Measures of cardiovascular autonomic activity in insomnia disorder

31 Pages·2017·1.62 MB·English

RESEARCHARTICLE
Measures of cardiovascular autonomic
activity in insomnia disorder: A systematic
review
Marina-MarinelaNano1,2,3*,PedroFonseca1,3,RikVullings1,RonaldM.Aarts1,3
1DepartmentofElectricalEngineering,EindhovenUniversityofTechnology,Eindhoven,TheNetherlands,
2SleepMedicineCentreKempenhaeghe,Heeze,TheNetherlands,3PhilipsResearch,HighTechCampus,
Eindhoven,TheNetherlands
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*[email protected]
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Abstract
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Background
Insomniadisorderisawidespreadsleepdisorderwithaprevalenceofapproximately10%.
OPENACCESS
Eventhoughthelinkbetweeninsomniaandcardiovascularactivityisnotexactlyclear,itis
Citation:NanoM-M,FonsecaP,VullingsR,Aarts
generallyassumedthatcardiovascularautonomicmodificationscouldoccurasaresultof
RM(2017)Measuresofcardiovascularautonomic
sleeplessness,or,alternatively,thatautonomicalterationscouldbeanexpressionofa
activityininsomniadisorder:Asystematicreview.
PLoSONE12(10):e0186716.https://doi.org/ hyper-arousalstate.Thisreviewinvestigateswhethercardiovascularmeasuresaredifferent
10.1371/journal.pone.0186716 betweeninsomniacsandcontrols.
Editor:JacobusP.vanWouwe,TNO,
NETHERLANDS Methods
Received:June16,2017 Electronicdatabasesweresystematicallysearched,and34studieswereidentified.Heart
Accepted:October8,2017 ratevariabilityfeatures,theassociationofcardiacandEEGactivity,physiologiccomplexity
measures,andcardiovascularactivity,assessedbymeasuressuchaspre-ejectiontime,
Published:October23,2017
bloodpressure,andheartratedynamicswerestudied.Giventheheterogeneityofthestud-
Copyright:©2017Nanoetal.Thisisanopen
ies,anarrativesynthesisofthefindingswasperformed.
accessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,and Results
reproductioninanymedium,providedtheoriginal
authorandsourcearecredited. Thisreviewstudyfoundoveralldifferencesincardiovascularactivitybetweeninsomniacs
andcontrolsinmostoftheobservationalstudies(21/26),whiletheexpressionofcardiovas-
DataAvailabilityStatement:Allrelevantdataare
withinthepaperanditsSupportingInformation cularregulationvariedbetweentheexaminedinsomniacgroups.Allthestudiesthatinvesti-
files. gatedtheassociationofcardiacactivityandEEGpowerreportedanalteredrelation
Funding:ThisworkhasbeendoneintheIMPULS betweenautonomicactivityandEEGparametersininsomniacs.
framework(EindhovenUniversityofTechnology,
PhilipsResearch,SleepMedicineCentre
Conclusion
Kempenhaeghe).Thefundershadnoroleinthe
studydesign,decisiontopublish,orpreparationof Autonomicregulationtendstobeconsistentbetweeninsomniacs,aslongastheyare
themanuscript.PhilipsResearchprovidedsupport
groupedaccordingtotheirrespectivephenotype,asshownintheinsomniasubgroupwith
intheformofsalariesforauthorsPFandRMA,but
objectivelyshortsleepduration.Ourhypothesisisthatthesedifferencesintheexpression
didnothaveanyadditionalroleinthestudydesign,
datacollectionandanalysis,decisiontopublish,or ofcardiovascularactivitycouldbeexplainedbytheheterogeneityofthedisorder.Therefore,
PLOSONE|https://doi.org/10.1371/journal.pone.0186716 October23,2017 1/31
Cardiovascularautonomicactivityininsomniadisorder
preparationofthemanuscript.Thespecificrolesof thedeterminationofinsomniaphenotypes,andthestudyofcardiovascularmeasures,
theseauthorsarearticulatedinthe‘author ratherthanheartratevariabilityalone,willgivemoreinsightintothelinkbetweeninsomnia
contributions’section.
andcardiovascularregulation.Thisstudysuggeststhatcardiovascularactivitydiffers
Competinginterests:M-MN,PFandRMAdeclare betweeninsomniacsandcontrols.Thesenewfindingsareofinteresttocliniciansand
tobeaffiliatedwithPhilipsResearch.RVreports
researchersforamoreaccurateinsomniaassessment,andthedevelopmentofpersonal-
otherfromNemoHealthcare,outsidehissubmitted
work.ThisdoesnotalterouradherencetoallPLOS izedtechnologicalsolutionsininsomnia.
ONEpoliciesonsharingdataandmaterials.
Introduction
Difficultiesinitiatingormaintainingsleepareveryprevalentsleepcomplaintsinthegeneral
population[1,2].Ifsleeplessnessmeetspecificdiagnosticcriteriatheterminsomniadisorder
isused.MultinationalstudiesthatusedtheDiagnosticandStatisticalManualofMentalDisor-
dersfourthedition(DSM-IV)criteriareportedprevalenceratesofinsomniadisorderthat
rangefrom3.9%to22.1%,withanaverageofapproximately10%[3].Thisisabroadrange
thatreflectsdifferentmodalitiesofinvestigationandthepopulationunderstudy[1].Informa-
tionfromnewstudiesontheprevalenceofinsomniadisorderusingDSM-Vcriteria,iscur-
rentlylimited.
OnthelatestupdateofDSM,insomniadisorderisdefinedasapredominantcomplaintof
dissatisfactionwithsleepqualityordurationandisaccompaniedbydifficultiesininitiating
sleepatbedtime,frequentorprolongedawakenings,orearly-morningawakening,withan
inabilitytoreturntosleep[4].Thissleepdisturbancecausesclinicallysignificantsocial,occu-
pational,educational,academic,andbehavioraldistressorimpairment.Thesedifficulties
occurdespiteadequateopportunityforsleep.Diagnosisofinsomniaismadewhensleepdiffi-
cultiesarepresentfor3ormorenightsperweek,andlastformorethan3months[4].Thus,
insomniaisaconditioncharacterizedbybothnocturnalanddiurnalsymptoms.
Thecardiovascularautonomicnervoussystem(ANS)appearstobecloselylinkedtosleep
andcircadianphysiology,asdemonstratedbythedisruptedautonomiccontrolthataccompa-
niessleeploss[5].Additionally,autonomicactivityisintegratedwithcognitionandemotion,
amongothers[6].Sleeplossordeficiencycanusuallyoccursasaresultofsleepdeprivation,
sleepfragmentation,ordifficultyoffallingasleep.Ininsomniadisordersleeplossisusually
causedbydifficultiesofmaintaining(fragmentedsleep)orinitiatingsleep.Inadditiontosleep
loss,insomniadisorderisfrequentlyaccompaniedbyvariouschanges,suchascognitive
arousal/stress,degradedmood,depressionoranxietyandfatigue[7].Todate,twomajor
hypotheseshavebeenmadeaboutthelinkbetweenautonomicfunctionandinsomnia[8].
Accordingtothefirsthypothesis,autonomicmodificationscouldoccurasaresultofsleep
fragmentation[9].Thishypothesisissupportedbystudiesshowingthatautonomicarousals
withoutcorticalinvolvementareanepiphenomenonofsleepfragmentationandalteredsleep
continuity[9].Furthermore,autonomicsleepfragmentationhasbeenlinkedtodiurnal
increaseinsympatheticactivityandelevatedbloodpressure(BP)inhealthyelderly[10].
Accordingtothesecondhypothesis,autonomicalterationscouldbeanexpressionofahyper-
arousalstate[8].Evidenceofanincreaseinheartrate(HR)andtheabsenceofanormaldrop
inautonomicactivityduringfallingasleep,alongwithalterationsofotherphysiologicparame-
ters(e.g.bodytemperatures,stresshormones),couldbeconsideredindicatorsofastateof
arousalthatpredisposestheindividualtopoorsleep[11–13].Therefore,relevantphysiology
dataobtainedbycardiovascularANSmeasuresmayprovidenewinsightintothelinkbetween
insomniadisorderandcardiovascularautonomicactivity.
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Cardiovascularautonomicactivityininsomniadisorder
Whiletworeviews[14,15]examiningheartratevariability(HRV)andonereview[16]
investigatingcardiovasculardysfunctionbetweennormalsleepandsleepdisordershavebeen
published,theirprimaryfocuswasnotinsomniadisorder,sofindingsregardinginsomnia
werenotmethodicallyincorporated.Onereview[17]focusingexclusivelyonHRVandinsom-
niawasrecentlypublished.Cardiovascularactivity,comparedtoHRValone,providesamore
completeoverviewoftheautonomicactivity.Forinstance,studieshaveshownthattheuseof
HRVfortheestimationofautonomicregulationhaslimitations[18]andadditionaldiagnostic
valuecanbeobtainedfrommeasuressuchaspre-ejectionperiod(PEP)[19].Inthisstudy,we
donotrestrictthereviewtoHRV,asDoddsetal.[17]did,butalsoincorporateothercardio-
vascularmeasuresofautonomicactivity,suchasPEP,cardiopulmonarycoupling(CPC),left
ventricularejectiontime,BPandHRslopefortheanalysisofHRdynamicsinordertoinvesti-
gatewhethercardiovascularactivitymeasuresaredifferentbetweeninsomniacsandcontrols.
Inaddition,weaimtoexaminehowinterventionsinfluencecardiovascularactivity.
Methods
Searchstrategy
Forthisreview,thePubMedandScopuselectronicdatabasesweresystematicallysearchedfor
articlespublisheduntil9thofOctober2016,usingkeywordstoidentifyallstudiesspecifically
designedtodefinecardiovasculardifferencesbetweeninsomniacsandhealthycontrols.A
searchofpublicationswasconductedusingthefollowingmedicalsubjectheadingsorkey
words:“heartrate”,“cardiac”,“cardio”,“bloodpressure”,“autonomic”,“sympathetic”,“para-
sympathetic”,“arterial”,“vascular”,“baroreflex”and“insomnia”.Basedonsearchoptionspro-
videdbythetwoelectronicdatabases,thesearchapproachwasadjustedasshowninS1
Appendix.Toensureliteraturesaturation,weexaminedthereferencelistsoftheincluded
papersandoftherelevantreviewswhichwereidentifiedbythesearch.Theliteraturesearch
waslimitedtostudiesconductedwithhumanparticipants,publishedintheEnglishlanguage.
Studyselection
Inordertoidentifyrelevantpublications,thefollowingcriteriawereappliedintheinitial
stagesofthescrutinyprocess:(1)participantswereadult((cid:21)18yearsold),(2)studiesinclude
adultsparticipantsdiagnosedwithinsomnia(observational)ortreatedforinsomnia(interven-
tional),(3)comparisonofinsomniacswithcontrolgroup(observationalstudies)orsame
groupofinsomniacsbeforeandafterintervention(interventionalstudies),and(4)observa-
tionalstudiesincludenon-invasivetechniques,butnotinvitrotests,suchassalivatest.Articles
meetingthesecriteriawerecollectedanddatawasextractedforanalysisbythefirstauthor.
Afterduplicateremovalstudieswerereviewedforeligibilityusingtitle,abstractandfulltext
whenitwasrequired.
Cardiovascularmeasuresusedtoexploreautonomicchangesandtheir
physiologicalsignificanceinterpretation
Inthissection,cardiovascularmeasuresusedinliteraturetoinvestigateandstudyautonomic
changesareintroduced.Additionally,theirphysiologicalinterpretationispresented.
Overthepastyears,differentmethodsofcardiovascularautonomicactivityandHRVquan-
tificationhavebeendeveloped,suchasfrequency,time-frequency,temporal,geometrical,and
nonlinearanalysis[20].Autonomiccardiovascularmeasurescanbeexaminedtraditionally
throughthequantificationofaverageHRandBP[5]andmorerecentlythroughnon-linear
approachesbyusingdetrendedfluctuationanalysis(DFA),[21]entropyderived[15,22–24],
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Table1.Summaryoftimedomaincardiovascularmeasuresandtheirphysiologicalinterpretation.
Feature Description ANSinterpretation Study
PEP thetimefromtheonsetoftheECGQ-wavetotheopeningofthe amarkerofbeta-adrenergicsympatheticactivity [12,59–64]
aorticvalve
RPP theproductofHRandSBP indexoftheoverallcardiacworkload [63]
SDNN standarddeviationofRRorNNintervalsforadesiredperiodand bothsympatheticandparasympatheticactivityand [8,13,47,60,
ismeasuredinms thereforeprovidesanindexofoverallHRV 64–67]
RMSSD squarerootofthemeansquareddifferencesofsuccessiveNN parasympatheticactivity [8,13,47,60,
intervalsforadesiredperiod,measuredinms 61,64–67]
pNN50 percentageofsuccessiveNNintervalsthatdiffermorethan50 parasympatheticactivity [8,13,60,64–
ms 66]
Abbreviations—ANS:Autonomicnervoussystem,ECG:electrocardiogram,HRV:heartratevariability,ms:milliseconds,PEP:pre-ejectiontime,RPP:rate
pressureproduct,RRtimeseries:thetimeelapsedbetweentwosuccessiveR-wavesoftheQRScomplexontheelectrocardiogram,study:representsthe
studiesthatthefeaturewasused,Note:Abbreviationnotmentionedherearedescribedinthe“Description”columnofthetable.
https://doi.org/10.1371/journal.pone.0186716.t001
Poincare´Plot[25],andLempel-Ziv[26,27]measures.Asdescribedindetailpreviously[5],
HRandBPvariationscanbeexpressedbythestandarddeviationaroundthemean,orbytheir
rhythmicandnon-rhythmiccomponents.RRtimeseries(thetimeelapsedbetweentwosuc-
cessiveR-wavesoftheQRScomplexontheelectrocardiogram(ECG))andBPalsoshow
short-termoscillationsinafrequencyrangebetween0and0.5Hz.Traditionally,HRVand
cardiovascularparametersaremeasuredinthetimeandfrequencydomain.
StandardHRVanalysishasbeenwellsummarizedbythetaskforceoftheEuropeansociety
ofcardiology[28].ThemostcommonlyusedtimedomainmeasuresaredescribedinTable1.
Ratepressureproduct(RPP)isanindexoftheoverallcardiacworkload[29],andiscalculated
asfollows:HR(cid:3)systolicBP/100[30].HRandBPphysiologicallydecreaseatnight,compared
toduringtheday.SystolicBPreductionatleast10%duringsleep,comparedtodaytime,is
commonlyreferredtoas“dipping”.ThePEPisinfluencedbysympatheticactivity[5].
Inthefrequencydomain,HRVisevaluatedbyspectralanalysis.Asdescribedindetailpre-
viously[5,28,31],spectralanalysisofRRintervalsandBPvariabilitygivesinformationon
howpowerofthesignalisdistributedasafunctionofthefrequency.KayandMarplepre-
sentedanextensivesummaryofseveraltechniquesusedforspectralanalysis[32].Methodsfor
powerspectraldensityestimationcanbegenerallyclassifiedasnon-parametricandparametric
[28].Thetwomostcommonapproaches[33,34]usedforspectralanalysisofRRtimeseries
areFouriertransform(FFT)[31]andautoregressivemodel(AR)[35].Thehighfrequency
power(HF)components(0.15-0.4Hz)reflecttherespiration-drivenmodulationofsinus
rhythm,andhavebeenusedasanindexoftonicvagaldrive[5,28,31,34,36,37].Thephysio-
logicalsignificanceoftheverylowfrequency(VLF)componentisstillunclear,andlimited
datasuggestthatitmightreflectvagalandrein-angiotensinsystemeffectsonHR[14,28,31,
34].Thephysiologicalinterpretationofthelowfrequency(LF)powercomponents(0.04-0.15
Hz)iscontroversial.Somestudies[28,31,38]supporttheconclusionthatLFpowerisconsid-
eredtoreflectbothsympatheticandvagalmodulationoftheheart,whileotherstudies[5,39]
indicatethatitmightbeanindexofthebaroreflexsensitivity(BRS)forcontrolofHR.More-
over,forsomeresearchers[28,37,40,41],LFisseenasamarkerofsympatheticmodulation,
particularlywhenitisexpressedinnormalizedunits.LFrhythmcanalsobemodulatedby
irregularbreathingpatterns[5].Consequently,theLF/HFratioisconsideredbysome
researcherstoexpresssympatho-vagalbalance,andbyothers,toreflectonlysympathetic
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Cardiovascularautonomicactivityininsomniadisorder
modulations[28].ItshouldbenotedthatEckbergetal.[42]questionedtheuseoftheLFasan
indicatorofsympatho-vagaltonebalance.Asdescribedpreviously[28],thesedisagreements
intheinterpretationofLFcanbeattributedtothefactthatseveralconditionsassociatedwith
sympatheticactivation,cancauseadecreaseintheabsolutepoweroftheLFcomponent.For
example,duringsympatheticactivation,tachycardiafollows,andisusuallycharacterizedbya
reductionintotalpower,whiletheoppositehappensduringvagalactivation[28].Inthisway,
whentheLFismeasuredinmillisecondssquared,thevariationsintotalpoweraffectLFand
HFinthesamedirection(fordetailssee[28]).Duetothereductionintotalpower,LFcould
remainunalteredifitismeasuredinmillisecondssquared.Nevertheless,ifnormalizationis
performed,anincreaseinLFbecomesmoreevident[28].Otherreasonsthatcouldexplainthis
discrepancyincludethefactthatrespirationparametersandbehaviorareinfluencedbyage
andactivity,amongothers.Forinstance,duringtasks,individualdifferencesmightexhibita
widerangeofspontaneousbreathingrates,whichmayresultinacontributiontotheHFband
byindividualswithfasterbreathingfrequencies,andacontributiontotheLFbandbyindivid-
ualswithslowerbreathingfrequencies[43].
RegardingBPvariability,LF componentsinsystolicBPvariabilityareconsideredan
BP
indexofefferentsympatheticvascularmodulation,whereastheHF componentsexpress
BP
mechanicaleffectsofrespirationonbloodpressurechanges[5].BRSregulatesBPinorderto
preservestability.BRScanbemeasuredbyeitherprovocationofthecarotidbaroreceptors
withphenylephrineorbythespectraltechniquewhichquantifiesspontaneousfluctuationsof
thesystolicbloodpressurespectralpowerandthecorrespondingRRtimeseriesspectral
powerindifferentfrequencybands[44–46].Thelatterapproachwasfirstintroducedby
Robbeetal.[45]andisusedbytheauthorsofthereviewedstudies[47].TheαBRSiscomputed
usingthesquarerootoftheratioofRRtimeseriesandsystolicBPpowerspectraintheLFand
HFbands(αLFandαHF)[47–49].Theα-indexiscomputedonlywhenthesquaredcoherence
function(k2)ofthesystolicBPandRRtimeseriesexceeded0.56[47–49].αTotalisdefinedas
themeanofαLFandαHF.TF-BRS(theevaluationofthetransferfunctionbetweentimeseries
ofsystolicBPandRRtimeseries)iscomputedbyaveragingthegainfunctionintheLFband
regardlessofagivencoherencebetweensystolicBPandRRtimeseries[47,48,50].TheαLF
describesthegainoftherelationbetweentheBPandRRtimeseriespowerspectraintheLF
band[47,48,50].TheαLFcomponentdescribesthegaininthespectralbandoftherespiration
frequency.αTotalgivesanassessmentoftheoverallbaroreceptorgain[51].
Recently,newmethodshavebeenusedfortheanalysisofHRV,inordertoconsiderthe
non-stationarycharacteristicsoftheECGsignalandthenon-linearfluctuationsinHR.These
techniquesattempttocharacterizecardiovascularANSintermsofregularityandcomplexity,
basedoninformationcarriedbyRRtimeseriesthroughtheuseofentropyderivedandLem-
pel-Zivmeasures[22,23,26,27].Sampleentropyisthenegativelogarithmofconditional
probabilityofthesequencesofRRtimeseries.Highsampleentropyshowsthatthereisalow
probabilityofrepeatedsequencesintheRRtimeseries,whichmeanslowerregularityand
morecomplexityintheRRtimeseries[22,52].Multiscaleentropyisestimatedbasedonthe
computationofthesampleentropyoverarangeoftemporalscales[23](Formoredetails
aboutsampleandmultiscaleentropysee[22,23]).TheLempel-Zivcomplexityalgorithmpro-
videsinformationregardingthecomplexityofRRtimeseries[27].Complexityisrelatedtothe
numberofdistinctpatternsalongtheRRtimeseriesandtherateoftheiroccurrencewithina
givensequence[26].(FormoredetailsregardingtheLempel-Zivcomplexityalgorithmand
thecodingprocedureusedinthereviewedstudiessee[53,54]).Detrendedfluctuationanalysis
(DFA)examinesthefractalscalingpropertiesofHRfluctuationsinthenon-stationaryRR
timeseriesondifferenttimescalesforthedetectionoflong-rangecorrelationbetweentheRR
intervals[21].CPCwasintroducedbyThomasetal.[55]astheproductofthecoherenceand
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Cardiovascularautonomicactivityininsomniadisorder
Table2.Summaryofnonlinearcardiovascularmeasures.
Feature Description Study
entropyofRRtimeseries anon-linearmeasurewhichexaminestheregularityofRRtime [53,
seriesanditincreaseswithgreaterdegreeofirregularityreachinga 68]
maximumatcompletelyrandomsystem
Lempel-Zivcomplexityof anon-linearmeasurethatestimatesthecomplexityofRRtime [53]
RRtimeseries seriesandquantifiestherateofnewpatternsalongthesequence
DFAofRRtimeseries anon-linearmeasurethatcharacterizesthepatternofvariationand [53]
long-rangecorrelationsofRRtimeseriesacrossmultipletime
scales
Abbreviations—DFA:detrendedfluctuationanalysis,RRtimeseries:thetimeelapsedbetweentwo
successiveR-wavesoftheQRScomplexontheelectrocardiogram,study:representsthestudiesthatthe
featurewasused,Note:Abbreviationnotmentionedherearedescribedinthe“Description”columnofthe
table.
https://doi.org/10.1371/journal.pone.0186716.t002
cross-spectralpoweroftheRRorNNtimeseriesandtheECG-derivedrespiratorytimeseries.
ECG-spectrographicvariableswerefoundtocorrelatestronglywithEEGmeasuresofsleep
stability,suggestingthattheresultingsleepspectrogramcanclassifysleepas“stable”(high-fre-
quencycouplingband(0.1—0.4Hz)(HFC))and“unstable”(low-frequencycouplingband
(0.1—0.4Hz)(LFC))[55–57].Thecardiovascularmeasuresandtheirinterpretationthatare
usedinthereviewedstudiesarepresentedinTables1,2and3.Fordetailsaboutthe
Table3.Summaryofthefrequencycardiovascularmeasuresandtheirphysiologicalinterpretation.
Feature Description ANSinterpretation Study
Total varianceofallRRorNNintervalsmeasuredinms2 [59,60]
power
VLF Lowfrequencypower(0.003—0.04Hz)measuredinms2 parasympatheticactivityandrenin- [68]
angiotensinsystemeffectsonHR
LF verylowfrequencypower(0.04—0.15Hz)measuredinms2 measurethatincludesbothsympathetic [8,11–13,47,59,60,
andvagalinfluence* 64–67,69–78]
LF lowfrequencypower(0.04—0.15Hz)normalizedusingtotalpower markerofsympatheticmodulation* [8,11–13,47,59,60,
norm
64–67,69–78]
HF highfrequencypower(0.15—0.4Hz)measuredinms2 markerofparasympathetic/vagalactivity [8,13,47,60,64–67]
HF highfrequencypower(0.15—0.4Hz)normalizedusingtotalpower markerofparasympathetic/vagalactivity [8,13,47,60,64–67]
norm
LF/HF ratioofLFtoHF reflectssympatho/vagalbalanceor [8,11,13,59,60,64–
sympatheticmodulations* 67,69–71,73–77]
1/f slopeofthepower-lowregressionlineofRRtimeseriesfittedtothe [53]
powerspectrumforf<0.01Hz
CPC theproductofthecoherenceandcross-spectralpoweroftheRRorNN [57]
timeseriesandtheECG-derivedrespiratorytimeseries
αLF thesquaredrootoftheratioofRRtimeseriesandsystolicBPpower [47]
spectrainthe(0.04-0.15Hz)frequencybandmeasuredinms/mmHg
αHF thesquaredrootoftheratioofRRtimeseriesandsystolicBPpower [47]
spectrainthe(0.15-0.4Hz)frequencybandmeasuredinms/mmHg
αTotal meanofαLFandαHFmeasuredinms/mmHg [47]
Abbreviations—ANS:autonomicnervoussystem,CPC:cardiopulmonarycoupling,HRV:heartratevariability,mmHg:millimeterofmercury,ms:
milliseconds,Totalpower:varianceofallNNorRRintervals,study:representsthestudiesthatthefeaturewasused
*:theinterpretationiscontroversial,Note:Abbreviationnotmentionedherearedescribedinthe“Description”columnofthetable.
https://doi.org/10.1371/journal.pone.0186716.t003
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Cardiovascularautonomicactivityininsomniadisorder
Fig1.Studysearchandselectionformeasuresofcardiovascularactivityininsomniacsandcontrols.
ModifiedPRISMA2009flowdiagram[89].
https://doi.org/10.1371/journal.pone.0186716.g001
descriptionandANSinterpretationcolumnsoftheTables1,2,and3pleasesee[5,14,21–23,
28,47–51,53–55,58].
Results
Reviewedstudies
Theinitialcombineddatabasesearchgenerated709records.Afterduplicateremovaland
Englishlanguagerestriction,427electronicrecordswereidentifiedandscreenedforeligibility.
Themanualsearchofreferencelistsofrelevantpapersandreviewsidentifiedthreepapers
[53,64,72].Threeadditionalstudies[79–81]wereaddedtoexplainthetransitionfrom“poor”
sleeperstoclinicallydefinedinsomniacs.Thevastmajorityofthesearticles(n=366)were
excludedbytitleorabstractalone(seeFig1)basedoncriteriamentionedearlier.Fulltextarti-
cleswereobtainedforthe61remainingarticles.Ultimately,34studieswereidentifiedthatmet
theinclusioncriteriaforthisreview.Twentysixobservationalstudies([8,11–13,47,53,57,
59–63,65,66,68–73,82–87])andeightinterventionalstudies([64,67,74–78,88]).Study
detailssuchasdiagnosticcriteria,demographics,numberofparticipants,insomniaseverity,
andtypeofinterventionarepresentedinTables4and5.
Observationalstudies
Studieswithoutspecificdiagnosticcriteriaforinsomniadisorder. Instudieswithout
specificdiagnosticcriteriaforinsomniadisorder,physiologicaldifferencesduringsleepwere
investigatedbetweenthe“poor”and“good”sleepergroups[79],aswellassubjectswithsleep-
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Cardiovascularautonomicactivityininsomniadisorder
Table4.Characteristicsofthe26observationalstudies.
Authors Sample,SexAge Diagnosticcriteria InsomniaSeverity SleepEfficiency Monitoringandanalysis
(mean±std, (Insomniacs- details
range) Controls)
Stepanski Insomniacs: DIMS(psychophysiologicalor ND <85%—>90% Monitoringtime:duringsleep
etal.[82] 24M idiopathicinsomnia)andSE<85% (PSGof1night) andamorningtask,ECG
34.5±8.3,ND ononePSGnight samplingrate:ND,Periodof
analysis:averagedoveran
Controls: hour,Spectralanalysis
25M technique:Notapplicable
34.0±7.6,ND
Bonnetetal. Insomniacs: Subjectivelyreportedinsomnia Insomniacssubjectively 82±11%—93 Monitoringtime:during
[11] 12(M&F) for(cid:21)4nightsperweekforayear reported:i)asleepproblem; ±3.2% sleep,ECGsamplingrate:
31.2±6.8,ND AND(SOL>30minorSE<85%)on ii)(SOL(cid:21)45minOR 500Hz,Periodofanalysis:5
bothPSGnights WASO(cid:21)60min)for(cid:21)4 min,Spectralanalysis
Controls: nightsperweekandiii) technique:BMDPTl
25(M&F) condition>1year Program
29.1±5.2,ND
deZambotti Insomniacs: DSM-IVcriteriaforprimary PSQI:9.67±1.67,AIS: 91(±5)%—96 Monitoringtime:during
etal.[59] 9(4M) insomniaandsubjectivelyreported 10.00±3.16,HS:44.56± (±3)% sleep,ECGsamplingrate:
23.0±2.4,20-26 insomniahistoryfor(cid:21)1year 4.03 500Hz,Periodofanalysis:2
min,Spectralanalysis
Controls: technique:FFT
9(4M)
23.6±3.2,19-28
deZambotti Insomniacs: ResearchDiagnosticCriteriafor PSQI:10.0±2.0,AIS:15.8 87.1(±8.4)%— Monitoringtime:during
etal.[60] 13(8F) primaryinsomniaand(PSQI(cid:21)5, ±3.3,Lengthofinsomnia 94.0(±3.9)% sleep,ECGsamplingrate:
23.0±2.4,20-28 ISI(cid:21)11) (months):58.5±39.9 512Hz,Periodofanalysis:2
mininfrequencydomainand
Controls: 5minintimedomain,
14(7F) Spectralanalysistechnique:
23.6±3.2,23-28 FFT
Spiegelhalder Insomniacs: DSM-IV.Forsecondanalysis: PSQI:11.2±2.8,BDI:9.7 85.8(±9.8)%— Monitoringtime:during
etal.[13] 58(36F) INSDSE(cid:21)85%vsISSD ±6.6,Lengthofinsomnia 89.0(±9.2)% sleep,ECGsamplingrate:
39.5±11.8,ND SE<85%basedonPSG (years):10.9±9.9 (2ndPSGnight) 400Hz,Periodofanalysis:5
min,Spectralanalysis
Controls: technique:FFT
48(27F)
37.3±11.4,ND
Bianchietal. Insomniacs: ND—subjectsunderwent ND ND Monitoringtime:during
[53] 11(M&F) polysomnographicevaluation sleep,ECGsamplingrate:
39.5±11.8,35-50 128Hz,Periodofanalysis:
ND,Spectralanalysis
Controls: technique:ND
17(M&F)
37.3±11.4,40-50
Jurystaal.[69] Insomniacs: DSMIVandICSD-R(revised NDclearly.Availablesleep 74(±9)%—90 Monitoringtime:during
14M edition)forchronicprimary characteristicsforrevision (±3)% sleep,ECGsamplingrate:
42±12,16-63 insomnia,subjectivecomplaints 200Hz,Periodofanalysis:2
for(cid:21)1month,SE<85% min,Spectralanalysis
Controls: technique:FFT
14M
41±10,16-55
Farinaal.[8] Insomniacs: ICSD-2forprimaryinsomnia Meandurationof 82.4(±22)%— Monitoringtime:during
85(38M) insomnia>2years 86.9(±14.2)% sleep,ECGsamplingrate:
53.2±13.6,27-81 256Hz,Periodofanalysis:5
min,Spectralanalysis
Controls: technique:Autoregressive
55(23M) Model
54.2±13.9,27-76
(Continued)
PLOSONE|https://doi.org/10.1371/journal.pone.0186716 October23,2017 8/31
Cardiovascularautonomicactivityininsomniadisorder
Table4. (Continued)
Authors Sample,SexAge Diagnosticcriteria InsomniaSeverity SleepEfficiency Monitoringandanalysis
(mean±std, (Insomniacs- details
range) Controls)
Mazzaetal. Insomniacs: Diagnosisofchronic ValidatedItalianversionof 86.2(±8.5)%— Monitoringtime:during
[70] 6(2F) benzodiazepineabuseaccording thePSQI>5,ESS>6 92.0(±5.3)% sleep,ECGsamplingrate:
53.3±14.9,34-70 totheDSM-IV-TR.Inallcases ND,Periodofanalysis:ND,
patientswereinitiallyprescribed Spectralanalysistechnique:
Controls: forthetreatmentofchronic AutoregressiveModel
55(32F) insomnia
54.2±13.0,27-76
Lanfranchi Insomniacs: DSM-IV-Rforchronicinsomnia Allsubjectssufferedfrom 65(±12)%—92 Monitoringtime:during
etal.[83] 13(9F) andmeetthefollowingcriteria: mixed(difficultiesinitiating (±7)% daytimeandsleep,ECG
42±9,30-60 SubjectivelyreportedSOLand/or andmaintainingsleep) samplingrate:256Hz,
WASO>30min,TST<6.5h, insomnia,ISI:18.2±2.1, Periodofanalysis:averaged
Controls: SE<85%ii)presenceof BDI:9.5±2.1 overonehour,Spectral
13(9F) insomnia(cid:21)3nightsperweek analysistechnique:NA
42±7,30-60 for(cid:21)6monthsiii)ISI(cid:21)15
Fangetal.[65] Insomniacs: DSM-IVforprimaryinsomniaand SubjectivelyreportedSOL 90.2(±4.8)%— Monitoringtime:during
18(6M) atleastoneofthefollowingcriteria and/orWASO>30min, 96.9(±2.1)% daytime,ECGsamplingrate:
34.2±14.5,20-60 onbothactigraphyanddiary TST<6.5,SE<85%b) (basedon 500Hz,Periodofanalysis:5
measures:i)WASO>30min,ii) presenceofinsomnia(cid:21)3 actigraphy) min,Spectralanalysis
Controls: TST(cid:20)6.5h,ii)SE(cid:20)85% nightsperweekfor(cid:21)6 technique:FFT
21(7M) months(c)ISI(cid:21)15.23
27.8±8.7,20-50
Varkevisser Insomniacs: ICSD-Rforchronic Availablecharacteristics 73.3(±3.6)%— Monitoringtime:during
etal.[61] 11(6M) psychophysiologicinsomnia(with (basedonactigraphy)for 82.3(±6.7)% daytime,ECGsamplingrate:
43.8±8.9,31-54 ambulatoryPSG) revision (basedon 1000Hz,Periodofanalysis:
actigraphy) averagedover30sec
Controls: segments,Spectralanalysis
13(7M) technique:NA
44.9±7.7,33-53
Yangetal.[68] Insomniacs: DSM-IVforprimaryinsomnia PSQI:10.7±3.9,BDI: ND Monitoringtime:during
47(4M) 10.9±6.5.Available daytimeandsleep,ECG
41.6±11.7,23-63 characteristicsforrevision samplingrate:ND,Periodof
analysis:ND,Spectral
Controls: analysistechnique:ND
88(4M)
24.8±2.7,22-64
Floametal. Insomniacs: DSM-Vforprimaryinsomnia PSQI:11.2±0.7,insomnia ND Monitoringtime:during
[84] 29(19F) disorder duration(years):6.4±0.8, daytime,ECGsamplingrate:
25.3±1.6,18-55 actigraphybasedSOL: NA,Periodofanalysis:
27±4,WASO:30±3,SFI: averageofthe5
Controls: 15.5±1.4 measurementsovera
19(13F) 15-minperiodSpectral
25.4±1.4,ND analysistechnique:NA
Covassinetal. Insomniacs: DSM-IVforprimaryinsomniaforat Insomniaforatleast1year 90.6(±5.1)%— Monitoringtime:during
[62] 8(4M) least1yearandPSQI:(cid:21)6, andPSQI:9.6±1.3,AIS 96.3(±2.4)% daytime,ECGsamplingrate:
22.9±2.4,ND AIS(cid:21)6,ISI:(cid:21)11 10.8±2.4,ISI:14.0±2.7, 500Hz,Periodofanalysis:
SOL:16.9±14.7,WASO: averagedover30sec
Controls: 27.1±19.1 segments,Spectralanalysis
8(4M) technique:NA
24.8±2.7,ND
Jiangetal.[66] Insomniacs: DSM-IVforprimaryinsomnia PSQI:8.6±2.3 ND Monitoringtime:during
55(25M) daytime,ECGsamplingrate:
30.4±8.4,22-38 ND,Periodofanalysis:ND,
Spectralanalysistechnique:
Controls: ND
63(29M)
31.3±7.7,23-39
(Continued)
PLOSONE|https://doi.org/10.1371/journal.pone.0186716 October23,2017 9/31
Cardiovascularautonomicactivityininsomniadisorder
Table4. (Continued)
Authors Sample,SexAge Diagnosticcriteria InsomniaSeverity SleepEfficiency Monitoringandanalysis
(mean±std, (Insomniacs- details
range) Controls)
Cellinietal. Insomniacs: ResearchDiagnosticCriteriafor PSQI:10.0±2.0,AIS: 87(±8)%—95 Monitoringtime:during
[63] 13(8F) primaryinsomnia,subjectively 15.77±3.27,SOL: (±3)% daytime,ECGsamplingrate:
24.4±1.6,20-28 reportedsymptoms±6months 16.19±16.42,WASO: 512Hz,Periodofanalysis:3
and(PSQI(cid:21)5,ISI(cid:21)11) 45.88±30.17 min,Spectralanalysis
Controls: technique:FFT
14(6F)
23.3±2.5,20-28
Baglionietal. Insomniacs: DSM-IV ISI:12.09±3.32 ND Monitoringtime:during
[85] 21(19F) daytime,ECGsamplingrate:
22.8±3.31,18-30 ND,Periodofanalysis:ND
clearly,Spectralanalysis
Controls: technique:NA
18(12F)
22.0±2.64,18-30
Peteretal.[47] Insomniacs: DSM-IVandPSQI(cid:21)5 PSQIrange:10-17and ND Monitoringtime:during
21(18F) sleepcharacteristics daytime,ECGandBP
48.2±10.4,18-75 availableforrevision samplingrate:200,Periodof
analysis:5-7min,Spectral
Controls: analysistechnique:FFT
21(18F)
48.5±11.1,18-75
Nelsonetal. Insomniacs: DSM-IVandPSQI(cid:21)5 PSQI:9.5±3.0,BDI: ND Monitoringtime:during
[86] 34(18F) 10.3±6.0.Available sleep,ECGsamplingrate:
21.1±4.9,18-45 characteristicsforrevision ND,Periodofanalysis:ND,
Spectralanalysistechnique:
Controls: NA
38(26F)
20.5±2.2,18-45
deZambotti Insomniacs: DSM-IVforprimaryinsomniaand PSQI:9.6±1.3,AIS: 90.0(±4)%—95.0 Monitoringtime:duringsleep
etal.[12] 8(4F) PSQI:(cid:21)6,AIS(cid:21)6,ISI:(cid:21)11 9.6±3.2,ISI:13.4±3.3 (±2)% onset,ECGsamplingrate:
23.3±2.4,20-26 Availablecharacteristicsfor 500Hz,Periodofanalysis:
revision 2.5min,Spectralanalysis
Controls: technique:FFT
8(5F)
23.3±3.2,19-28
Tsaietal.[87] Insomniacs: Subjectivelyreporteddifficultyof PSQI:11.3±2.2,SOL: 90.1(±8.7)%— Monitoringtime:duringsleep
19(13F) fallingasleep(cid:21)20-30minfor(cid:21)3 25.9±40.9.Availablesleep 94.8(±2.8)% onset,ECGsamplingrate:
22.9±1.6,20-25 daysperweekover6monthsand characteristicsforrevision 500Hz,Periodofanalysis:
daytimeconsequencesandPSQI: NA,Spectralanalysis
Controls: >5.Definedas technique:NA
14(5F) psychophysiologicalinsomnia
22.4±1.1,20-25 basedontheobjectivefinding
Maesetal.[71] Insomniacs: DSM-IV-TRandsubjective SOL:33.8±17.1,Mean 79.1(±10.1)%— Monitoringtime:duringsleep
17F SOL>30min,atleast5nightsper durationofinsomnia 89.0(±6.8)% onsetandfirstNREMcycle,
36.2±9.6,19-53 week 10.8±10.9years.Available ECGsamplingrate:1000
sleepcharacteristicsfor Hz,Periodofanalysis:5min,
Controls: revision Spectralanalysistechnique:
11F FFT
37.6±12.6,21-59
Rothenberger Insomniacs: Self-reportInsomniaSymptom ND ND Monitoringtime:during
etal.[72] 19F Questionnaire(Incorporatedto sleep,ECGsamplingrate:
52.1±2.2,ND defineDSM-IVcriteriaforinsomnia 1024Hz,Periodofanalysis:
andResearchDiagnosticCriteria) 2min,Spectralanalysis
Controls: technique:FFT
146F
52.1±2.2,ND
(Continued)
PLOSONE|https://doi.org/10.1371/journal.pone.0186716 October23,2017 10/31