European Journal of Neuroscience EuropeanJournal of Neuroscience, pp. 1–14,2011 doi:10.1111/j.1460-9568.2011.07793.x The neural network of phantom sound changes over time: a comparison between recent-onset and chronic tinnitus patients Sven Vanneste,1 Paul van de Heyning2 and Dirk De Ridder1 1TRITinnitusClinic,Brai2n,TRI&DepartmentofNeurosurgery,UniversityHospitalAntwerp,Wilrijkstraat10,2650Edegem,Belgium 2Brai2n,TRI &ENT,University Hospital Antwerp,Edegem,Belgium Keywords:network, sLORETA,time,tinnitus Abstract Tinnitus is characterized by an ongoing conscious perception of a sound in the absence of any external sound source. Chronic tinnitusisnotoriouslycharacterizedbyitsresistancetotreatment.Inthepresentstudytheobjectivewastoverifywhethertheneural generators and⁄or the neural tinnitus network, evaluated through EEG recordings, change over time as previously suggested by MEG. We therefore analyzed the source-localized EEG recordings of a very homogenous group of left-sided narrow-band noise tinnitus patients. Results indicate that the generators involved in tinnitus of recent onset seem to change over time with increased activityin severalbrainareas [auditorycortex,supplementarymotorareaand dorsalanterior cingulatecortex (dACC) plusinsula], associated with a decrease in connectivity between the different auditory and nonauditory brain structures. An exception to this generalconnectivitydecreaseisanincreaseingamma-bandconnectivitybetweentheleftprimaryandsecondaryauditorycortexand the left insula, and also between the auditory cortices and the right dorsal lateral prefrontal cortex. These networks are both connectedtotheleftparahippocampalarea.Thusacuteandchronictinnitusarerelatedtodifferentialactivityandconnectivityina network comprising theauditory cortices, insula,dACC and premotorcortex. Introduction Tinnitus is characterized by an ongoing conscious perception of a At least two different hypotheses can be proposed to explain why sound in the absence of any physical sound source. Hence it is tinnitusismoredifficulttosuppressifthetinnitusdurationincreases. considered an auditory phantom phenomenon similar to central Firstly, it is possible that the neural generators change over time, i.e. neuropathicpain(Tonndorf,1987;Moller,2000).Tinnitusisperceived new areas become involved in tinnitus generation and the auditory continuouslyby(cid:2)5–15%oftheadultpopulation.Theneurobiological cortex becomes less involved over time. Another possibility can be basisoftinnitusischaracterizedbyanongoingabnormalspontaneous proposed in which the neural connectivity within the same network activity and reorganization of the auditory central nervous system changes over time. In a recent magnetoencephalographic (MEG) (Weisz etal., 2005, 2007a,b; Moazami-Goudarzi etal., 2010), but connectivity study with selected ROIs it was shown that in patients nonauditory brain structures such as the dorsal prefrontal cortex, with recent tinnitus onset (i.e. <4years) the gamma network anterior cingulate cortex, and the (para)hippocampus (Mirz etal., connectionsareconcentratedinthelefttemporalarea(auditorycortex) 2000; De Ridderetal., 2006; Muhlau etal., 2006; Landgrebe etal., whileinchronictinnituspatients(i.e.>4years)thenetworkiswidely 2009)arealsoinvolvedintinnitus,andhowtheseareasco-activatehas distributedovertheentirecortex,withlessinvolvementoftheauditory recentlybeeninvestigated(Schleeetal.,2009). temporalareas(Schleeetal.,2009).However,thetwopropositionsare Several studies have shown that focal stimulation of the temporal notmutuallyexclusive.Itispossiblethatboththeneuralgeneratorand cortex by repetitive transcranial magnetic stimulation (rTMS) (De neuralconnectivitychangewithincreasingtinnitusduration. Ridderetal.,2005b;Kleinjungetal.,2007;Plewniaetal.,2007a)can In the present research the objectives were to verify whether new suppresstinnitusperception.However,theamountofmaximaltinnitus neural generators arise and⁄or whether the neural tinnitus network suppression by rTMS decreases with time (De Ridder etal., 2005b; changes over time. We used the source-localized electroencephalo- Plewniaetal.,2007a;Kleinjunget al.,2007;Khedretal.,2008). graphic (EEG) recordings of a homogenous group of unilateral left- sided narrow-band noise tinnitus patients and analyzed the spectral componentsrelatedtothetinnitusdurationaswellastheconnectivity Correspondence:SvenVanneste,asabove. withinagroupofselectedregionsofinterest(ROIs).TheROIswere E-mail:sven.vanneste@ua.ac.be chosen based on areas involved in tinnitus according to the positron Received20February2011,revised22May2011,accepted13June2011 emission tomography (PET), single-photon emission computed ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd 2 S. Vanneste et al. tomography (SPECT), magnetoencephalography (MEG), EEG and Table1. Patients’characteristics voxel-basedmorphometry (VBM) tinnitus literature. Duration Recentonset Chronic P-value Materials and methods Patients Sex Male 5 4 – Eighteenpatients(N=18;ninemalesandninefemales)withstrictly Female 5 4 unilateral left-sided narrow-band noise tinnitus with a mean age of 60.82yearswereselectedfromthemultidisciplinaryTinnitusResearch Age M 59.78 62.12 0.74 Initiative(TRI)ClinicoftheUniversityHospitalofAntwerp,Belgium. SD 10.62 12.43 NoneofthepatientsincludedinthisstudyhadbeentreatedwithrTMS priortothestudy.Individualswithpulsatiletinnitus,Meńie`re’sdisease, Tinnitusduration M 1.72 8.00 0.001 otosclerosis,chronicheadacheandneurologicaldisorderssuchasbrain SD 0.62 1.85 tumors, and individuals being treated for mental disorders, were excludedfromthestudyinordertoobtainaveryhomogeneoussample. VASintensity M 6.43 7.43 0.21 Assuch,10patientswithtinnitusofrecentonset(<4 years)andeight SD 1.40 1.27 patientswithchronictinnitus(>4but<10years)wereselected.The4- year cutoff was based on the available tinnitus literature. Results of TQ M 53.00 53.80 0.79 microvascular decompression (Moller et al., 1993; Brookes, 1996; SD 10.73 9.86 Jannetta,1997;Ryuetal.,1998;DeRidderetal.,2004,2005a,2007, 2010)andtranscranialmagneticstimulation(DeRidderetal.,2005b; Tinnitusfrequency(Hz) M 4937.50 4720.83 0.85 Plewnia etal., 2007a; Kleinjung et al., 2007; Khedr etal., 2008) SD 2771.14 2777.08 suggestthattinnitusresultsworsenovertime,withaturningpointof efficacy between 3 and 5years. This fits with a magnetoencephalo- Hearingloss*(dBHL) M 26.83 35.00 0.28 graphicstudythatdemonstratesthatafter4yearsthetinnitus-generating SD 20.55 15.37 networkchangesitsconnectivity(Schleeetal.,2009). All patients were investigated for the extent of hearing loss using *MeanHLatthetinnitusfrequency audiograms. Tinnitus matching was performed looking for tinnitus pitch(frequency)andtinnitusintensity.Participantswererequestedto collected with eyes closed (sampling rate 1024Hz, bandpass-filtered refrain from alcohol consumption 24h prior to recording, and from 0.15–200Hz).Datawereresampledto128Hz,bandpass-filtered(fast caffeinated beverage consumption on the day of recording. Each Fouriertransformfilter)to2–44Hzandsubsequentlytransposedinto patient’s subjective tinnitus loudness perception was obtained on a Eureka! Software (Congedo, 2002), plotted and carefully inspected visual analogue scale (VAS) from 0 to 10 and a validated Dutch withmanualrejectionofartifacts.Allepisodicartifactsincludingeye translationofthetinnitusquestionnaire(TQ;Meeuset al.,2007)was blinks, eye movements, teeth clenching, body movement and ECG used to asses tinnitus related distress. A Mann–Whitney U-test was artifacts wereremovedfrom thestream of theEEG.AverageFourier conductedtoverifydifferencesbetweenbothgroupsforage,tinnitus cross-spectral matrices were computed for bands delta (2–3.5Hz), duration,VAS,TQ,andHearingloss.Nosignificantdifferenceswere theta (4–7.5Hz), alpha1 (8–10Hz), alpha2 (10–12Hz), beta1 (13– foundbetweenrecent-onsetandchronictinnituspatientsforage,VAS 18Hz), beta2 (18.5–21Hz), beta3 (21.5–30 Hz) and gamma (30.5– or TQ. Gender was equally balanced. See Table1 for overview. No 44Hz). significantdifferenceswerefoundforhearingloss,asmeasuredbythe lossin decibels (dBSPL) atthe tinnitus frequency. Also, an age- and gender-matched control group (N=12; Source localization mean±SD, 61. 32±10.91years; six males and six females) was Standardizedlow-resolutionbrainelectromagnetictomography(sLO- collected. None of these subjects was known to suffer from tinnitus. RETA) was used to estimate the intracerebral electrical sources that Exclusion criteria were known psychiatric or neurological illness, generated the scalp-recorded activity in each of the eight frequency psychiatric history, abuse of drugs or alcohol, history of head injury bands(Pascual-Marqui,2002).sLORETAcomputeselectricneuronal (withlossofconsciousness),seizures,headache,orphysicaldisability activity as current density (A⁄m2) without assuming a predefined inaparticipant. Toour knowledgethe tinnitus patientsdidnotdiffer number of active sources. The sLORETA solution space consists of fromthe control groupin anyaspect excepttheir tinnitus. 6239 voxels (voxel size 5·5·5mm) and is restricted to cortical gray matter and hippocampi, as defined by digitized Montreal Neurological Institute (MNI)152 template (Fuchs et al., 2002). Scalp EEGdatacollection electrode coordinates on the MNI brain are derived from the EEGrecordings(Mitsar-201;NovaTechhttp://www.novatecheeg.com/) international 5% system(Jurcak etal., 2007). wereobtainedinaquietanddimlylightedroomwitheachparticipant The tomography sLORETA has received considerable validation sitting upright on a small but comfortable chair. This EEG system is from studies combining LORETAwith other more established local- usedbyseveral research groupsover the world (Sherlin etal., 2007; izationmethods,suchasfunctionalmagneticresonanceimaging(fMRI; Muelleretal.,2010;Phlypo&Congedo,2010).Theactualrecording Vitaccoet al.,2002;Mulertetal.,2004),structuralMRI(Worrelletal., lasted(cid:2)5min.TheEEGwassampled with19electrodes (Fp1,Fp2, 2000) andPET(Dierks etal., 2000; Pizzagalli etal.,2004; Zumsteg F7,F3,Fz,F4,F8,T7,C3,Cz,C4,T8,P7,P3,Pz,P4,P8,O1O2)in etal.,2005),andhasbeenusedinpreviousstudiestodetectforexample thestandard10–20Internationalplacement,referencedtolinkedears, activity in the auditory cortex (Zaehle etal., 2007; Vanneste etal., and impedances were checked as remaining below 5kX. Data were 2011). Further sLORETAvalidation has been based on accepting as ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 Theneural network of phantomsoundchanges overtime 3 groundtruththelocalizationfindingsobtainedfrominvasive,implanted Table2. Regionsofinterest depthelectrodes,ofwhichthereareseveralstudiesinepilepsy(Zumsteg et al., 2006a,c) and cognitive event-related potentials (Volpe etal., Authors 2007).Itisworthemphasizingthatdeepstructuressuchastheanterior Amygdala DeRidderetal.(2006)and cingulate cortex (Pizzagalli et al., 2001) and mesial temporal lobes Landgrebeetal.(2009) (Zumsteget al.,2006b)canbecorrectlylocalizedwiththesemethods. InthecurrentimplementationofsLORETA,computationsweremadein Anteriorcingulatecortex Dorsal Plewniaetal.(2007b),Vannesteetal.(2010) arealisticheadmodel(Fuchsetal.,2002),usingtheMNI152template andSchleeetal.(2009) (Mazziotta et al., 2001), with the three-dimensional solution space Subgenual Muhlauetal.(2006)and restricted to cortical gray matter, as determined by the probabilistic Vannesteetal.(2010) Talairachatlas(Lancasteretal.,2000).Thestandardelectrodepositions Auditorycortex Muhlnickeletal.(1998),Schneideretal.(2009), on the MNI152 scalp were taken from (Jurcak et al., 2007) and Smitsetal.(2007)andWeiszetal.(2007a,b) (Oostenveld & Praamstra, 2001). The intracerebral volume is parti- Dorsallateralprefrontal Mirzetal.(2000) tioned into 6239 voxels at 5-mm spatial resolution. Thus, sLORETA cortex images represent the standardized electrical activity at each voxel in Insula Smitsetal.(2007)andVannesteetal.(2010) neuroanatomic MNI space as the exact magnitude of the estimated Parahippocampus Landgrebeetal.(2009) currentdensity.AnatomicallabelsasBrodmannareasarealsoreported usingMNIspace,withcorrectiontoTalairachspace(Brettet al.,2002). the left and right secondary auditory cortex (BA21 and BA22), and werepredefinedbasedontheMNIcoordinates,belongingtoaspecific Brodmannareaonastandardbrain.ROIanalysiswerecomputedfor Functional connectivity the different frequency bandsseparately. Brainconnectivitycanrefertoapatternofanatomicallinks(anatomical Amultivariateanova(i.e.Wilks’Lambda)wasusedforthedifferent connectivity),ofstatisticaldependencies(functionalconnectivity)orof frequency bands with the respective ROIs [i.e. left and right primary causalinteractions(effectiveconnectivity)betweendistinctunitswithin auditorycortex(BA40andBA41)andleftandrightsecondaryauditory anervoussystem.Thepresentresearchfocusesonfunctionalconnec- cortex(BA21andBA22)]asdependentvariablesanddifferentgroups tivitywhichcapturesdeviationsfromstatisticalindependencebetween (recent-onset,chronicandcontrolsubjects)asindependentvariables.A distributed and often spatially remote neuronal units. Statistical Bonferronicorrectionwasappliedformultiplecomparisons. dependencemaybeestimatedbymeasuringcorrelationorcovariance, spectral coherence or phase-locking. Functional connectivity is often calculatedbetweenallelementsofasystem,regardlessofwhetherthese Statistical analyses elements are connected by direct structural links. Unlike structural Themethodologyusedisnonparametric.Itisbasedonestimating,via connectivity,functionalconnectivityishighlytime-dependent.Statis- randomization, the empirical probability distribution for the max- tical patterns between neuronal elements fluctuate on multiple time statistic, under the null hypothesis comparisons (Nichols & Holmes, scales,someasshortastensorhundredsofmilliseconds.Itshouldbe 2002). This methodology corrects for multiple testing (i.e. for the notedthatfunctionalconnectivitydoesnotmakeanyexplicitreference collectionoftestsperformedforallvoxels,andforallfrequencybands). tospecificdirectionaleffectsortoanunderlyingstructuralmodel. Duetothenonparametricnatureofthemethod,itsvaliditydoesnotrely Coherence and phase synchronization between time-series corre- onanyassumptionofGaussianity(Nichols&Holmes,2002). sponding to different spatial locations are usually interpreted as sLORETAstatisticalcontrastmapswerecalculatedthroughmultiple indicatorsoftheconnectivity.However,anymeasureofdependenceis voxel-by-voxelcomparisonsinalogarithmoftheF-ratio.Thesignif- highly contaminated with an instantaneous, nonphysiological contri- icancethresholdwasbasedonapermutationtestwith5000permuta- butionduetovolumeconduction(Pascual-Marqui,2007b).However, tions.Acomparisonwasmadebetweenthetinnitusgroup(recent-onset Pascual-Marqui (2007a) introduced a new technique (i.e. Hermitian andchronictinnitusgroup)andcontrolsubjectsaswellasbetweenthe covariance matrices) that removes this confounding factor. As such, chronictinnitusgroupandthegroupwithtinnitusofrecentonset. this measure of dependence can be applied to any number of brain Connectivitycontrastmapswerecalculatedthroughmultiplevoxel- areas jointly, i.e. distributed cortical networks, whose activity can be by-voxel comparisons using t-statistics. The significance threshold estimatedwithsLORETA.Measuresoflineardependence(coherence) was based on a permutation test with 5000 permutations. Again, a between the multivariate time-series are defined. The measures are comparison was made between the tinnitus group (recent-onset and expressed as the sum of lagged dependence and instantaneous chronictinnitusgroup)andcontrolsubjectsaswellasbetweenchronic dependence. The measures are non-negative and take the value zero tinnitus andtinnitus with recent onset. only when there is independence, and are defined in the frequency To further confirm our connectivity analysis we conducted a split- domain:delta(2–3.5Hz),theta(4–7.5Hz),alpha1(8–10Hz),alpha2 halfreliabilityanalysis.Werandomlydividedindividualsforeachof (10–12Hz), beta1 (13–18Hz), beta2 (18.5–21Hz), beta3 (21.5– the recent-onset and chronic groups into two groups and conducted 30Hz) and gamma (30.5–45Hz). Based on this principle lagged similar connectivity analyses between the recent-onset and chronic linear connectivity was calculated. ROIs were defined based on groupfor both groups. previous brain research ontinnitus (see Table2 for overview). Results ROI analysis Neural generators–tinnitus vs.control Thelog-transformedelectricalcurrentdensitywasaveragedacrossall Acomparisonbetweentinnituspatientsandcontrolsubjectsrevealed voxels belonging to the ROI. ROIs were the left and right primary significant differences for theta, beta2, beta3 and gamma frequency auditorycortices[Brodmannarea(BA)40andBA41respectively]and bands. Increased activity could be found for tinnitus patients in, ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 4 S. Vanneste et al. respectively,thesupplementarymotorarea(BA6)fortheta,thedorsal Table3. Region of interest comparison between patient with recent onset anterior cingulate (BA24) for beta2 and beta3 and the right tinnitus, chronic tinnitus and control subjects for the primary and secondary parahippocampal area (BA37) for gamma (see Fig.1; P<0.05). No auditorycortexingammabandfrequency significantdifferencescouldberetrievedforthedelta,alpha1,alpha2 Recentonset Chronic Control orbeta1 frequencies. primaryAC left 1.77a 2.22a 1.33b Neuralgenerators–chronictinnitusvs.tinnitusofrecentonset right 1.72a 2.49a 1.42b The same frequencies as when comparing tinnitus patients with the secondaryAC controlgroupshowedsignificantdifferencesbetweenchronictinnitus left 3.04a 3.24b 1.84c andtinnituswithrecentonset.Increasedspontaneouselectricalactivity right 2.54a 3.55b 1.88a couldbefoundforchronictinnituspatientsincomparisontotinnitus a,b,cSignificantdifferencesbetweenrecentonsettinnitus,chronictinnitusand patientswithrecentonset,inthesupplementarymotorarea(BA6)for controlsubjects(Bonferronicorrectionformultiplecomparisons). theta, the dorsal anterior cingulate (BA24 and BA32) for beta2 and beta3,theinsula(BA13)forbeta3andtheauditorycortex(BA21and frequencies (see Figs5 and 6; P<0.05). Decreased phase-lagged BA22) for gamma (see Fig.2; P<0.05). No significant differences connectivitycouldbefoundingeneralforthesethreefrequencybands couldberetrievedindelta,alpha1,alpha2orbeta1frequencies. forchronictinnituspatientsincomparisontotinnitusofrecentonset. Furthermore,asignificantincreaseinphase-laggedconnectivitycould ROIanalysis befoundforthegammabandbetweentheleftparahippocampalarea (BA37),leftprimaryandnon-primaryauditorycortices(BA21,BA22, Asignificanteffectwasfoundforthelog-transformedcurrentdensity BA41 and BA42), the left insula (BA13) and the right dorsal lateral for the different groups on the ROI for the gamma frequency band prefrontal cortex (DLPFC; BA9 and BA46) for chronic tinnitus (F =2.43, P<0.05; see Table3). Including all frequency bands 8,48 patients.Twoclosedconnectivityloopswerediscerned.Thefirstwas nexttothegammafrequencybandinoneanalysisdidnotresultina betweentheinsulaandBAs21,22,41and42oftheauditorycortex. significanteffect.However,thissignificanteffectmightremainifthe A second closed connectivity loop was found between DLPFC, and samplesize increased. BA21, BA22 and BA41, BA42 of the auditory cortex (See Fig.3, Univariateanovafurtheryieldedsignificanteffectsforleftprimary below panel). auditorycortex(F =3.54,P<0.05),rightprimaryauditorycortex 2,27 The split-half reliability estimate showed similar results for both (F =5.32,P<0.05),leftsecondaryauditorycortex(F =4.84, 2,27 2,27 theta (see Supporting Information Fig.S1) and gamma bands (see P<0.05) and right secondary auditory cortex (F = 9.30, 2,27 Supporting Information Fig.S3) between the chronic group and the P<0.001). A Bonferroni multiple comparison analysis (P<0.05) acute tinnitus group. That is, decreased phase-lagged connectivity revealed that the control subjects had significant lower log-averaged could be found in general for these frequency bands for chronic current density than either recent-onset tinnitus or chronic tinnitus tinnituspatientsincomparisonwithtinnituspatientswithrecentonset. patientsfortheleftandrightprimaryauditorycortex.Chronictinnitus Foralpha2similarresultswerealsoobtainedalthoughwithadecrease was significantly different from tinnitus with recent onset for the left in phase-lagged connectivity for chronic tinnitus patients in compar- andrightsecondaryauditorycortex.Nosignificanteffectwasobtained isontotinnituspatientswithrecentonset(seeSupportingInformation forthe other frequency bands(P>0.25). Fig.S2).Somedifferenceswiththefrontalareaswerenotedbetween the two split-half groups but these disappeared when the two groups were combined. In addition, significant increases in functional Neuralconnectivity–tinnitus vs. control connectivity could be found for the gamma band between: (i) the A comparison between tinnitus patients and control subjects demon- left-sided parahippocampal area and primary and non-primary audi- stratedsignificantdifferencesfortheta,alpha2andgammafrequency torycortices,and(ii)theinsulatothetinnitussideandtheright-sided bands(seeFigs3and4;P<0.05).Decreasedfunctionalconnectivity DLPFC for chronic tinnitus patients in both groups, with two closed couldbefoundingeneralforthesethreefrequencybandsfortinnitus connectivityloops.Theselatterfindingsfurtherconfirmthereliability patients in comparison to control subjects. Increased synchronized of our results. activity could be found for tinnitus patients in comparison to control subjects within the theta (4–7.5Hz) band between the left and right parahippocampalarea(BA37)andinalpha2(10–12Hz)connectivity between the left parahippocampal area (BA37) and the left auditory Discussion cortex(BA21,BA22),andtherightparahippocampalarea(BA37)and Themainobjectiveofthisstudywastocharacterizethedifferencesin the right auditory cortex (BA21, BA22; see Fig.3; P<0.05). In neural generators and the neural network between tinnitus of recent addition,gamma(30–45Hz)connectivitywasincreasedbetweenthe onset and chronic tinnitus in a very homogenous group. When left parahippocampal area (BA37) and the left and right auditory comparing the tinnitus group with a control group, we found cortex (BA21, BA22) for tinnitus patients in comparison to control differences within the anterior cingulate, medial premotor cortex and subjects (see Fig.4; P< 0.05). No significant differences could be parahippocampal area. Differences were demonstrated in auditory retrieved indelta, alpha1,beta1, beta2 or beta3 frequencies. areas (primary auditory cortex) as well as in nonauditory areas (anteriorcingulate,insulaandmedialpremotorcortex)forthechronic tinnitusgroupincomparisontothetinnitusofrecentonsetgroup.ROI Neuralconnectivity–chronictinnitusvs.tinnitusofrecentonset analysis further revealed that the control subjects had significantly Connectivityanalysisyieldedasignificantdifferencebetweenchronic lowerlog-averagedcurrentdensityincomparisontobothrecent-onset tinnitus and tinnitus with recent onset for theta, alpha2 and gamma tinnitus and chronic tinnitus patients for the left and right primary ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 Theneural network of phantomsoundchanges overtime 5 A B C D Fig.1. sLORETAcontrastanalysisbetweentinnituspatientsandcontrolgroup(P<0.05).Increasedneuralsynchronizationwithin(A)theta(4–7.5Hz),(B)beta2 (18.5–21Hz),(C)beta3(21.5–30Hz),and(D)gamma(30.5–45Hz)in,respectively,(A)supplementarymotorarea(BA6),(B)rightdorsalanteriorcingulate(BA24 andBA32),(C)rightdorsalanteriorcingulate(BA24),and(D)parahippocampalarea(BA19andBA37)fortinnituspatients.L,left;R,right;A,anterior;P,posterior. ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 6 S. Vanneste et al. A B C D Fig.2. sLORETAcontrastanalysisbetweenchronictinnituspatientsandtinnituspatientswithrecentonset(P<0.05).Increasedneuralsynchronizationwithin(A) theta(4–7.5Hz),(B)beta2(18.5–21Hz),(C)beta3(21.5–30Hz),and(D)gamma(30.5–45Hz)in,respectively,(A)rightlateralpremotorarea(BA6),(B)right dorsalanteriorcingulate(BA24andBA32),(C)rightdorsalanteriorcingulate(BA24andBA32)andrightinsula(BA13),and(D)rightauditorycortex(BA21and BA22)forchronictinnituspatients.L,left;R,right;A,anterior;P,posterior. ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 Theneural network of phantomsoundchanges overtime 7 auditory cortex. Furthermore, chronic tinnitus patients had signifi- cortical dysrhythmia as the pathophysiological model for the devel- cantly higher log-averaged current density in comparison to tinnitus opmentofgamma-bandactivityrelatedtothetinnituspercept(Llina´s with recent onsetfor the left andrightsecondary auditory cortex. etal., 1999). According to this model tinnitus is caused by an Differenceswerealsofoundintheneuralnetworkwithadecreased abnormal, spontaneous and constant gamma-band activity (>30Hz) functionalconnectivitybetweenthedifferentROIsfortheta,alphaand generatedasaconsequenceofdeafferentation-inducedhyperpolariza- gamma frequency band for tinnitus patients in comparison to the tionofthe medialgeniculate body.Innormal circumstancesauditory control subjects as well as in the chronic tinnitus patients in stimuli increase thalamocortical rhythms to gamma-band activity comparison to the tinnitus patients of recent onset. Increased phase- (Joliot etal., 1994). In the deafferented state, however, oscillatory laggedconnectivitycould beseenfortinnitus patientsincomparison alpha activity decreases to theta-band activity (4–7Hz; Steriade, to control subjects in the theta frequency band between the left and 2006).Asaresultlateralinhibitionisreduced,inducingasurrounding right parahippocampal area and in alpha2 between the left parahip- gamma-bandactivityknownasthe‘edgeeffect’(Llina´setal.,2005). pocampal area and the left auditory cortex, and the right parahippo- Thisabnormallypersistentcoupledtheta–gammabanddysrhythmiais campal area and the right auditory cortex. Increased phase-lagged relayed to the cortex, selectively in the deafferented thalamocortical connectivity was found in the gamma band between the left columns.Ithasbeenproposedthatsynchronizedgamma-bandactivity parahippocampal area and the left and right auditory cortex for in the auditory cortex binds auditory events into one coherent tinnituspatientsincomparisontocontrolsubjects.Increasedgamma- conscious auditory percept (Ribary etal., 1991; Llinas et al., 1998; band connectivity was also found between the left parahippocampal Crone etal., 2001). The decrease in alpha activity and associated area and primary auditory cortex, the left auditory cortex and right gamma-band activity has been shown to exist in tinnitus (Lorenz auditorycortex,andtheleftauditorycortexandleftinsula,aswellas etal., 2009). However, why there was more activity in the right between the left auditory cortices and the right DLPFC for chronic auditory cortex for chronic left-sided tinnitus patients it not yet tinnitus in comparison to tinnitus of recent onset. established,butahypothesiscanbeproposed.Ourresultsrevealthat there was increased gamma connectivity between the left and right auditorycortexviatheleftparahippocampalareafortinnituspatients in comparison to control subjects. ROI analysis further demonstrated Auditory cortex,parahippocampal areaand supplementary that both the left and right auditory cortex have a higher gamma motor area currentdensityinchronictinnitusincomparisontothecontrolgroup Increased gamma activity was found for tinnitus patients in compar- and that the left auditory cortex for chronic tinnitus patients is ison to control subjects in the parahippocampal area. This might be involved in closed loop with the insula as well as with the DLPFC. related to the constant updating of the tinnitus percept, preventing The reason why only the right auditory cortex is hyperactive in the habituation(DeRidderetal.,2006).Cellsinthehumanhippocampus gamma band and not the left auditory cortex in the global brain andparahippocampalareasrespondtonovelstimuliwithanincrease analysismightberelatedtothefactthattinnitusintensityiscorrelated in firing. However, even on the second presentation of a stimulus, to increased contralateral gamma-band activity (van der Loo etal., neurons in these regions show very different firing patterns. In the 2009),increasingtherightgamma-bandactivityevenmoreintheright parahippocampal region there is dramatic decrease in the number of auditory cortex. cells responding to the stimuli (Viskontas etal., 2006), suggesting a For tinnitus patients increased theta activity was also found in the rapid habituation. This rate of response decrement during trains of supplementarymotorareaincomparisontoacontrolgroup,aswellas several stimulus repetitions is linear for acoustic responses (Wilson intherightsupplementarymotorareaforpatientswithchronictinnitus et al., 1984). In contrast to the rapid auditory habituation in the in comparison to patients with recent-onset tinnitus. The (visual) parahippocampal area, in the hippocampus there is recruitment of a global workspace model has been suggested as a model for the largesubsetofneuronsshowinginhibitoryresponses(Viskontasetal., awareness component of consciousness (Dehaene et al., 2006). It 2006). Thus a novel stimulus is normally associated with parahippo- proposesthatconsciousperceptionofsensoryeventsrequiressensory campal habituation and active hippocampal inhibitory activity. cortex activation embedded in a larger cortical network, the global Repetitive auditory stimuli both in animals (Bickford etal., 1993) workspace, extending beyond the primary sensory regions including andhumans(Boutrosetal.,2008)leadtoattenuationofevent-related prefrontal, parietal and cingulate cortices (Dehaene etal., 2006). potentials, but with differences in hippocampal and parahippocampal Therefore, to be aware of an auditory stimulus, activation of the areas,asearlyhippocampalevent-relatedpotentialsarenotattenuated, primaryauditorycortexisaprerequisitebutisnotsufficient(Laureys inaccordancewith theabovementionedsingle-cellrecordings.Based etal., 2000; Boly etal., 2005). Studies performed on patients in onthesedataitcanbehypothesizedthatintinnitusthismechanismis vegetative state who do not have conscious auditory percepts reveal disrupted with persistent parahippocampal activity, preventing habit- thatauditorystimulistillactivatetheprimaryauditorycortexbutthat uation.Ithasbeenhypothesizedthattheparahippocampalareaplaysa there is no functional connectivity to frontal areas in these patients central role in memory recollection, sending information from the (Bolyetal.,2004). Primary auditorycortex activation might beonly hippocampus to the association areas, and a dysfunction in this relatedtointensitycoding(Janckeetal.,1998)andnottheperceptper mechanismispositedasanexplanationforcomplexauditoryphantom se. Melloni andcolleagues foundthat theta oscillations in the frontal perceptssuchasauditoryhallucinations(Diederenetal.,2010).Inline regionsareessentialforconsciousperceptionduringthemaintenance with this hypothetical mechanism, tinnitus can be seen as a result of intervalofvisualstimuli(Mellonietal.,2007).Takingthesefindings constantsendingofstoredauditoryinformationfromthehippocampus together,weproposethatsynchronizedgammaactivityintheauditory totheauditoryassociationareasbypersistentparahippocampalactivity. cortex is responsible for the tinnitus intensity (van der Loo etal., For chronic tinnitus patients increased gamma activity was also 2009), while synchronized theta activity in the supplementary motor found in the right auditory cortex in comparison to patients with areamightbeaccountablefortheconsciousperceptionofthephantom recent-onset tinnitus, and an ROI analysis demonstrated increased sound, analogous to the conscious perception for somatosensory gammacurrentdensityintinnituspatientsbothinleft-andright-sided stimuli (de Lafuente & Romo, 2002, 2005, 2006). The functional primaryandsecondaryauditorycortices.MEGdatasupportthalamo- heterogeneityofthesupplementalmotorarea(SMA)hasbeenshown ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 8 S. Vanneste et al. A B Fig.3. Connectivitycontrastanalysisbetweentinnituspatientsandcontrolgroup(P<0.05).Decreasedneuralphase-laggedsynchronizationwithin(A)theta(4– 7.5Hz)and(B)alpha2(10–12Hz)connectivityintinnituspatients.Anincreasedneuralphase-laggedtheta(4–7.5Hz)synchronizationcanbeseenbetweentheleft andrightparahippocampalareaandanincreasedneuralphase-laggedalpha2(10–12Hz)synchronizationisevidentbetweentheleftparahippocampalareaandthe leftauditorycortexandtherightparahippocampalareaandtherightauditorycortex.L,left;R,right;A,anterior;P,posterior;S,superior. before and demonstrates that the SMA has multiple functions, auditory imagery and auditory hallucinations (Linden etal., 2011), including motor, sensory, word generation and working memory two conditions of auditory perception without and external sound functions (Chung et al., 2005). The SMA is also activated in both source, analogous to tinnitus. This might be related to illusionary ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 Theneural network of phantomsoundchanges overtime 9 Fig.4. Connectivitycontrastanalysisbetweenbetweentinnituspatientsandcontrolgroup(P<0.05).Decreasedphase-laggedgamma(30–45Hz)synchronization for tinnitus patients is found, except for increased phase-lagged gamma (30–45Hz) synchronization between the left parahippocampal area, the left and right auditorycortex.L,left;R,right;A,anterior;P,posterior;S,superior. continuity, filling in missed auditory input, as unconscious sensory Connectivity repair for missed speech occurs in Broca’s area, bilateral anterior Both decreased and increased connectivity were found in tinnitus insulaandpre-SMA(Shahinetal.,2009).Thisisinaccordancewitha patientsincomparisontocontrolsubjectsbetweenthedifferentROIs PET study of tinnitus (Mirz et al., 2000) which found a right for theta, alpha and gamma activity. For the theta frequency band, prefrontal–temporal network subserving tinnitus perception. In increased connectivity was demonstrated between the left and right chronic tinnitus theta activity is increased in the lower part of the parahippocampal areas. For the alpha2 frequency band, increased premotor cortex. This might be related to tonal memory which in connectivitywasfoundbetweentheleftparahippocampalareaandthe fMRIisrelatedtoactivationofthelowerpremotorcortex(encroach- leftauditorycortex,andbetweentherightparahippocampalareaandthe ingonBroca’sarea),theauditorycortex,theinferiorparietallobeand rightauditorycortex.Increasedconnectivitywasalsorevealedwithin the anterior insula.Asin chronic tinnitus the auditory cortex and the thegammafrequencybandbetweentheleftparahippocampalareaand anterior insula are also more activated in comparison to tinnitus of theleftandrightauditorycortexfortinnituspatientsincomparisonto recent onset this could suggest that chronic tinnitus is mediated by control subjects. Previous research has already demonstrated that a similar areastothose implicated intonal memory. directconnectionbetweentheauditorycortexandtheparahippocampal area is necessary for auditory sensory gating (Grunwald etal., 2003; Boutros etal., 2005, 2008; Korzyukov etal., 2007). With respect to Dorsal anteriorcingulate cortex andinsula tinnitus,patientsshowedapatternofdecreasedfunctionalconnectivity Our result also revealed that the dorsal anterior cingulate cortex indicating that there are fewer connections formed within the brain, (dACC)andinsulabecomemoreinvolvedovertime.Anexplanation similartothefindingsobtainedwithMEG(Schleeetal.,2009). cannot be given yet for their involvement but a hypothesis can be Chronictinnitusincomparisontotinnitusofrecentonsetgoesalong proposed. withadecreaseinthetaandalphaconnectivity,aswellasadecreasein Whether an auditory stimulus is perceived consciously or not gamma connectivity. However, there is also an increase in gamma depends on fluctuations in the dACC and insula (Sadaghiani etal., connectivitybetweenleftparahippocampalcortex,leftauditorycortex, 2009), analogous to what has been described for pain (Boly etal., left insula and right DLPFC. A recent MEG study has indicated 2007). The dACC plus anterior insula are thought to be part of the decreased connectivity in the alpha frequency band together with an salience network (Seeley etal., 2007), encoding behaviourally increase in gamma-band connectivity for longer lasting tinnitus importantandfunctionallysignificantinputs.Thusitisplausiblethat (>4 years; Schlee etal., 2009). The connections between DLPFC, dACCandanteriorinsulasignifyalackofhabituationtotheconstant primary and secondary auditory cortex are interesting, as are those phantom sound, analogous to what has been described for pain betweentheinsulaandtheprimaryandsecondaryauditorycortex.In (Mobascheretal.,2010).Theseresultshavetobeseeninthelightof addition, reduced gamma phase-lagged connectivity was also found connectivity. between the left primary and secondary auditory cortex and the left ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14 10 S.Vannesteet al. A B Fig.5. Connectivitycontrastanalysisbetweenchronictinnituspatientsand tinnituspatientswithrecentonset(P<0.05).Decreased (A)theta(4–7.5Hz)and (B)alpha2(10–12Hz)connectivityforchronictinnituspatients.L,left;R,right;A,anterior;P,posterior;S,superior. parahippocampalarea.Thisisalsoinaccordancewiththefindingsof Asmentionedbefore,theinvolvementoftheparahippocampalarea Schlee etal. (2009) who argue that the left temporal lobe shows a in the network might be responsible for constantly updating the major hub in patients with short tinnitus duration, but this decreases tinnitus, preventing habituation (De Ridder etal., 2006) due to its with longer tinnitus duration. sensory gating function, which has been shown in both animals ª2011TheAuthors.EuropeanJournalofNeuroscienceª2011FederationofEuropeanNeuroscienceSocietiesandBlackwellPublishingLtd EuropeanJournalofNeuroscience,1–14

The neural network of phantom sound changes over time

Similar The neural network of phantom sound changes over time