonsetandworseprognosis.Therefore,theseclinicalfeaturesare takenintoaccountwhendecidingontheinitialtherapyorchangingto high-efficacytherapies.Inthefuture,acuteblurryvisionandsphinctericinvolvementmayfurtherintegraterecommendationsinstratifyingtheriskofMSworsening,andforthisreason,impactmajorclinical decisions.

Ourstudyhassomelimitations.First,symptomsatonsetaresusceptibletomemorybiassincethepatientmayrecallmoreseveresymptoms thanothers.Thisisparticularlyimportantbecauseitmayerroneously overestimateorunderestimatethefrequencyofspecificsymptoms. Therefore,theassociationsfoundinthestudymaynotcorrespondperfectlytothedailybasisclinicalpracticereality.Second,weonlyassessed sphinctericsymptomstocharacterizeanautonomicsyndrome.However, othersymptomsrelatedtodysautonomiaarealsodescribedinMS.Other essentialelements,suchasthenumberofwhitematterlesionsandlocations,arenotcollectedinthisstudy.Also,thescaledirectlymeasures mostsymptomsthatshowedsignificantassociationwithEDSS.Forthat reason,otherfunctionalstatusscalescouldenhancethisanalysis.

Despitetheselimitations,thisstudycontributessignificantlytoinvestigationsandunderstandingofMSprogression.Theonlyfirstacute manifestationsofMSirrespectivelycorrelatedtoworsefunctionaloutcomeswereacuteblurryvisionandautonomicsyndrome.Althoughsome othersymptomsweresignificantlyassociatedwithhigherEDSS,suchas acuteparalysis,acutehypoesthesia,andLhermittesign,theywereshown nottobeindependentpredictorsofworsefunctionaloutcomes,probably becauseofinevitableinteractionswithfactorsthathadnotbeentaken intoaccountintheunivariateanalysis.Forthatmatter,theseresultsmay helpbetterunderstandtherelationshipbetweenMSsymptomatology andfunctionalityand,inspecificsettings,mayhelpthephysicianestablishthepatient’sprognosis.

However,furtherstudies,preferentiallyprospectivecohortsfromthe timeofdiagnosis,areneededtohelpestablishotherpotentialpredictors ofworsefunctionaloutcomes.Also,followingpatientssincethediagnosisand/orthefirstacutemanifestationofthediseasemaymitigatethe memorybiasandpotentiallyallowforobjectiveneurologicalexamination inthiscontext.Furthermore,othermodelsthatbetteraccountforconfoundingvariables,suchasdiseaseprogressionindicators(numberofrelapses,neuroimagingfeatures),mayprovideamorereliableassociation. Interventionalstudieswouldalsohelpexplorepossibleinterventionsto mitigatetheeffectoftheseindependentpredictorsoffunctionality.

Methods Participants

FromJanuary2019toMay2022,allpatientswithconfirmeddiagnosis ofMSbasedonthe2017McDonaldcriteriawereenrolledinaNeuroimmunologyDiseasesreferencedcenter(22).Exclusioncriteriawereasfollows:(1)laterdiagnosisofanotherneuroimmunologydiseasethatbetterexplainedthesymptoms;(2)diseaserelapsewithin3monthsbefore admissiontothestudy;(3)incompleteinformationaboutdemographic characteristicsandclinicalfeaturesofthefirstacutemanifestationofMS.

DataCollection

Generaldataincludedage,sex,diseaseduration(yearssinceonset),totalnumberofrelapses,andEDSSscore.Thefirstacutemanifestationof thediseasevariablesincludedvarioussymptoms,suchasacuteblurryvision,acuteblindness,acuteparesis,acuteparalysis,acuteparesthesia, acutehypoesthesia,autonomicsyndrome(definedasacutebladderdysfunctionoracutesphincterdysfunction),nausea,vomiting,ataxia,cranial nervesdysfunction,headacheandLhermittesign(describedasashockingortinglingsensationthatrunsthroughthelimbsortrunkduringneck flexion).

TheEDSSisthemostusedscaletoquantifydisability,clinicalprogression,andtherapeuticefficacyinMS.Itrangesfrom0(normalfunction andexamination)to10(death).Between1and10,theintervalsaredividedinto0.5points.Scoresbiggerthan6areassociatedwithMS-related deficits,andtheintervalbetween4and6ishighlyinfluencedbydeambulation(15).

StatisticalAnalysis

SPSS26.0statisticalsoftware(IBMCorp.,Armonk,NY,USA)wasusedfor thestatisticalanalysis.TheKolmogorov–SmirnovandShapiro–Wilktests wereusedtoanalyzewhetherthedatawerenormallydistributed.AunivariateanalysisusingtheMann–WhitneyUtestwasperformedtoassess theassociationbetweenclinicalanddemographicfeaturesandworse functionaloutcomes.TheMann–WhitneyUwasusedsinceourstudydeals withanordinaldependentvariable,theEDSS,andvariousdichotomous symptomsasindependentvariables.Effectsizeswereestimatedbythe “r”statistics,derivedfromthez-value,inwhicha r below0.3isconsideredasmalleffectsize, r between0.3and0.5isofmediumeffectsize, andabove0.5isconsideredalargeeffectsize.Astepwisemultiplelinear regressionmodelincludedstatisticallysignificant(p < 0.05)variablesin theMann–WhitneyUtestorthosewithclinicalplausibility.Multicollinearitywastestedandverified.

Thesamplesizewasestimatedbythemaximumpossiblenumberof independentpredictorsinthemultivariateanalysis,consideringthevariablesusedintheunivariateanalysis.Theestimativewasof154participants,basedon13independentpossiblevariables.

StudyApproval

ThisstudywasapprovedbytheEthicsCommitteeoftheUniversityHospitalProfessorEdgardSantos,CAAE:50819021.1.0000.0049.Informed consentwasobtainedfromallparticipantsbeforedatacollection.Data confidentialityisensuredbypassword-protecteddatabases,whichare onlyaccessedbytheauthorsresponsibleforthestatisticalanalysis.

DataAvailability

Dataavailabilityisrestrictedduetohumansubjectinvolvementandis non-public.Alldatausedintheanalysisareavailableuponreasonable requesttothecorrespondingauthor.

AuthorDisclosures

Allcontributorshaveconfirmedthatnoconflictofinterestexits.

AuthorContributions

Manuscript: JPFG,GSMN,MYSL,LDMA,FABM Idea: ACSF

Statistics: JPFG,CSTA,GSMN

Revision: CSTA,PAPJ

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OPEN RESEARCHREPORT

Ultra-shortheartratevariability reliabilityforcardiacautonomic toneassessmentinseveretraumatic braininjury

HiagoMuriloMelo1 , 2 ,NormaBeatrizDiazRangel1 , 2 , GuilhermeLoureiroFialho1 , 3 ,CristianeRibeirodeCarvalho1 , 2 , 6 , KatiaLin1 , 4 , 5 , 7 ,andRogerWalz1 , 2 , 4 , 5 , 7

1 CenterforAppliedNeuroscience,UniversityHospital(HU),UFSC, Florianópolis,SantaCatarina88035-972,Brazil

2 GraduatePrograminNeuroscience,UFSC,Florianópolis, SantaCatarina88035-972,Brazil

3 CardiologyService,DepartmentofInternalMedicine,HU,UFSC, Florianópolis,SantaCatarina88035-972,Brazil

4 NeurologyDivision,DepartmentofInternalMedicine,University Hospital,UFSC,Florianópolis,SantaCantarina,88035-972,Brazil

5 GraduatePrograminMedicalSciences,UFSC,Florianópolis, SantaCatarina88035-972,Brazil

6 ToxicologyDivision,DepartmentofPathology,UFSC,Florianópolis, SantaCatarina88035-972,Brazil

7 CenterforEpilepsySurgeryofSantaCatarina(CEPESC),HU,UFSC, Florianópolis,SantaCatarina88035-972,Brazil

CorrespondingAuthor: RogerWalz,DepartamentodeClínicaMédica, HospitalUniversitário,3°andar,UniversidadeFederaldeSantaCatarina, Trindade,Florianópolis,SantaCatarina,Brasil,Tel.:88.040-970.

E-mail: rogerwalz@hotmail.com

BrainMedicine January2025;1(1):46–53; doi: https://doi.org/10.61373/bm024r.0070

Thisstudycomparesheartratevariability(HRV)indicesacrossdifferenttimeepochs(5minutes,1minute,and30seconds)toevaluatethereliabilityofultra-shortrecordingsforassessingcardiac autonomictone1yearafteraseveretraumaticbraininjury(TBI).Electrocardiogramrecordingswereobtainedfrom48patients1yearafter asevereTBI.Pearsoncorrelationanalysiswasperformedtoevaluate theassociationbetweenultra-shortHRVindices(1minuteand30seconds)andthestandard5-minuterecordings.Additionally,ANOVAwas usedtocomparethedifferencesinmeanHRVindicesacrossthedifferentepochs.Thecorrelationanalysissupportsthattime-domainindices presenthighercorrelationcoefficients(r = 0.63to0.99, p < 0.05)when comparedwithfrequency-domainindices(r = 0.51to0.97, p < 0.05). Thereductioninrecordingtimeincreasesthepercentagevariationof allindices.TherootmeansquareofthesuccessivedifferencesofRR intervals(rMSSD)showshigherPearsoncoefficientvaluesandlower percentagevariationatthe1-minuteand30-secondepochscompared withotherHRVindices.Ultra-shortHRVindicesarereliableforassessingcardiacautonomictoneinchronicpatientswhosurvivedsevereTBI. rMSSDwasthemostreliableHRVindexforultra-shortrecordings.The valueofultra-shortHRVforcardiovascularprognosisaftersevereTBI remainstobedeterminedinfuturestudies.

Keywords: Cardiacautonomictone,heartratevariability,rMSSD,TBI, ultra-shortrecording.

Introduction

Traumaticbraininjury(TBI)isamajorhealthandsocioeconomicproblem worldwide(1, 2).TBIisclassifiedaccordingtotheGlasgowComaScale

Received:3May2024.Revised:28August2024.Accepted:6September2024. Publishedonline:24September2024.

(GCS)scoreintomild,moderate,andseverecategories(3).Thecomplex interplaybetweenprimary(e.g.,trauma-relatedinjuries)andsecondary (e.g.,inflammatoryresponsesfollowinginjury)braindamageinfluences patientseverity(1, 4).PatientswithahistoryofsevereTBIcommonlydeveloppsychiatricdisorders(5, 6),cognitiveimpairments(7–10),oranincreasedriskofsuddenunexpecteddeath(11).Thedisabilitycausedby TBIimposeshighcostsonsociety,asmostaffectedindividualsareyoung adultswhorequiremedicaltreatmentandareoftenunabletoreturn towork(12, 13).InvestigatingfunctionaloutcomebiomarkersafterTBI presentsanopportunitytodeveloptechnologiesformonitoringtreatmentresponses,ultimatelyimprovingclinicalcareforpatients(14–16).

Thesympatheticandparasympatheticbranchesoftheautonomicnervoussystem(ANS)regulatecardiacrhythmviasynapsesatthesinoatrial nodetoproduceadaptiveresponses(17).Heartratevariability(HRV)is awidelyusednoninvasivemeasureforassessingcardiacANSfunction (18).HRVanalysisprovidesquantitativeindicesderivedfromthetime intervalsbetweensuccessiveheartbeatstoevaluatebothsympathetic andparasympatheticheartactivity(19).TheneurovisceralmodelsuggeststhatcardiacANSactivity,asassessedbyHRV,reflectsthesynapticinteractionsbetweentheprefrontalcortexandtheamygdalaviathe vagusnerve(20–22).Inthismodel,thesimilaritiesbetweencentralnervoussystemstructuresthatregulatecardiacautonomictoneandcognitiveperformancesuggestthatHRVmayserveasaperipheralindexof thefunctionalintegrityofcentralnervoussystemnetworksassociated withgoal-directedbehavior(23).NumerousstudiessupporttheassociationbetweenHRVandcognitiveperformance(21, 24),emotionalregulation(20, 25–27)andfunctionalmeasuresofthecentralnervoussystem (22, 28, 29).Consequently,severalstudiesproposethatHRVindicesmay serveaspotentialbiomarkersforfunctionaloutcomesinbothhealthyand clinicalpopulations.

Itisnowwellestablished,basedonavarietyofstudies,thatpatientswithTBIhavelowerHRVcomparedwithhealthycontrols(14, 30–33).ThereductioninHRVbeginsintheacutephaseofinjurybutcan graduallyrecoveroverthemonthsofrehabilitation(33).Despitetherecoveryofcardiacautonomictone,physiologicalchangesmayremainpermanentevenafteranextendedrecoveryperiod(31).PatientswithmoderateorsevereTBIexhibitamorepronouncedreductioninHRVcompared withthosewithmildTBI,suggestingthattheseverityoftraumaisassociatedwiththemagnitudeofcardiacautonomicdysfunction(34).Recently, therehasbeenincreasedinterestinusingHRVasabiomarkerformonitoringpost-TBIoutcomes(14).RecentstudiessuggestthatHRVisassociatedwiththepredictionofimminentbraindeathandglobalpatientoutcomes(14, 30, 35).Sung etal. (2016)reportedthatHRVwascorrelated withsymptomsofdepressionandanxietyinpatientswithTBI.Thisfinding issupportedbyotherstudiesthathavereportedanassociationbetween HRVandsymptomsofdepression(36)andanxiety(37).Datafromseveral studiessuggestthathigherHRVisassociatedwithbetterfunctionaloutcomes(e.g.,neurologicalorpsychiatricfunctioning)afterTBI(14).HRVis awell-describedmethodforassessingcardiacautonomictonewithvariousclinicalapplications,butatleast5minutesofrecordingisnecessarytoobtainreliablevaluesduetotheinfluenceofpostureoncardiac autonomicregulation(18).Developingfasterrecordingmethodscould enhancetheapplicabilityofHRVinclinicalpractice.

Previousresearchhasestablishedthatultra-shortHRVrecordings (≤1minute)canprovidereliableHRVindicesinbothhealthy(38–40)and clinicalpopulations(41, 42).Melo etal. (2018)comparedHRVintervals of1,2,and3minuteswiththegoldstandardperiod(≥5minutes)andreportedthattheultra-short-termrecordingmethodcanofferaquickand reliablemeansofassessingcardiacANSfunction.ThereliabilityofultrashortHRVindices(includingrecordingsof ≤1minute)hasbeenreplicatedinotherstudies(39–42).Theexistingbodyofresearchsuggests thatrMSSDisthemostreliableHRVindexinultra-shortepochs,butthe debatecontinuesregardingtheminimumtimerequiredtoobtainreliable assessmentsoftimeorfrequencydomainindices.Althoughseveralreportssupportthereliabilityofultra-shortHRVrecordings,thereareno

Table1. ClinicalanddemographiccharacteristicsofpatientswithTBI

Predominanceoflesionside Right > Left

< Right

studiesinvestigatingthereliabilityoftheserecordingsspecificallyinpatientswithTBI.Thereliabilityofsomeultra-shortHRVindicesreported inpreviousstudiesmaynotbedirectlygeneralizabletopatientswithTBI. ThisstudycomparestimeandfrequencydomainHRVindicesacrossdifferenttimeepochs(5minutes,1minute,and30seconds)toevaluatethe reliabilityofultra-shortrecordingsforassessingcardiacautonomictone inpatientswithTBI.

Results

TheclinicalanddemographicdataofpatientswithTBIareshownin Table1.Thisstudyincluded9women(18.75%)and39men(81.25%)with ameanageof37.18(±15.56)years.Thepatientshadameanhospitalizationdurationof30.60(±16.49)days,withameanICUstayof15.00 (±7.51)days.MostpatientswithTBIhadassociatedtrauma(61.7%)and wereclassifiedasMarshallIII(44.68%).GCSdistributionshowedthat 55.32%ofpatientshadscoresof6(12.77%),7(17.02%),and8(25.53%), with82.98%presentingwithisochoricpupils.MostpatientshadaGCS scoreof3(56.25%)athospitaldischarge.

ThePearsoncorrelationanalysisbetween5-minute,1-minute,and30secondepochsofHRVindicesisshownin Table2.For1-minuteepochs, time-domainHRVindices(RR,HR,SDNN,rMSSD,andpNN50)exhibited highermean r values(r = 0.84to0.99)comparedwithfrequency-domain

indices(VLF,LF,HF)(r = 0.30to0.93)(see Figure1).Similarresultswere observedfor30-secondepochs(time-domain: r = 0.80to0.99;frequencydomain: r = 0.24to0.93)(see Figure2).Themean r coefficientswere higherfor1-minuteepochsinbothtime-domain(r = 0.84to0.99)and frequency-domainindices(r = 0.30to0.93)comparedwith30-second epochs(time-domain: r = 0.80to0.99;frequency-domain: r = 0.24to 0.93).rMSSDpresentedhigher r valuescomparedwithotherHRVindices forboth1-minuteand30-secondepochs(alltimeepochswith r = 0.99, p < 0.05).

TheANOVAcomparisonofmeanHRVindicesbetween5-minute, 1-minute,and30-secondepochsisshownin Table3.ANOVAindicated thatthereisnosignificantdifferenceinHRVmeanvaluesbetweenthe 5-minuteand1-minuteepochs(p > 0.05).However,theposthocanalysisrevealedthatthemeanVLFdifferedsignificantly(F = 1.95, p = 0.08 fortheANOVA,but p < 0.05forposthoccomparisonsofthe1st,3rd,and 5thepochs).Thecomparisonbetween30-secondepochsand5-minute HRVmeanvaluesrevealedthatthemeanvaluesof30-secondVLFepochs weresignificantlydifferent(F = 10.75, p = 0.0001).Theposthocanalysis indicatedthatsomeSDNNepochsweresignificantlydifferent(F = 1.17, p = 0.32forANOVA,but p < 0.05forposthoccomparisonsofthe1stand 4thepochs).Nosignificantdifferenceswereobservedforotherindices. rMSSDexhibitedlowerpercentagevariationsacross1-minute(0.97%) and30-second(0.46%)epochscomparedtootherHRVindices(see Figure3).

Discussion

Thisstudyinvestigatedthereliabilityofultra-shortHRVindicesforassessingcardiacautonomictoneinpatientswithTBI.TheresultssuggestthatallHRVindicesshowsignificantassociationsfor1-minuteand 30-secondepochs(exceptVLFandthe4th30-secondepochforLF).Timedomainindicesexhibithighercorrelationcoefficientscomparedwith frequency-domainindices.AllHRVindicesshowapercentagevariationin meanvaluesacrossdifferenttimeepochs,indicatingthatpositiveassociationsdonotnecessarilyreflectnumericalequivalence.Thecomparison ofmeanvaluesrevealedthatVLFvaluesin30-secondepochsweresignificantlydifferent.Theposthocanalysisindicatedthatsome1-minute VLFepochsandthe4thSDNN30-secondepochweresignificantlydifferent(p < 0.05).Forboth1-minuteand30-secondepochs,rMSSDshowed higherPearsoncorrelationcoefficientsandalowerpercentageofmean valuevariationacrossthetwo-timeepochs.

ThisfindingisconsistentwithNussinovitch etal. (2011),whoreportedthatrMSSDexhibitshigherreliabilityfor ≤1-minuteHRVultrashortrecordings.SimilarresultswerereportedbyMelo etal. (2018), whocompared1-minute,2-minute,and3-minuteepochsandfoundthat rMSSDhadhigherPearsoncoefficientsacrossalltimeepochs.Munoz etal. (2015)alsoreportedasignificantassociationforrMSSDin30secondepochs.Theseresults,previouslyreportedinhealthysamples(38–40)arereplicatedinclinicalpopulations,asobservedinepilepsy(41)and diabetes(42).Theexistingbodyofresearchonultra-shortHRVsuggests thatrMSSDisthemostreliableindexforultra-shortrecordings.rMSSDis lessinfluencedbyheartratefluctuationsandismorestableduringperiodsofstationaryoscillationsbecauseitiscalculatedbasedonthedifferencebetweenRRintervals(43, 44).Consistentwiththeliterature,this researchfoundthatthereliabilityofrMSSDreportedforhealthysamples,aswellasforepilepsyanddiabetes,canbeextendedtopatients withTBI.

Surprisingly,thecomparisonbetween1-minuteand30-secondepochs forotherHRVindicesshowedsignificantPearsoncoefficientsforRR,HR, SDNN,pNN50,LF,andHF.Thisfindingcontrastswithpreviousstudies(38, 39, 45),whichhavesuggestedthatlongerrecordingsarerequiredfor SDNNandfrequencydomainindices.However,itcorroboratesthefindingsreportedbyMunoz etal. (2015),whichdemonstratedSDNNreliabilityfor30-secondepochs.SimilarresultswerereportedbyMcNames andAboy(2006),whodemonstratedasignificantassociationbetween ≤1-minuteand5-minuteepochsforHF.Thecontroversyregarding SDNNandfrequencydomainreliabilitymayarisefromtheinfluenceof nonstationaryartifactsthatimpairthereplicabilityofultra-shortindicescomparedwith5-minuterecordings.Consequently,selectingonly

Table2. PearsoncorrelationanalysisofHRVindicesbetweentimeepochs

1-minuteepoch1stepoch2ndepoch3rdepoch4thepoch5thepochMean r coefficient

MeanRRintervals(RR,ms);Meanheartrate(HR,bpm);StandarddeviationofRRintervals(SDNN,ms);Rootmeansquareofthesuccessivedifferencesof RRintervals(rMSSD,ms);PercentageofRRintervalswithdifferenceinsuccessiveRRintervalslongerthan50ms(pNN50,%);Verylowfrequency (0.01–0.04Hz,VLF,ms2 );Lowfrequency(0.04–0.15Hz,LF,ms2 );Highfrequency(0.15–0.4Hz,HF,ms2 ); p < 0.05for Bonferroni multiplecomparison correction(∗ ).

afew(≤3)randomepochsfroma5-minuterecordingmayintroduce selectionbiasthataffectsreliability.ThereliabilityofSDNNandfrequencydomainindiceswouldbenefitfromfurtherstudies(38).Although SDNNandtime-domainindicesshowsignificantassociationswith5minuteepochs,theirmeanvaluesexhibitgreatervariancecomparedwith rMSSD.Therefore,ourresultsshouldbeinterpretedwithcaution.rMSSD, whichclearlyrepresentsparasympatheticactivity(18, 21),showslower meanvaluevariationacross5-minuterecordingsandhigherPearson coefficientsfor ≤1-minuteepochs(38–40).Thus,ourresultssupportthe conclusionthatrMSSDisthemostreliableindexforultra-shortrecordingsinpatientswithTBI.

Cardiacautonomicdysfunction,assessedbyHRV,hasbeenreported inseveraldiseases.However,thecommonpathophysiologicalmecha-

nismsunderlyingtheseconditionshavebeenthesubjectofintensedebatewithinthescientificcommunity(20–22, 26, 27).HRVmaintenance isassociatedwithvariouscardiovascular,physiological,metabolic,and psychologicalvariables(18, 21, 46).RecenttrendsinHRVclinicalapplicationssuggestthatHRVcanreflectageneralstateofwell-being,servingas asensitivebutnonspecificbiomarkerforindividualsymptoms(47).While someresearchershavereportednormativevaluesforhealthysamples, thereisnoconsensusona“safezone”forHRVvalues(48).Developing ageneralizednormativedatabasecanbechallengingduetotheprecise quantitativemeasurementrequiredforalldailyvariablesassociatedwith HRVfluctuations.Apossiblestrategyforclinicalapplicationdevelopmentmightbetouseasingle-subjectmodel,whichcomparesvalueswith baselinereferencevalues.Thismodelisusedformonitoringfatigueand

Resultsarepresentedinmean ± sd;meanRRintervals(RR,ms);Meanheartrate(HR,bpm);StandarddeviationofRRintervals(SDNN,ms);Rootmean squareofthesuccessivedifferencesofRRintervals(rMSSD,ms);PercentageofRRintervalswithdifferenceinsuccessiveRRintervalslongerthan50ms (pNN50,%);Verylowfrequency(0.01–0.04Hz,VLF,ms2 );Lowfrequency(0.04–0.15Hz,LF,ms2 );Highfrequency(0.15–0.4Hz,HF,ms2 );Meanvalues percentageofvariationacrossepochs(% ); p < 0.05forposthoccomparisonto5-minuteepoch(∗ ).

Table3. ComparisonofmeanHRVindicesbetweentimeepochs

Figure1. Associationsbetween1-minutewith5-minuteepochsofHRVindices.

trainingloadinhigh-performanceathletes(49).Therefore,ultra-short measurementscouldenhancepatientadherencetodailyHRVrecording. Ourresultssupportthatultra-shortHRVrecordingisasimple,fast,and noninvasivemethodforevaluatingcardiacautonomictoneinpatients withTBI,withrMSSDbeingthemostreliableindexforultra-shortrecordings.Theultra-shortrecordingmethodcouldimprovetheapplicabilityof HRVinclinicalsettings.

ResearchReport Meloetal.

Ultra-shortHRVmeasurements,definedasrecordingsshorterthan 5minutes,haveshownpotentialasanoninvasivetoolformonitoringANS function.InthecontextofTBIcare,thesemeasurementscouldprovide valuableinsightsintoautonomicdysregulation,whichiscommonlyobservedinpatientswithTBIandisassociatedwithpooroutcomes(50). Byapplyingultra-shortHRVmeasurementsinclinicalsettings,itmaybe possibletodevelopmoretimelyandpersonalizedinterventionsaimedat

https://doi.org/10.61373/bm024r.0070

Figure2. Associationsbetween30-secondwith5-minuteepochsofHRVindices. improvingpatientoutcomes.Futureresearchshouldfocusonvalidating theefficacyofthesemeasurementsinpredictingTBIprogressionandrecovery,aswellasdeterminingtheirutilityinguidingtreatmentdecisions. Thisapproachalignswiththegrowingbodyofevidencesupportingthe useofHRVasabiomarkerforvariousneurologicalconditions,including TBI(33, 36, 37, 51–53).

Ourresultsshouldbeinterpretedwithcaution.TheHRVdatausedin theseanalyseswererecordedundercontrolledconditions(e.g.,supine position,quietroom,properbaselinerestingperiod),sotheseresultsmay notfullyreflecttypicalenvironmentalconditionsinvarioushospitalsor

clinicswhereelectrocardiogram(EKG)recordingsareperformed. AddressingmeasurementissuessuchasvariabilityandartifactmanagementiscrucialforimprovingtheaccuracyandreliabilityofHRV assessmentsacrossdifferentpopulations(54).Moreover,incorporating longitudinaldesignscouldprovidevaluableinsightsintothetemporal aspectsofpatientcompliancewithbrainrecoveryinterventionsthat utilizeHRVmeasurementsandtraining.Suchstudieswouldhelptobetter understandhowadherencetothesemethodschangesovertimeandits effectonpatientrecovery(47, 55).ThisapproachwilladvanceourunderstandingofthepracticalintegrationofHRVmetricsintoTBIrehabilitation

Figure3. ComparisonbetweenmeanvaluesofHRVindicesintimeepochs(5-minute,1-minute,30-second).

protocols.AlthoughsomeHRVindicesremainreliableforultra-short recordings,generalprecautionsforpreparingpatientsforregularEKG recordingsshouldbemaintained.Thereliabilityofultra-shortrecordings maynotbegeneralizabletouncontrolledenvironmentsorsituations whereproperposturalpositionorbaselinerestingconditionsarenot followed.ShortHRVassessmentsmay,inthefuture,offerapractical andefficientmethodforevaluatingpatientswithTBI,particularlyin resource-constrainedsettings.

Ultra-shortHRVindicesarereliableforassessingcardiacautonomic toneinpatientswithTBI.Thecorrelationbetweenultra-shortrecordings(1minuteand30seconds)andstandardtimerecordings(5minutes)supportsthattime-domainindicesexhibithighercorrelationcoefficientscomparedtofrequency-domainindices.Thecomparisonbetween theresultsofthe1-minuteand30-secondepochsindicatesthatreducingrecordingtimeincreasesthepercentagevariationofallHRVindices. rMSSDexhibitshigherPearsoncoefficientvaluesandlowerpercentage ofvariationatboth1-minuteand30-secondepochscomparedwithother

HRVindices.rMSSDisthusthemostreliableHRVindexforultra-short recordingsinpatientswithTBI.SDNNandfrequencydomainindices (e.g.,VLForLF)requirelongerrecordingtimestoprovidereliablevalues. TheassociationsbetweenclinicalorsociodemographicvariablesandHRV indices,aswellastheprognosticvalueofHRVforTBIsurvivors,remainto bedeterminedinfuturestudies.

Methods

Participants

Thisstudyincluded48patientswithTBIfromHospitalGovernadorCelso Ramos(HGCR)andHospitalHomerodeMirandaGomes(HHMG),tworeferencehospitalsforbraintraumainthepublichealthsystemofSanta Catarinastate,southernBrazil,betweenApril2014andJanuary2016.The inclusioncriteriawereaGCSscoreof8orlowerafteracuteneurosurgicalresuscitation,withoutsedation,oradeteriorationtothatlevelwithin 48hoursofhospitaladmission,andafavorableoutcome(GlasgowOutcomeScale4or5)oneyearafterhospitalization,whentheEKGwasperformed.TheexclusioncriteriawerepoorqualityoftheEKGsignalduring thepredeterminedsamplingperiodandpatientswithahistoryofknown cardiacdisease(asindicatedbymedicalrecordsandpatientoralconfirmation).TheresearchprotocolwasapprovedbytheEthicsCommitteefor HumanResearchatUniversidadeFederaldeSantaCatarina(Plataforma BrazilRegistration02832612.6.1001.0121),andwritteninformedconsentwasobtainedfromallparticipants.

ElectrocardiographicRecording

TheNihonKohdenamplifierwasusedforEKGrecording,sampledat 512Hz.AllEKGrecordingswereperformedbetween2and4PMwhilethe patientswereinasupineposition.Theskinareaswherethedisposable Ag/AgClelectrodeswereappliedwerecleanedwith70%isopropylalcohol.Theelectrodeswereplacedinatriangularchestconfiguration.Muscleartifactepochs(<2%)wereidentifiedthroughvisualinspectionand excludedfromtheanalysis.Thefirst5minutesofEKGrecording,without muscularartifacts,wereusedforHRVanalysis.TheQRScomplexidentification,RRintervalextraction,andHRVanalysiswereperformedusingKubiosv2.3software(56).Thefollowingtime-domainandfrequencydomainHRVindiceswerecalculated:a)MeanRRintervals(RR,ms);b) Meanheartrate(HR,bpm);c)StandarddeviationofRRintervals(SDNN, ms);d)RootmeansquareofsuccessivedifferencesofRRintervals(rMSSD, ms);e)PercentageofRRintervalswithdifferencesinsuccessiveRRintervalslongerthan50ms(pNN50,%);f)Verylowfrequency(0.01–0.04Hz, VLF,ms2 );g)Lowfrequency(0.04–0.15Hz,LF,ms2 );h)Highfrequency (0.15–0.4Hz,HF,ms2 ).AfastFouriertransformusingaHanningwindow of256secondswidthwith50%overlapwasusedforfrequencydomain indicesanalysis.AllHRVindicesextractionwasbasedontheTaskForce ofTheEuropeanSocietyofCardiologyandTheNorthAmericanSociety ofPacingandElectrophysiologyguidelines(1996).The5-minuterecordingswerereanalyzedinconsecutive1-minuteepochs(1st–1minute; 2nd–1minute;3rd–1minute;4th–1minute;5th–1minute)and30secondepochs(1st–30seconds;2nd–30seconds;3rd–30seconds; 4th–30seconds;5th–30seconds).Topreventselectionbias,the30secondepochswereselectedfromthefinalportionoftheconsecutive1minuteepochs.

StatisticalAnalysis

AlldatawerenormallydistributedasassessedbytheShapiro–Wilktest (p > 0.05).ANOVAwasusedtocomparethemeanvaluesofHRVindices acrossdifferenttimeepochs.Pearsoncorrelationwasusedtoevaluate theassociationbetweenHRVvaluesatdifferenttimeintervals(5minutes,1minute,and30seconds).The p-valuesfromthePearsoncorrelationanalysiswerecorrectedusingtheBonferronimultiplecomparisons correction.A p-valueof <0.05wasconsideredstatisticallysignificant.All statisticalprocedureswereperformedusingStata14.0(Version14;StataCorpLLC,Texas,USA).

AuthorDisclosures

Theauthorsdeclarenoconflictsofinterest,sourcesoffunding,orfinancialtiestodisclose.Theyhavenocurrentorpastrelationshipswithcompaniesormanufacturersthatcouldbenefitfromtheresultsofthepresent study.

AuthorContributions

HiagoMuriloMelo:Writing–review&editing,Writing–originaldraft, Visualization,Validation,Supervision,Software,Projectadministration, Methodology,Investigation,Formalanalysis,Datacuration,Conceptualization. BeatrizRangel:Writing–review&editing,Visualization. GuilhermeLoureiroFialho:Writing–review&editing,Validation. KatiaLin: Writing–review&editing,Visualization. RogerWalz:Writing–review& editing,Visualization,ValidationandSupervision.

Acknowledgments

ThisworkwassupportedbyProgramadePesquisaparaoSUS–PPSUS–FAPESC(TO2021TR000564).KLandRWareResearchFellows fromCNPq(BrazilianCouncilforScientificandTechnologicalDevelopment,Brazil).KLisalsosupportedbyPRONEM(ProgramadeApoioaNúcleosEmergentes–KETODIET-SCProject–ProcessNo2020TR736)from FAPESC/CNPq,SantaCatarina,Brazil.HMMissupportedbyaCAPES/DS scholarship.

EthicalReview

TheresearchprotocolwasapprovedbytheEthicsCommitteeforHuman ResearchatUniversidadeFederaldeSantaCatarina(PlataformaBrazil Registration02832612.6.1001.0121),andwritteninformedconsentwas obtainedfromallparticipants.

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OpenAccess. ThisarticleislicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercial-NoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Credit mustbegiventotheoriginalwork,withalinktothelicenseandnotification ofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement. (2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3) NoDerivatives:Modifiedversionsoftheworkcannotbedistributed.(4)Noadditional legalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutoryexceptionsareexempt fromtheseterms.Thislicensedoesnotcoverallpotentialrights,suchaspublicity orprivacyrights,whichmayrestrictmaterialuse.Third-partycontentinthisarticle fallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfrom thecopyrightholder.Forcompletelicensedetails,visit https://creativecommons. org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

BREVIA

Anovelanimalparadigmoflong-term,stress-inducedhippocampalatrophy

BrainMedicine January2025;1(1):54–55;doi: https://doi.org/10.61373/bm024l.0040

Long-termhippocampalatrophyisakey featureofmajordepression.Incontrast, inrodentssubjectedtochronicstressthereis reversiblydecreasedhippocampalvolume.We showthatexposuretosevendaysofrestraint stressaloneorwithantidepressanttreatment combinedwithapersistenthigh-fatdietenvironmentlasting165daysresultedinlongterm,stress-inducedhippocampalvolume reductioninrats,betterreflectingthehippocampalshrinkagethatiswelldocumented inpatientswithmajordepressivedisorder.

Hippocampalvolumereductionisoneof themostreproducedimagingfindingsdocumentedinpatientswithmajordepressivedisorder(MDD)(1).Understandingthemechanisms bywhichthisshrinkagehappensisrelevant,as thehippocampusispartofthelimbicstress pathwayandplaysvitalrolesinlearning,memory,andneuroendocrineregulation(2).Thehippocampushasessentialrolesin“declarative memory”formation,whichinvolvesrepresentationsoffactsandeventsthataresubjecttoconsciousrecollection,verbalreflection,andexplicitexpression;italsohasakeyroleinmemory consolidation,acrucialprocessthatconverts short-termmemoryintolong-lastingmemory thatisstoredintheneocortex(3).Otherrecentlypublishedhippocampalfunctionsand networksthatmayalsobeinvolved,suchasappetitiveprocessing(4).

Cognitiveimpairmentshavebeenreported inMDD(5).Thoseincludeexplicitmemory deficitsthatarenegativelycorrelatedwith baselineplasmacortisolconcentrations.The severityofcognitiveimpairmentandhippocampalvolumedecreasearemoresignificantinpatientswithmultipleMDDepisodes(1).Ahippocampalvolumedecreaseofupto20%has beendemonstratedaftercontrollingforthetotalbrain,amygdala,ortemporallobevolume. Significantly,thisshrinkage(i)correlateswith thetotaldurationofmajordepression,(ii)may bedetecteddecadesafterthelastdepressive episodehasresolved(1),and(iii)canbepreventedbyantidepressanttreatment.Adamagedhippocampusaffectsthememoryrecall oftraumaticeventsandleadstofragmentationofmemoryelementsofpersonalhistory andimpairmentinlearningcapacitywithclinicalconsequences,whichleadstodissociative symptomatology,perceptualdistortions,iden-

tityinstability,decreasedsocialperformance, andinflexibleandmaladaptivebehaviors.

Otherlinesofinvestigationhaveshown convincingevidenceforaroleofchronicstress inMDD,includingthefollowingfindings:(i) antidepressantsdirectlydownregulatehypothalamic-pituitary-adrenal(HPA)axisfunction; (ii)antagonismofcorticotropin-releasinghormoneattenuatesbehavioral,neuroendocrine andautonomicresponsestostressinprimates, and(iii)increasednoradrenalineconcentrationiselevatedinthecerebrospinalfluid throughout24hoursoftheday,evenduring sleep,whichsuggeststhatdysregulationofa stress-relatedsystemisprimaryandnotmerely areactiontodepressedmood(6).

Incontrasttohumans,stress-inducedhippocampalatrophyisreversibleinrats.Here wepresentanovelrodentmodeloflongterm,stress-inducedhippocampalatrophy.In ourstudies,wehaveusedchronicrestraint stress(CRS)because(i)Ithasgoodpredictive validity,asantidepressanttreatmentimproves behavioralcorrelatesofCRS.(ii)Ithasgoodface validity,asCRSincreasesplasmacortisoland immobilitytimeintheforcedswimmingtest. (iii)Itdecreaseshippocampalneurogenesis. (iv)TheconstructvalidityoftheCRSmodelis similartothatofotherchronicstressmodels.

DatafromourlabshowthattheCRSprotocol,consistingofdaily6hsessionsofrestraintstressfor2weeks,induces,inmalerats, whathasbeendescribedasstress-inducedbehaviors(7).AfterCRS,ratsdisplayedanhedonia (decreasedsucrosepreference, Fig.1A),avoidance(increasedfeedlatencyinthenoveltysuppressedfeeding, Fig.1B),andincreasednumber ofmarblesburiedinthemarbleburyingtest, Fig.1C)wewellasweightloss(Fig.1D).

Wesubsequentlydevelopedananimal paradigmthatmodelsexposuretostressand antidepressantsinahigh-fatenvironment(8), bettermimickingwhathappensinhumans.Our paradigm,lastingatotalof177days,consists ofchronicrestraintstressfor7days,antidepressanttreatmentfor7days,andlong-term high-fatdiet(TD95217;Harlan)intakestarting atday12andlastingthroughouttherecovery phaseuntilday177,the“stress-dietinduced obesity”(SDIO)paradigm(8).

WeshowherethattheSDIOparadigm resultsindecreasedhippocampalweightthat

Received:6March2024.Revised:3April2024.Accepted:19April2024. Publishedonline:2May2024.

Figure1. Short-andlong-termeffectsofchronicrestraintstress(CRS).Short-termeffects(n = 8pergroup): after2weeksofCRS,maleratsdisplayeddecreasedsucrosepreference(A),increasedfeedlatencyinthenoveltysuppressedfeedingtest/assay(B),increasednumberof marblesburiedinthemarbleburyingtest(C),andweight loss(D).Long-termeffects:atexperimentalday177,in comparisonwithnon-restraintcontrolsonfatdiet(NRCF, n = 13)hippocampalweightwasdecreasedinthreerestraintgroupsthatwerealsoonthesamefatdiet:RC, restraintwith0.5mlofsaline(0.9%NaCl;Hospira)and withoutantidepressant(n = 13);RFX,restrainttreated withfluoxetine(Sigma-Aldrich,10mgkg–1 , n = 13); RIM,restrainttreatedwithimipramine(Sigma-Aldrich, 10mgkg–1 , n = 13)(E). ∗∗ = P<0.01; ∗∗∗ = P<0.001,Student’s t-test(A-D)andANOVA(E).

persistsmonthsafterstressandantidepressant treatmenthaveended,atapointinwhichthe animalsnolongerdisplayavoidanceorchronic stress-inducedbehaviors.Animalssubmittedtochronicstress,treatedornon-treated withantidepressants,displayeddecreased hippocampalweightincomparisonwith experimentalcontrolanimalsthatwerenonstressedandnon-treated(Fig.1E).Short-term antidepressanttreatmenthadnosignificant effectsonhippocampalweight.Pleasesee the supportingonlinematerial forfurther experimentaldetails.

Inpreviouslydescribedanimalmodelsof chronicstress,stress-inducedhippocampalalterationsreversewiththecessationofstress. Therefore,thefactthatwehavefounddecreasedhippocampalmassinanimalssubmittedtoCRSinourSDIOmodelseveralmonths afterterminationofstresssupportsthenotionthatourmodelconstitutesabetterapproximationofthehumancondition,asclinicaldatasupportaprolongednatureofthe volumelossseeninremittedMDDindividuals(9).Itshouldbenotedthatitispossible thatchronicallyincreasedbodyweightcould contributetoanenduringstressresponsethat wouldperpetuatehippocampalatrophy.These featuresandtimecoursemaketheSDIOmodel suitableforthoseinterestedinexploringthe natureofchronicstress-inducedhippocampal shrinkage.Futurestudiesshouldtestthehypothesisthatenvironmentalfactorssuchaslongtermhigh-fatdiet(comparedtoregulardiet), andantidepressanttreatmentcontributeto long-term,stress-inducedhippocampalshrinkage.Therefore,itmayberelevanttomonitorhippocampalvolumeinhumanpatients

withdepressionsubjectedtochronicphysiologicalstresssuchasthatpropelledbyhighfatdiets.Moreover,thisparadigmmayinform futurestudiesonhippocampalnetworksthat areimpactedbystress,includingthoserelatedtolong-termhigh-fatexposure,suchas hypothalamic-hippocampalorexigenicsubnetworks(4).

Ma-LiWong1 ,ClaudioMastronardi2 ,and JulioLicinio1

1 StateUniversityofNewYork,UpstateMedical University,Syracuse,NewYork13210,USA

2 INPACResearchGroup,FundaciónUniversitaria Sanitas,Bogotá,Colombia e-mail: maliwong7@gmail.com

FundingSources

Thisworkwassupportedinpartbygrants fromtheNationalInstitutesofHealth (NIH)R01MH127423,R21MH128726,and R21MH126405toM.-L.W.andJ.L.

1.ShelineYI,WangPW,GadoMH,CsernanskyJG,Vannier MW.ProcNatiAcadSciUSA.1996;93(9):3908-13.DOI: 10.1073/pnas.93.9.3908 PMC39458

2.HermanJP,CullinanWE.TrendsNeurosci.1997;20(2): 78-84.DOI: 10.1016/s0166-2236(96)10069-2

3.KugaN,SasakiT.NeurosciRes.2022.DOI: 10.1016/j. neures.2022.07.010

4.BarbosaDAN,GattasS,SalgadoJS,KuijperFM,WangAR, HuangY,etal.Nature.2023;621(7978):381-8.DOI: 10. 1038/s41586-023-06459-w PMC10499606

5.KriescheD,WollCFJ,TschentscherN,EngelRR, KarchS.EurArchPsychiatryClinNeurosci.2023; 273(5):1105-28.DOI: 10.1007/s00406-022-01479-5 PMC10359405

6.WongML,KlingMA,MunsonPJ,ListwakS,Licinio J,ProloP,etal.ProcNatiAcadSciUSA.2000; 97(1):325-30.DOI: 10.1073/pnas.97.1.325 PMC26662

7.BeckerM,PinhasovA,OrnoyA.Diagnostics(Basel). 2021;11(1):123.DOI: 10.3390/diagnostics11010123 PMC7830961

8.MastronardiC,Paz-FilhoGJ,ValdezE,Maestre-MesaJ, LicinioJ,WongML.MolPsychiatry.2011;16(3):265-72. DOI: 10.1038/mp.2010.122 PMC3042256

9.LeeAL,OgleWO,SapolskyRM.BipolarDisord.2002; 4(2):117-28.DOI: 10.1034/j.1399-5618.2002.01144.x

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