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THEHUMANHYPOTHALAMUS:

NEUROENDOCRINEDISORDERS

HANDBOOKOFCLINICAL NEUROLOGY

SeriesEditors

MICHAELJ.AMINOFF,FRANÇOISBOLLER,ANDDICKF.SWAAB

VOLUME181

THEHUMAN HYPOTHALAMUS: NEUROENDOCRINE DISORDERS

SeriesEditors

MICHAELJ.AMINOFF,FRANÇOISBOLLER,ANDDICKF.SWAAB

VolumeEditors

DICKF.SWAAB,RUUDM.BUIJS,PAULJ.LUCASSEN, AHMADSALEHI,ANDFELIXKREIER

VOLUME181

3rdSeries

ELSEVIER

Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates

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HandbookofClinicalNeurology3rdSeries

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Vol.81,Pain,F.CerveroandT.S.Jensen,eds.ISBN9780444519016

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Vol.175,Sexdifferencesinneurologyandpsychiatry,R.Lanzenberger,G.S.Kranz,andI.Savic,eds.ISBN9780444641236

Vol.176,Interventionalneuroradiology,S.W.HettsandD.L.Cooke,eds.ISBN9780444640345

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Vol.178,Neurologyofvisionandvisualdisorders,J.J.S.BartonandA.Leff,eds.ISBN9780128213773

Vol.179,Thehumanhypothalamus:Anteriorregion,D.F.Swaab,F.Kreier,P.J.Lucassen,A.SalehiandR.M.Buijs,eds. ISBN9780128199756

Vol.180,Thehumanhypothalamus:Middleandposteriorregion,D.F.Swaab,F.Kreier,P.J.Lucassen,A.SalehiandR.M.Buijs, eds.ISBN9780128201077

Allvolumesinthe3rdSeriesofthe HandbookofClinicalNeurology arepublishedelectronically, onScienceDirect: http://www.sciencedirect.com/science/handbooks/00729752 .

Foreword

Fewareasofneurosciencehavereceivedsomuchattentionandyieldedsomanynewandimportantfindingsinrecent yearsasthehypothalamusandrelatedstructures.Earlierseriesofthe HandbookofClinicalNeurology includedover 100entriesunderthekeyword “hypothalamus,” dispersedwithinall75volumes.Thecurrentthirdseriesstarted withtwovolumesdedicatedentirelytobasicandclinicalaspectsofthehypothalamus,thefirst(Volume79)dealing withthehypothalamicnucleiandthesecond(Volume80)withitsneuropathology.Theywereauthoredby ProfessorDickSwaabandwerepublishedalmost20yearsago(in2003and2004).Asserieseditors,wefeltthat thenumberofnewdevelopmentssincethattimerequiredthattheentiretopicbereviewedoncemore.Thesenewdevelopmentsincludeabetterunderstandingoftheanatomyandconnectionsofthehumanhypothalamusbasedonnovel imagingtechniquesandtheaccumulatingmolecularinformationonthehypothalamus.Also,itisnowapparentthatthe hypothalamusregulatesmorehormonesthanpreviouslyrecognizedandisthekeystructureinclinicalneuroendocrinology.Aboveall,thehypothalamusisnowseentorelatetoalargenumberofneurologicdomains includingmemory,sleep,epilepsy,Parkinsondiseaseandotherneurodegenerativedisorders,andheadaches,aswellasbehavioral issuessuchaseatingbehavior,depression,andaggression.Lastbutnotleast,thehypothalamusplaysacrucialrole inreproductionandshowssexualdimorphismsinvariousnuclei.Theseadvancesandtheassociatedvastexpansion ofknowledgethathasresultedhaverequiredanincreaseincoveragefromtwotofourvolumesofthe Handbook

WethankandcongratulateDickSwaabwhoistheChiefEditorofthesefournewmultiauthoredvolumes.They werepreparedincollaborationwithfourotherhighlyexperiencedneuroscientists.RuudBuijsisintheInstitutefor BiomedicalInvestigation,UniversidadNacionalAutónomadeMexico,MexicoCity;FelixKreierisintheDepartment ofPediatrics,OLVGhospital,Amsterdam;PaulLucassenisattheCenterforNeuroscience,SwammerdamInstitutefor LifeSciences,UniversityofAmsterdam;andAhmadSalehiisintheDepartmentofPsychiatryandBehavioral Sciences,StanfordMedicalSchool,California.Togethertheyhavegatheredaremarkablegroupofcontributing authors,thusassuringtherightmixofcontinuityandhighlyupdatedinformationaboutthehumanhypothalamus.

Asserieseditors,wereviewedallthechaptersinthevolumesandmadesuggestionsforimprovement,butweare delightedthatthevolumeeditorsandchapterauthorsproducedsuchscholarlyandcomprehensiveaccountsofdifferent aspectsofthetopic.Wehopethatthevolumeswillappealtocliniciansasastate-of-the-artreferencethatsummarizes theclinicalfeaturesandmanagementofthemanyneurologic,neuroendocrine,andpsychiatricmanifestationsofhypothalamicdysfunction.Wearealsosurethatbasicresearcherswillfindwithinthemthefoundationsfornewapproaches tothestudyofthecomplexissuesinvolved.

Inadditiontotheprintversion,thevolumesareavailableelectronicallyonElsevier ’sScienceDirectwebsite,which ispopularwithreadersandwillimprovethebooks’ accessibility.Indeed,allofthevolumesinthepresentseriesofthe Handbookareavailableelectronicallyonthiswebsite.Thisshouldmakethemmoreaccessibletoreadersandfacilitate searchesforspecificinformation.

Asalways,itisapleasuretothankElsevier,ourpublisher,andinparticularMichaelParkinsoninScotland,Nikki LevyandKristiAndersoninSanDiego,andPunithavathyGovindaradjaneatElsevierGlobalBookProductionin Chennai,fortheirassistanceinthedevelopmentandproductionofthe HandbookofClinicalNeurology. MichaelJ.Aminoff Franc ¸ oisBoller

Preface

Iknowverywellthatthereaderhasnogreatneedtoknowallthis;itisIwhohaveaneedtotellhim J.J.Rousseau

THEHCNVOLUMESONTHEHUMANHYPOTHALAMUS

Morethan20yearsago,I(DFS)hadwrittenamonographonthehumanhypothalamus,meantasastartingpointformy PhDstudentsandthestudentsofmyformerstudents,myscientificallygiftedchildrenandgrandchildren.Traditionallythe hypothalamuswasconsideredtobeaneuroendocrinestructureoflimitedinteresttoneurologists.Inaddition,this extremelycomplexstructure,whichconsistsofalargenumberofverydifferentfunctionalnuclei,wasnotincluded inthestandardneuropathologicinvestigationofthehumanbrain.Neuropathologistsweretrainedtocutrightthrough theopticchiasma,therebydestroyingthehypothalamus.DuringtheperiodinwhichIwrotethemonograph,itbecame clear,however,thatthehypothalamusnotonlyregulateshormonelevelsbutalsocontributestothememoryandattention deficitsinthedementias;thatadisorderoftheorexin/hypocretinsystemisthecauseofnarcolepsy;thathypothalamic hamartomasareresponsibleforgelasticepilepsy;thatthesubthalamicnucleusisagoodtargettoplacedepthelectrodesin parkinsonianpatients;andthatthesourceofclusterheadachemaybesituatedintheposteriorhypothalamus.Moreover, thehypothalamusappearedtobethebasisofmanysignsandsymptomsofdisorderssituatedontheborderbetween neurologyandpsychiatry,suchasdepression,eatingdisorders,aggression,andmentalretardation.Asaconsequence, thehypothalamusbecameameetingpointforneuroscientists,neurologistsandpsychiatrists,neuropathologists,endocrinologists,andpediatricians.ItwasthevisionofmyfriendProfessorGeorgeBruynthatmymonographwouldbe astartingpointforanew(third)seriesofthe HandbookofClinicalNeurology (HCN).Themonographywaspublished intwoHCNvolumes,79and80.TogetherwithmyfellowserieseditorsMichaelJ.AminoffandFranc ¸ oisBollerandthe staffofElsevier,morethan100additionalvolumesinthisnewserieshavesincebeenpublished.

Theothertwoserieseditorshaveaskedmerepeatedlytoconsiderafollow-upofmytwoearlierHCNvolumes. Sincetheywerepublished,therehasindeedbeengreatprogressinthefield,e.g.,indeepbrainstimulation,molecular biology(includinggeneandcelltherapy,thevariousomics,transgenicanimalmodels,andgenerationofhypothalamic neuronsfromhuman-inducedpluripotentstemcells),moleculargenetics,advancedscanningtechniques(e.g.,functionalconnectivityofhypothalamicnuclei),centraleffectsofneuropeptidesinhealthanddisease,humanbraindonation,andbrainbanking(e.g.,putativeconfoundingfactorsforhypothalamicresearch).Othertopicsweresimplynot dealtwithinVolumes79and80,suchasthehistoryofneuroendocrinology/hypothalamicresearch,orareabsolutely necessarytoplacetheotherchaptersinperspective,suchasmicroscopicneuroanatomyofthehypothalamus,borders, andmarkersofnuclei.OnlyaftermyfriendsandexcellentcolleaguesPaulLucassen,RuudBuijs,FelixKreier, andAhmadSalehiagreedtoparticipateascovolumeeditorsdidIfeelthatwecouldfacethischallenge.

Fromthestart,theCovid-19pandemicinterferedwiththecompositionofthevolumes.Weareverygratefulforthe authorsthatmanagedtodelivertheirchapters,inspiteoftheoftenextremelydifficultcircumstances.WearealsogratefulforthecontinuousandessentialhelpandsupportofMichaelJ.AminoffandFranc ¸ oisBollerandMichaelParkinson duringtheentireprocess.Thenewvolumesareagainsubdividedintoabasicpart(TheNucleioftheHypothalamus) andaclinicalpart(Neuropathology,Neuropsychiatricdisorders),butnowasmultiauthoredvolumes,consistingof in-depthreviewsoftopicsthatwerenovel,hadprogressedmarkedlysincetheearliervolumes,orneededtobereviewed inacriticalway.Becauseofthelargenumberofcrucialtopics,fourvolumesemerged.Theyareinmanyaspectsstill complementarytoHCNvolumes79and80,asisindicatedlater.

Thehypothalamus:Arbitraryborders

Theexactbordersofthehypothalamusareratherarbitraryandtheexactterminologyhasoftenbeencontroversial(see HCNvolume79forreferencesanddetails).Asstatedby Crosbyetal.(1962): Nomenclatureisman-made;thereis

strictlyspeakingnocorrectandnoincorrectwayofdesignatingnucleargroupsofaregion,exceptascertainnamesare sanctionedbyusage

Thebordersaregenerallyconsideredtobe:rostrally,thelaminaterminalis,andcaudally,theplanethroughtheposterioredgeofthemamillarybodyormamillothalamictractorthebundleofVicqd’Azyr.Thehypothalamicsulcusis generallylookeduponasthedorsalborder.However,theparaventricularnucleusisoftenfoundpartiallydorsallyofthe hypothalamicsulcus.Cellsdonotrespecthypothalamicboundaries.Theanteriorcommissurehasalsobeenmentioned asadorsalborderofthehypothalamus,butthisstructuremightpenetratethethirdventricleondifferentlevelsandthe centralnucleusofthebednucleusofthestriaterminalisispartlysituateddorsallyandpartlyventrallyoftheanterior commissure.The ventral borderofthehypothalamusincludesthefloorofthethirdventriclethatblendsintotheinfundibulumoftheneurohypophysis.Theexactlocationofthe lateral boundaries,i.e.,thenucleusbasalisofMeynert, striatum/nucleusaccumbens,amygdala,theposteriorlimboftheinternalcapsuleandbasispedunculi,and,morecaudodorsally,theborderofthesubthalamicnucleusisnotamatterofclear-cutcertaintyeither.Finally,thereisgreat variability:notwohypothalamiarealikeasGr€ unthalremarkedearlier(1950).

SinceI(DFS)foundedtheNetherlandsBrainBankin1985, thebrainhasbeendissectedfreshinmorethan100pieces alonganatomicalborders.TheNetherlandsBrainBankhasprovidedmorethan100,000clinicallyandneuropathologically well-characterizedbrainsamplesfrommorethan4500rapidautopsiestoresearchprojectsin25countries.Myownmain interestwasthehypothalamus.Becauseofthispersonalfocusandthedelineationproblemsmentionedpreviously,wedid notdealwiththequestionofwhichstructuredoesordoesnotbelongtothehypothalamussensustrictoorsensulatobasedon theirembryologyoradulthypothalamicborders.Thewaywedissectedthehypothalamus enbloc duringanautopsy(Fig.1)

Fig.1. Ablockoftissue(frontalcut)containingthehypothalamusandadjacentstructures; OC,opticchiasm; OVLT,organum vasculosumlaminaterminalis(notethatthethirdventricleisshiningthroughthethinlaminaterminalis); ac,anteriorcommissure, ontopofwhichtheseptumwiththefornixatbothsidesislocated.Thelateralventriclescontainingplexuschoroidsarepresent andbothsidesoftheseptumandunderthe CC,corpuscallosum. x PREFACE

resultedinahypothalamusandsurroundingstructuresthatarealsoincludedforpragmaticreasonsinthesevolumes andprovidesabasisforneurobiologicalandneuropathologicalresearchofthisbrainregion.Thismeansthatweinclude intheseHCNvolumesstructuresthatarenottraditionallyconsideredtobecomponentsofthehypothalamusbutaresurroundingandoftenstronglyinterconnectedtothecorehypothalamicnuclei.Anexampleisthebasalcholinergicnucleithat areincludedinspiteofthefactthatthediagonalbandofBrocaandthenucleusbasalisofMeynertaretelencephalic.In addition,thebednucleusofthestriaterminalisisincluded,althoughitisonlypartlylocalizedbelowtheanteriorcommissure.Othersintroducetheconceptofawiderhypothalamicregionthatincludespartsoftheformermesencephalicventral thalamussuchasthezonaincertaandthesubthalamicnucleus,baseduponthefactthatthesestructureshavefewcommon anatomicanddevelopmentalfeatureswiththethalamus.Moreover,thepreopticareathatoriginatesfromthetelencephalon isincludedsinceithasanintimaterelationshipwiththeanteriorandotherportionsofthehypothalamus,withwhichitforms afunctionalunit.

DickF.Swaab

RuudM.Buijs PaulJ.Lucassen

AhmadSalehi

FelixKreier

REFERENCES

CrosbyEC,HumphreyT,LauerEW(1962).CorrelativeAnatomyoftheNervousSystem.MacMillan,NY,310. Gr€ unthalE(1950).In:WRHess(Ed.),Symposion € uberdasZwischenhirn.HelvPhysiolPharmActa.SupplVI:1–80.

Contributors

N.C.Adams

DepartmentofRadiology,Children'sHospitalof Philadelphia,Philadelphia,PA,UnitedStates

S.L.Asa

DepartmentofPathology,CaseWesternUniversityand UniversityHospitals,Cleveland,OH,UnitedStates; DepartmentofPathology,UniversityHealthNetwork, Toronto,ON,Canada

S.Bacigaluppi

DepartmentofNeurosurgery,E.O.OspedaliGalliera, Genova,Italy

A.-M.Bao

DepartmentofNeurobiologyandDepartmentof NeurologyoftheSecondAffiliatedHospital,Zhejiang UniversitySchoolofMedicine;NHCandCAMSKey LaboratoryofMedicalNeurobiology,SchoolofBrain ScienceandBrainMedicine,ZhejiangUniversity, Hangzhou,China

A.Bernal

DepartmentofPsychobiology,andMind,Brainand BehaviorResearchCenter,UniversityofGranada, Granada,Spain

A.Bianchi

PituitaryUnit,FondazionePoliclinicoUniversitario

A.GemelliIRCCS,UniversitàCattolicadelSacro Cuore,Rome,Italy

E.G.Bochukova

BlizardInstitute,BartsandTheLondonSchoolof MedicineandDentistry,QueenMaryUniversityof London,London,UnitedKingdom

N.L.Bragazzi

LaboratoryforIndustrialandAppliedMathematics, DepartmentofMathematicsandStatistics,York University,Toronto,ON,Canada

R.M.Buijs

HypothalamicIntegrationMechanismsLaboratory, DepartmentofCellularBiologyandPhysiology,

InstitutodeInvestigacionesBiomedicas,Universidad NacionalAutónomadeMexico(UNAM),Ciudadde Mexico,Mexico

D.Cai

DepartmentofMolecularPharmacology,AlbertEinstein CollegeofMedicine,Bronx,NY,UnitedStates

Z.Cardona

DivisionofEndocrinology,Diabetes,andMetabolism, DepartmentofMedicine,UniversityofIllinoisat Chicago,Chicago,IL,UnitedStates

S.Chiloiro

PituitaryUnit,FondazionePoliclinicoUniversitario A.GemelliIRCCS,UniversitàCattolicadelSacro Cuore,Rome,Italy

S.Cudlip

DepartmentofNeurosurgery,OxfordUniversity HospitalsNHSFoundationTrust,Oxford, UnitedKingdom

L.DeMarinis

PituitaryUnit,FondazionePoliclinicoUniversitario A.GemelliIRCCS,UniversitàCattolicadelSacro Cuore,Rome,Italy

R.deSouzaSantos

RegenerativeMedicineInstitute,Cedars-SinaiMedical Center,LosAngeles;Cedars-SinaiBiomanufacturing Center,WestHollywood,CA,UnitedStates

G.Diene

CentredeReferenceduSyndromedePrader-Willi, H^ opitaldesEnfants,CHUToulouse,Toulouse,France

Y.Eisenberg

DivisionofEndocrinology,Diabetes,andMetabolism, DepartmentofMedicine,UniversityofIllinoisat Chicago,Chicago,IL,UnitedStates

J.Epelbaum

UMR7179CNRS/MNHN,Brunoy,France

S.Ezzat

DepartmentofMedicine,UniversityHealthNetwork, UniversityofToronto,Toronto,ON,Canada

I.S.Farooqi

Wellcome–MRCInstituteofMetabolicScience, UniversityofCambridge,Cambridge,UnitedKingdom

T.P.Farrell

DivisionofNeuroradiology,ThomasJefferson UniversityHospital,Philadelphia,PA,UnitedStates

M.Ganau

DepartmentofNeurosurgery,OxfordUniversity HospitalsNHSFoundationTrust,Oxford, UnitedKingdom

A.Giampietro

PituitaryUnit,FondazionePoliclinicoUniversitario

A.GemelliIRCCS,UniversitàCattolicadelSacro Cuore,Rome,Italy

S.M.Gold

DepartmentofPsychiatryandMedicalDepartment, CampusBenjaminFranklin,Charit e UniversitatsmedizinBerlin,Berlin;Institutefor NeuroimmunologyandMultipleSclerosis, UniversitatsklinikumHamburg-Eppendorf,Hamburg, Germany

C.H.Gravholt

DepartmentofMolecularMedicine;Departmentof EndocrinologyandInternalMedicineandMedical ResearchLaboratories,AarhusUniversityHospital, Aarhus,Denmark

A.RGross

RegenerativeMedicineInstitute,Cedars-SinaiMedical Center,LosAngeles;Cedars-SinaiBiomanufacturing Center,WestHollywood,CA,UnitedStates

A.J.Holland

DepartmentofPsychiatry,UniversityofCambridge, Cambridge,UnitedKingdom

I.Huitinga

DepartmentofNeuroimmunology,NetherlandsInstitute forNeuroscience;BrainPlasticityGroup,Swammerdam InstituteforLifeSciences,UniversityofAmsterdam, Amsterdam,TheNetherlands

R.Iorio

NeurologyUnit,FondazionePoliclinicoUniversitario

A.GemelliIRCCS,andUniversitàCattolicadelSacro Cuore,Rome,Italy

A.R.Isles

NeuroscienceandMentalHealthResearchInstitute, SchoolofMedicine,CardiffUniversity,Cardiff, UnitedKingdom

J.Jayamohan

DepartmentofNeurosurgery,OxfordUniversity HospitalsNHSFoundationTrust,Oxford, UnitedKingdom

G.Kaltsas

EndocrinologyUnit,FirstDepartmentofPropaedeutic andInternalMedicine,NationalandKapodistrian UniverstiyofAthens,MedicalSchool,LAIKOGeneral HospitalofAthens;DepartmentofMedicalResearch, LCHAdultClinic,HellenicAirForceandVAGeneral Hospital,Athens,Greece

K.Kamperis

DepartmentofPaediatricsandAdolescentMedicine, AarhusUniversityHospital,Aarhus,Denmark

F.Kelestimur

DepartmentofEndocrinology,YeditepeUniversity, Istanbul,Turkey

S.Khor

DepartmentofMolecularPharmacology,AlbertEinstein CollegeofMedicine,Bronx,NY,UnitedStates

B.R.Kornum

DepartmentofNeuroscience,UniversityofCopenhagen, Copenhagen,Denmark

V.Kothari

DivisionofEndocrinology,Diabetes,andMetabolism, DepartmentofMedicine,UniversityofIllinoisat Chicago,Chicago,IL,UnitedStates

F.Kreier

DepartmentPediatrics,OLVGHospitals,Amsterdam, TheNetherlands

S.Looby

DepartmentofNeuroradiology,BeaumontHospital, Dublin,Ireland

P.J.Lucassen

BrainPlasticityGroup,SwammerdamInstituteforLife Sciences,UniversityofAmsterdam,Amsterdam,The Netherlands

J.Mahía

DepartmentofPsychobiology,andMind,Brainand BehaviorResearchCenter,UniversityofGranada, Granada,Spain

N.Makita

DepartmentofNephrologyandEndocrinology, GraduateSchoolofMedicine,UniversityofTokyo, Tokyo,Japan

K.Manaka

DepartmentofNephrologyandEndocrinology, GraduateSchoolofMedicine,UniversityofTokyo, Tokyo,Japan

J.Melief

DepartmentofOncology-Pathology,Karolinska Institute,Stockholm,Sweden

C.Papi

NeurologyUnit,FondazionePoliclinicoUniversitario A.GemelliIRCCS,andUniversitàCattolicadelSacro Cuore,Rome,Italy

J.M.Pascual

DepartmentofNeurosurgery,LaPrincesaUniversity Hospital,Madrid,Spain

T.M.Plant

DepartmentofObstetrics,Gynecologyand ReproductiveSciences,UniversityofPittsburgh, Pittsburgh,PA,UnitedStates

R.Prieto

DepartmentofNeurosurgery,PuertadeHierro UniversityHospital,Madrid,Spain

N.Ramoz INSERMU1266,Paris,France

C.Robba

AnaesthesiaandIntensiveCare,SanMartinoPoliclinico Hospital,IRCCSforOncologyandNeuroscience, Genova,Italy

G.L.Robertson

DepartmentofMedicine,NorthwesternUniversity SchoolofMedicine,Chicago,IL,UnitedStates

M.Rosdolsky

IndependentMedicalTranslator,Jenkintown,PA, UnitedStates

A.Salehi

DepartmentofPsychiatryandBehavioralSciences, StanfordMedicalSchool,PaloAlto,CA,UnitedStates

D.Sareen

RegenerativeMedicineInstitute,Cedars-SinaiMedical Center,LosAngeles;Cedars-SinaiBiomanufacturing

Center,WestHollywood;DepartmentofBiomedical Sciences,Cedars-SinaiMedicalCenter,LosAngeles; iPSCCore,DavidandJanetPolakFoundationStemCell CoreLaboratory,Cedars-SinaiMedicalCenter,Los Angeles,CA,UnitedStates

I.Sataite

DepartmentofNeurosurgery,OxfordUniversity HospitalsNHSFoundationTrust,Oxford, UnitedKingdom

J.Sato

DepartmentofNephrologyandEndocrinology, GraduateSchoolofMedicine,UniversityofTokyo, Tokyo,Japan

W.A.Scherbaum

DepartmentofEndocrinology,Heinrich-HeineUniversity,Duesseldorf,Germany

A.Skakkebæk

DepartmentofMolecularMedicine;Departmentof ClinicalGenetics,AarhusUniversityHospital,Aarhus, Denmark

D.F.Swaab

DepartmentNeuropsychiatricDisorders,Netherlands InstituteforNeuroscience,anInstituteoftheRoyal NetherlandsAcademyofArtsandSciences,Amsterdam, TheNetherlands

G.Tamma

DepartmentofBiosciences,Biotechnologies,and Biopharmaceutics,UniversityofBari,Bari,Italy

T.Tartaglione

DepartmentofRadiologyandDiagnosticImaging, IstitutoDermatopaticodell’ImmacolataIRCCS;Institute ofRadiology,CatholicUniversityoftheSacredHeart, Rome,Italy

M.Tauber

CentredeReferenceduSyndromedePrader-Willi, H^ opitaldesEnfants,CHUToulouse,Toulouse,France

V.Tolle INSERMU1266,Paris,France

M.Tsoli

EndocrinologyUnit,FirstDepartmentofPropaedeutic andInternalMedicine,NationalandKapodistrian UniverstiyofAthens,MedicalSchool,LAIKOGeneral HospitalofAthens;DepartmentofMedicalResearch, LCHAdultClinic,HellenicAirForceandVAGeneral Hospital,Athens,Greece

G.Valenti

DepartmentofBiosciences,Biotechnologies,and Biopharmaceutics,UniversityofBari,Bari,Italy

A.M.vanOpstal

DepartmentofRadiology,LeidenUniversityMedical Center,Leiden,TheNetherlands

A.Voutetakis

DepartmentofPediatrics,SchoolofMedicine, DemocritusUniversityofThrace,Alexandroupolis, Thrace,Greece

M.Wallentin

CenterofFunctionallyIntegrativeNeuroscience,Aarhus UniversityHospital;CenterforSemiotics,Aarhus University,Aarhus,Denmark

J.E.Whittington

DepartmentofPsychiatry,UniversityofCambridge, Cambridge,UnitedKingdom

S.F.Witchel

PediatricEndocrinology,UPMCChildren'sHospitalof Pittsburgh,UniversityofPittsburgh,Pittsburgh,PA, UnitedStates

S.E.C.Wolff

DepartmentNeuropsychiatricDisorders,Netherlands InstituteforNeuroscience,AnInstituteoftheRoyal NetherlandsAcademyofArtsandSciences,Amsterdam, TheNetherlands

M.P.Yavropoulou

EndocrinologyUnit,FirstDepartmentofPropaedeutic andInternalMedicine,NationalandKapodistrian UniverstiyofAthens,MedicalSchool,LAIKOGeneral HospitalofAthens;DepartmentofMedicalResearch, LCHAdultClinic,HellenicAirForceandVAGeneral Hospital,Athens,Greece

S.Zahova

NeuroscienceandMentalHealthResearchInstitute, SchoolofMedicine,CardiffUniversity,Cardiff, UnitedKingdom

Forewordvii

Prefaceix

Contributorsxiii

1.Introduction:Thehumanhypothalamusandneuroendocrinedisorders

1 D.F.Swaab,R.M.Buijs,P.J.Lucassen,A.Salehi,andF.Kreier(Amsterdam,TheNetherlands, CiudaddeMexico,MexicoandPaloAlto,UnitedStates)

SECTION15Structuraldisordersofthehypothalamo-pituitaryregion

2.Pituitarystalkinterruptionsyndrome

9 A.Voutetakis(Thrace,Greece)

3.Emptysellasyndrome:Multipleendocrinedisorders

29 S.Chiloiro,A.Giampietro,A.Bianchi,andL.DeMarinis(Rome,Italy)

4.Pituitarydysfunctionafteraneurysmalsubarachnoidalhemorrhage

41 S.Bacigaluppi,C.Robba,andN.L.Bragazzi(Genova,ItalyandToronto,Canada)

5.Septo-opticdysplasia

51 I.Sataite,S.Cudlip,J.Jayamohan,andM.Ganau(Oxford,UnitedKingdom)

SECTION16Tumorsofthehypothalamus

6.Hypothalamichormone-producingtumors

67 S.L.AsaandS.Ezzat(Cleveland,UnitedStatesandToronto,Canada)

7.Craniopharyngiomasprimarilyaffectingthehypothalamus

75 J.M.Pascual,R.Prieto,andM.Rosdolsky(Madrid,SpainandJenkintown,UnitedStates)

SECTION17Neuroimmunologicaldisorders

8.Thestress-axisinmultiplesclerosis:Clinical,cellular,andmolecularaspects

119 J.Melief,I.Huitinga,andS.M.Gold(Stockholm,Sweden,Amsterdam,TheNetherlandsand BerlinandHamburg,Germany)

9.NeuroendocrinemanifestationsofLangerhanscellhistiocytosis

127 M.P.Yavropoulou,M.Tsoli,andG.Kaltsas(Athens,Greece)

10.NeuroendocrinemanifestationsofErdheim–Chesterdisease

137 K.Manaka,J.Sato,andN.Makita(Tokyo,Japan)

11.Hypothalamitisandpituitaryatrophy

S.Chiloiro,T.Tartaglione,A.Giampietro,andA.Bianchi(Rome,Italy)

149

12.NarcolepsyTypeIasanautoimmunedisorder 161 B.R.Kornum(Copenhagen,Denmark)

13.Neuromyelitisoptica,aquaporin-4antibodies,andneuroendocrinedisorders

173 R.IorioandC.Papi(Rome,Italy)

14.Antibodiesagainstthepituitaryandhypothalamusinboxers 187 F.Kelestimur(İstanbul,Turkey)

15.Autoimmunediabetesinsipidus 193 W.A.Scherbaum(Duesseldorf,Germany)

SECTION18Drinkingdisorders

16.Neuroimagingofcentraldiabetesinsipidus

T.P.Farrell,N.C.Adams,andS.Looby(Philadelphia,UnitedStatesandDublin,Ireland)

17.Differentialdiagnosisoffamilialdiabetesinsipidus

G.L.Robertson(Chicago,UnitedStates)

18.Thevasopressin–aquaporin-2pathwaysyndromes

G.ValentiandG.Tamma(Bari,Italy)

19.Adipsicdiabetesinsipidus 261 V.Kothari,Z.Cardona,andY.Eisenberg(Chicago,UnitedStates)

20.Animalmodelsfordiabetesinsipidus

J.MahíaandA.Bernal(Granada,Spain)

21.Nocturnalenuresisinchildren:Theroleofarginine–vasopressin

K.Kamperis(Aarhus,Denmark)

SECTION19Eatingdisorders

22.Monogenichumanobesitysyndromes

I.S.Farooqi(Cambridge,UnitedKingdom)

23.Hypothalamicmicroinflammation

D.CaiandS.Khor(Bronx,UnitedStates)

24.Glucoseandfatsensinginthehumanhypothalamus

323 A.M.vanOpstal(Leiden,TheNetherlands)

25.Hypothalamusandneuroendocrinediseases:Theuseofhuman-inducedpluripotentstemcells fordiseasemodeling 337 R.deSouzaSantos,A.RGross,andD.Sareen(LosAngelesandWestHollywood,UnitedStates)

26.Prader–Willisyndrome:Hormonetherapies

M.TauberandG.Diene(Toulouse,France)

27.TranscriptomicsofthePrader–Willisyndromehypothalamus

369 E.G.Bochukova(London,UnitedKingdom)

28.Disordersofhypothalamicfunction:InsightsfromPrader–Willisyndromeandtheeffects ofcraniopharyngioma 381

J.E.WhittingtonandA.J.Holland(Cambridge,UnitedKingdom)

29.AnimalmodelsforPrader–Willisyndrome

391 S.ZahovaandA.R.Isles(Cardiff,UnitedKingdom)

30.Isthereahypothalamicbasisforanorexianervosa?

V.Tolle,N.Ramoz,andJ.Epelbaum(ParisandBrunoy,France)

SECTION20Reproduction,olfactionandsexualbehavior

31.Sexualdifferentiationofthehumanhypothalamus:Relationshiptogenderidentityandsexual orientation

405

427 D.F.Swaab,S.E.C.Wolff,andA.-M.Bao(Amsterdam,TheNetherlandsandHangzhou,China)

32.Klinefeltersyndromeortesticulardysgenesis:Genetics,endocrinology,andneuropsychology445 A.Skakkebæk,M.Wallentin,andC.H.Gravholt(Aarhus,Denmark)

33.Neurobiologyofpubertyanditsdisorders 463

S.F.WitchelandT.M.Plant(Pittsburgh,UnitedStates)

Contentsofrelatedvolumes

Volume179(TheHumanHypothalamus:AnteriorRegion)

Volume180(TheHumanHypothalamus:MiddleandPosteriorRegion)

Volume182(TheHumanHypothalamus:NeuropsychiatricDisorders)

ContentsofVolume179

Forewordvii

Prefaceix

Contributorsxiii

SECTION1Introduction

1.Introduction:Theanteriorhypothalamus3 D.F.Swaab,R.M.Buijs,F.Kreier,P.J.Lucassen,andA.Salehi(Amsterdam,TheNetherlands, CiudaddeMexico,MexicoandPaloAlto,UnitedStates)

2.Historyofhypothalamicresearch: “Thespringofprimitiveexistence”

7 F.KreierandD.F.Swaab(Amsterdam,TheNetherlands)

3.Anatomyandcytoarchitectonicsofthehumanhypothalamus

45 B.Dudás(Erie,UnitedStatesandSzeged,Hungary)

4.Morphologyanddistributionofhypothalamicpeptidergicsystems

67 B.DudásandI.Merchenthaler(ErieandBaltimore,UnitedStatesandSzeged,Hungary)

5.MRImaps,segregation,andwhitematterconnectivityofthehumanhypothalamusinhealth87 J.-J.LemaireandA.DeSalles(Clermont-Ferrand,France,LosAngeles,UnitedStatesandSãoPaulo, Brazil)

6.Magneticresonanceimagingofthehypothalamo–pituitaryregion

95 M.Perosevic,P.S.Jones,andN.A.Tritos(Boston,UnitedStates)

7.Resting-statefunctionalconnectivityofthehumanhypothalamus

113 S.KullmannandR.Veit(TubingenandNeuherberg,Germany)

8.Neurogenesisintheadulthypothalamus:Adistinctformofstructuralplasticityinvolvedinmetabolic andcircadianregulation,withpotentialrelevanceforhumanpathophysiology

125 A.Sharif,C.P.Fitzsimons,andP.J.Lucassen(Lille,FranceandAmsterdam,TheNetherlands)

9.Matchingofthepostmortemhypothalamusfrompatientsandcontrols

141 D.F.SwaabandA.-M.Bao(Amsterdam,TheNetherlandsandHangzhou,China)

SECTION2Thebasalforebraincholinergicsystem

10.Spatialtopographyofthebasalforebraincholinergicprojections:Organizationandvulnerability todegeneration

159 T.W.SchmitzandL.Zaborszky(London,CanadaandNewark,UnitedStates)

11.ThediagonalbandofBrocainhealthanddisease

175 A.K.L.LiuandS.M.Gentleman(London,UnitedKingdom)

12.NucleusbasalisofMeynertdegenerationpredictscognitiveimpairmentinParkinson'sdisease189 H.Wilson,E.R.deNatale,andM.Politis(London,UnitedKingdom)

13.Enlargementofearlyendosomesandtrafficjaminbasalforebraincholinergicneuronsin Alzheimer'sdisease

207 A.Fahimi,M.Noroozi,andA.Salehi(LosAngelesandPaloAlto,UnitedStates)

14.GeneandcelltherapyforthenucleusbasalisofMeynertwithNGFinAlzheimer'sdisease219 M.EriksdotterandS.Mitra(StockholmandHuddinge,Sweden)

SECTION3Thecircadiansystem

15.Thecircadiansystem:Fromclockstophysiology

233 R.M.Buijs,E.C.SotoTinoco,G.HurtadoAlvarado,andC.Escobar(CiudaddeMexico,Mexico)

16.Developmentofthecircadiansystemandrelevanceofperiodicsignalsforneonataldevelopment249 C.Escobar,A.Rojas-Granados,andM.Angeles-Castellanos(CiudaddeMexico,Mexico)

17.Disruptedcircadianrhythmsandmentalhealth

259 W.H.WalkerII,J.C.Walton,andR.J.Nelson(Morgantown,UnitedStates)

18.DiurnalandseasonalmolecularrhythmsinthehumanbrainandtheirrelationtoAlzheimerdisease271 A.S.P.Lim(Toronto,Canada)

19.CircadianchangesinAlzheimer'sdisease:Neurobiology,clinicalproblems,andtherapeutic opportunities

285 K.ToljanandJ.Homolak(Cleveland,UnitedStatesandZagreb,Croatia)

20.ThecircadiansysteminParkinson'sdisease,multiplesystematrophy,andprogressive supranuclearpalsy

301 K.FifelandT.DeBoer(Ibaraki,JapanandLeiden,TheNetherlands)

21.Retinaandmelanopsinneurons

315 C.LaMorgia,V.Carelli,andA.A.Sadun(Bologna,ItalyandLosAngeles,UnitedStates)

22.Melatoninandthecircadiansystem:Keysforhealthwithafocusonsleep

331 P.Pevet,E.Challet,andM.-P.Felder-Schmittbuhl(Strasbourg,France)

23.Melatoninreceptors,brainfunctions,andtherapies

345 A.Oishi,F.Gbahou,andR.Jockers(Paris,France)

24.Chronotherapy

357 D.P.Cardinali,G.M.Brown,andS.R.Pandi-Perumal(BuenosAires,ArgentinaandToronto,Canada)

25.Theuseofmelatonintomitigatetheadversemetabolicsideeffectsofantipsychotics

371 F.Romo-Nava,R.M.Buijs,andS.L.McElroy(MasonandCincinnati,UnitedStates andCiudaddeMexico,Mexico)

SECTION4Bednucleusofthestriaterminalisandthefearcircuit

26.Chemoarchitectureofthebednucleusofthestriaterminalis:Neurophenotypicdiversity andfunction

S.E.Hammack,K.M.Braas,andV.May(Burlington,UnitedStates)

27.Functionalanatomyofthebednucleusofthestriaterminalis–hypothalamusneuralcircuitry: Implicationsforvalencesurveillance,addiction,feeding,andsocialbehaviors

385

403 I.Maita,A.Bazer,J.U.Blackford,andB.A.Samuels(PiscatawayandNashville,UnitedStates)

28.Rolesofthebednucleusofthestriaterminalisandamygdalainfearreactions

419 A.M.Hulsman,D.Terburg,K.Roelofs,andF.Klumpers(NijmegenandUtrecht,TheNetherlandsand CapeTown,SouthAfrica)

SECTION5Preopticarea

29.Themedianpreopticnucleus:Amajorregulatoroffluid,temperature,sleep,andcardiovascular homeostasis

M.J.McKinley,G.L.Pennington,andP.J.Ryan(Parkville,Australia)

30.Theneuroendocrinologyofthepreopticareainmenopause:Symptomsandtherapeuticstrategies455 M.ModiandW.S.Dhillo(London,UnitedKingdom)

31.Theintermediatenucleusinhumans:Cytoarchitecture,chemoarchitecture,andrelationto sleep,sex,andAlzheimerdisease

C.B.Saper(Boston,UnitedStates)

Forewordvii

Prefaceix

Contributorsxiii

ContentsofVolume180

1.Introduction:Themiddleandposteriorhypothalamus

D.F.Swaab,F.Kreier,P.J.Lucassen,A.Salehi,andR.M.Buijs(Amsterdam,TheNetherlands, PaloAlto,UnitedStatesandCiudaddeMéxico,Mexico)

SECTION6Supraopticandparaventricularnucleusmorethananeuroendocrinesystem

2.Vasopressinandoxytocinbeyondthepituitaryinthehumanbrain 7 M.Møller(Copenhagen,Denmark)

3.Centralandperipheralreleaseofoxytocin:Relevanceofneuroendocrineandneurotransmitter actionsforphysiologyandbehavior

25 F.Althammer,M.Eliava,andV.Grinevich(Atlanta,UnitedStatesandMannheim,Germany)

4.Organizationoftheneuroendocrineandautonomichypothalamicparaventricularnucleus45 A.KalsbeekandR.M.Buijs(Amsterdam,TheNetherlandsandCiudaddeMexico,Mexico)

5.Sexdifferencesofoxytocinandvasopressininsocialbehaviors65 Q.LuandS.Hu(Hangzhou,China)

6.Oxytocin,eatingbehavior,andmetabolisminhumans

89 L.KeremandE.A.Lawson(Boston,UnitedStates)

7.Thesupraopticandparaventricularnucleiinhealthyagingandneurodegeneration

105 C.A.StewartandE.C.Finger(London,Canada)

8.Perinatalstressandepigenetics

125 M.Szyf(Montreal,Canada)

9.Thehypothalamusinanxietydisorders

149 S.Fischer(Zurich,Switzerland)

10.Congenitalisolatedcentralhypothyroidism:Novelmutationsandtheirfunctionalimplications161 A.Boelen,A.S.P.vanTrotsenburg,andE.Fliers(Amsterdam,TheNetherlands)

SECTION7Zonaincerta

11.Thezonaincertasystem:Involvementinattentionandmovement

173 S.Chometton,M.Barbier,andP.-Y.Risold(LosAngelesandNewYork,UnitedStates andBesanc ¸on,France)

SECTION8Ventromedialnucleusanddorsomedialnucleus

12.Theroleofthedorsomedialandventromedialhypothalamusinregulatingbehaviorallycoupled andrestingautonomicdrive

187 L.A.HendersonandV.G.Macefield(SydneyandMelbourne,Australia)

SECTION9Circumventricularorgansofthehypothalamus

13.Thesubfornicalorganandorganumvasculosumofthelaminaterminalis:Criticalroles incardiovascularregulationandthecontroloffluidbalance 203 W.M.FryandA.V.Ferguson(WinnipegandKingston,Canada)

14.Laminaterminalisfenestration:Animportantneurosurgicalcorridor 217 C.GiussaniandA.DiCristofori(MilanandMonza,Italy)

15.Arcuatenucleus,medianeminence,andhypophysialparstuberalis 227 H.-W.KorfandM.Møller(D € usseldorf,GermanyandCopenhagen,Denmark)

16.Tanycytesintheinfundibularnucleusandmedianeminenceandtheirroleintheblood –brainbarrier253 V.Prevot,R.Nogueiras,andM.Schwaninger(Lille,France,SantiagodeCompostela,Spain andL € ubeck,Germany)

17.Thehumanhypothalamickisspeptinsystem:Functionalneuroanatomyandclinicalperspectives275 E.Hrabovszky,S.Takács, E.Rumpler,andK.Skrapits(Budapest,Hungary)

18.KisspeptinandneurokininBexpressioninthehumanhypothalamus:Relationtoreproduction andgenderidentity

297 J.Bakker(Liège,Belgium)

19.Theinfundibularpeptidergicneuronsandgliacellsinovereating,obesity,anddiabetes

315 M.J.T.KalsbeekandC.-X.Yi(Amsterdam,TheNetherlands)

20.Hypothalamusandweightlossinamyotrophiclateralsclerosis

327 R.M.Ahmed,F.Steyn,andL.Dupuis(SydneyandBrisbane,AustraliaandStrasbourg,France)

SECTION10Lateraltuberalnucleus

SECTION11Lateralhypothalamicarea,perifornicalarea

21.Theorexin/hypocretinsysteminneuropsychiatricdisorders:Relationtosignsandsymptoms343 R.Fronczek,M.Schinkelshoek,L.Shan,andG.J.Lammers(Leiden,HeemstedeandAmsterdam, TheNetherlands)

22.Pleasure,addiction,andhypocretin(orexin)

359 R.McGregor,T.C.Thannickal,andJ.M.Siegel(LosAngeles,UnitedStates)

SECTION12Tuberomamillarycomplex

23.Histaminereceptors,agonists,andantagonistsinhealthanddisease

377 P.Panula(Helsinki,Finland)

24.Thetuberomamillarynucleusinneuropsychiatricdisorders

389 L.Shan,R.Fronczek,G.J.Lammers,andD.F.Swaab(Leiden,HeemstedeandAmsterdam, TheNetherlands)

SECTION13Subthalamicnucleus

25.Imagingofthehumansubthalamicnucleus

403 A.AlkemadeandB.U.Forstmann(Amsterdam,TheNetherlands)

26.Neuropsychiatriceffectsofsubthalamicdeepbrainstimulation

417 P.E.MosleyandH.Akram(Brisbane,AustraliaandLondon,UnitedKingdom)

27.ThesubthalamicnucleusandtheplaceboeffectinParkinson'sdisease

E.Frisaldi,D.A.Zamfira,andF.Benedetti(Turin,ItalyandPlateauRosà,Switzerland)

SECTION14Corporamamillaria,fornix,andmamillothalamictract

28.Electricalstimulationofthefornixforthetreatmentofbraindiseases

S.HeschamandY.Temel(Maastricht,TheNetherlands)

29.ThecontributionofmamillarybodydamagetoWernicke'sencephalopathyandKorsakoff's syndrome

N.J.M.Arts,A.-L.Pitel,andR.P.C.Kessels(Venray,Wolfheze,andNijmegen,TheNetherlandsand CaenandParis,France)

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