Perisylvian GABA levels in schizophrenia and bipolar disorder

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Neuroscience

Letters

j ou rn a l h om epa g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u l e t

Research

article

Perisylvian

GABA

levels

in

schizophrenia

and

bipolar

disorder

Murat ˙Ilhan

Atagün

a,b,∗

_,

_Elif

_Muazzez

_S¸

_ıko˘glu

c

_,

_C¸

_a˘glar

_Soykan

a,b

_,

_Serdar

_Süleyman

_Can

a,b

_,

Semra

Ulusoy-Kaymak

b

_,

_Ali

_C¸

_ayköylü

a,b

_,

_Oktay

_Algın

d,e

_,

_Mary

_Louise

_Phillips

f

_,

Dost

Öngür

g,h

_,

_Constance

_Mary

_Moore

c,i

a_Department_of_Psychiatry,_Ankara_Yıldırım_Beyazıt_University_Medical_School,_Ankara,_Turkey b_Department_of_Psychiatry,_Ankara_Ataturk_Training_and_Education_Hospital,_Ankara,_Turkey

c_Department_of_Psychiatry,_University_of_{Massachusetts}_Memorial_Medical_School,_Memorial_Campus₁₁₉_Belmont_Street,_Worcester,_MA_01605,_USA d_Department_of_Radiology,_Ankara_Atatürk_Training_and_Education_Hospital,_Ankara,_Turkey

e_National_Magnetic_Resonance_Imaging_Research_Center,_Bilkent_University,_Ankara,_Turkey f_Department_of_Psychiatry,_Pittsburgh_University_Medical_School,_Pittsburgh,_PA,_USA g_Psychotic_Disorders_Division,_McLean_Hospital,_Belmont,_MA,_USA

h_Department_of_Psychiatry,_Harvard_Medical_School,_Boston,_MA,_USA

i_Department_of_Radiology,_University_of_{Massachusetts}_Medical_School,_Worcester,_MA,_USA

h

i

g

h

l

i

g

h

t

s

•GABAergicneurotransmissionisdisturbedinhistopathologicalexaminationsandneuroimagingstudiesschizophreniaandbipolardisorder.

•Auditorycorticesareoneofthemostrelevantbrainregionsinschizophreniaandbipolardisorder.

•RighthemisphereGABAconcentrationswerehigherinschizophreniaincomparisontothehealthycontrolgroup.

•GABAconcentrationsmightbealteredbyseveralclinicalandpharmacologicalmechanismsinpsychiatricdisorders.

•GABAergicneurotransmissionispronetorapidchangesstimulatedbycertaindynamicsofthereceptor,synapseornetwork.

a

r

t

i

c

l

e

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f

o

Articlehistory:

Received10September2016 Receivedinrevisedform 16November2016 Accepted23November2016 Availableonline24November2016

Keywords: Schizophrenia Bipolardisorder GABA

Magneticresonancespectroscopy Auditorycortex

a

b

s

t

r

a

c

t

TheaimofthisstudyistomeasureGABAlevelsofperisylviancorticesinschizophreniaandbipolar disorderpatients,usingprotonmagneticresonancespectroscopy(1_H-MRS)._Patients_with_{schizophrenia}

(n=25),bipolarIdisorder(BD-I;n=28)andbipolarIIdisorder(BD-II;n=20)werecomparedwithhealthy controls(n=30).1_H-MRS_data_was_acquired_using_a_Siemens₃_T_whole_body_scanner_to_quantify_right_and

leftperisylvianstructures’(includingsuperiortemporallobes)GABAlevels.RightperisylvianGABAvalues differedsigniﬁcantlybetweengroups[␹2₌_9.62,_df:_3,_p₌_0.022]._GABA_levels_were_{signiﬁcantly}_higher

intheschizophreniagroupcomparedwiththehealthycontrolgroup(p=0.002).Furthermore, Chlor-promazineequivalentdosesofantipsychoticscorrelatedwithrighthemisphereGABAlevels(r2₌_0.68,

p=0.006,n=33).GABAlevelsareelevatedintherighthemisphereinpatientswithschizophreniain com-parisontobipolardisorderandhealthycontrols.Thebalancebetweenexcitatoryandinhibitorycontrols overthecorticalcircuitsmayhavedirectrelationshipwithGABAergicfunctionsinauditorycortices.In addition,GABAlevelsmaybealteredbybrainregionsofinterest,psychotropicmedications,andclinical stageinschizophreniaandbipolardisorder.

1. Introduction

Severallinesofevidencehaveconvergedthatasaninhibitory

neurotransmitter, Gamma-Amino Butyric Acid (GABA)

neuro-∗ Correspondingauthorat:AnkaraYıldırımBeyazıtUniversityMedicalSchool, DepartmentofPsychiatry,Ankara,06800,Turkey.

E-mailaddress:miatagun@ybu.edu.tr(M.˙I.Atagün).

transmission servesfor network integrity by facilitating neural

synchronizationinthebrain[1].Postmortemstudieshaveshown

abnormalities in GABAergic cells [2–4]and theseﬁndings

sug-gestedthatdisturbancesintheearlyphasesofbraindevelopment

mayleadtoabnormalitiesofGABAergicneurotransmission

pos-sibly causing dysregulation in the inhibitory and excitatory

neurotransmissionincorticalcircuitries[2].DisturbedGABAergic

neurotransmissionmayleadtoabnormalitiesinintegrativebrain

functionsandcognitivedysfunction[5].

http://dx.doi.org/10.1016/j.neulet.2016.11.051

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Table1

Clinicalcharacteristicsoftheparticipants.

SZ BD-I BD-II HCs F/␹2_/t _P

(n=25) (n=28) (n=20) (n=30)

Age(Years) 38.4±13.25 35.32±9.13 38.85±14.03 32.77±10.65 1.58 0.207

Sex(M) 13 13 9 13 0.44 0.931

Education 9.16±3.85 10.89±4.85 12.40±3.95 12.20±3.36 2.67 0.052 AgeatOnsetofDisorder(years) 22.58±6.89 23.57±8.66 24.85±9.86 0.389 0.679 DurationofDisorder(months) 142.54±130.37 95.21±107.69 156.85±127.86 1.95 0.151 NumberofHospitalizations 1.36±1.77 1.36±1.76 0.40±0.68 2.2 1.18

NumberofEpisodes Total 7.82±5.64 8.68±7.00 −0.474 0.638

Manica _2.77_±_2.18 _3.63_±_3.56 _−1.006 _0.32 Depressive 4.22±3.42 4.95±4.26 −0.639 0.526 BPRS 8.00±4.41 2.43±2.86 2.25±1.77 24.51 <0.001 YMRS 1.07±1.61 1.55±1.50 −1.044 0.302 HDRS 3.46±3.51 3.35±3.28 0.114 0.91 SAPS Total 11.52±6.90 SANS Total 13.28±9.04

SZ:Schizophrenia,BD-I:BipolarIDisorder,BD-II:BipolarIIDisorder,HCs:HealthyControls,BPRS:BriefPsychiatricRatingScale,HDRS:HamiltonDepressionRatingScale, SANS:SchedulefortheAssessmentofNegativeSymptoms,SAPS:SchedulefortheAssessmentofPositiveSymptoms,YMRS:YoungManiaRatingScale.

a_Hypomania_for_the_Bipolar_II_Disorder.

IrregularitiesinGABAneurotransmissionhavecriticalrolesin

the pathophysiologyof schizophrenia and bipolar disorder [2].

AlteredRNA,proteinandneurochemicalmarkersofinterneurons

[6],decreasednumber[7]anddisturbedmaturationofGABAergic

cells[8]have indicatedGABAergicdysfunctioninschizophrenia

andbipolardisorder.MeasurementsofGABAlevelsusingproton

magneticresonancespectroscopy(1_H-MRS)_have_reported_altered

GABAlevelsinschizophrenia[9,10]andbipolardisorder[11–13].

However,theﬁndingsareinconsistentpossiblyduetoanumberof

reasonsincludingdifferentMRSmethods,variabilitybetweenbrain

regionsofinterest,medicationeffectsandclinicalcourse[10].Most

studieshavefocusedonfrontal,prefrontal,parietaloroccipital

cor-tices,medicatedpatientsandclinicallyremittedpatients,andallof

thesefactors,includingbrainregionsofinterest,psychotropic

med-ications,andclinicalstage,mayhavesigniﬁcanteffectsonGABA

levels.

Theauditorycorticeshave a long and delicate

developmen-taltrajectory[14],whichisvulnerabletothepathophysiologyof

schizophrenia andbipolar disorder[15]. Sinceauditory

halluci-nationsareoneofthemostfrequentsymptomsofschizophrenia

andabnormalitiesoftheauditorycorticesareassociatedwith

hal-lucinations [15],auditorycorticesareamong themostrelevant

brainregionsinschizophrenia.Inarecent1_H_MRS_study,_we_have

detectedmetabolicabnormalitieswithinthelefthemisphere

supe-riortemporallobeinbothschizophreniaandbipolardisorder[16].

Neuralsynchronizationdeﬁcitswithauditorytasksmayindicate

GABAergicabnormalitiesinauditorycorticesinbipolardisorder

andschizophrenia[17].Inaddition,arecent1_H_MRS_study_report

decreasedGABAlevelsin theleftperisylviancorticesinautism,

thisisconsistentwiththetheoryofexcitatory-inhibitorybalance

dysregulationinautismspectrumdisorders[18].

Inthisstudy,weaimedtoinvestigateGABAlevelswithinthe

auditorybeltandparabeltregionslocatedaroundtheSylvian

(Lat-eral)Fissure,whichhostprimaryandassociationauditorycortices.

Toourknowledge,thisistheﬁrststudythatmeasureGABAlevels

attheperisylvianstructuresinschizophreniaandbipolardisorder.

Sincethereareabnormalitiesinexcitatoryneurotransmissionand

GABAergiccells[2–13],wehypothesizedthatGABAlevelsmight

bealteredinschizophreniaandbipolardisorder.

2. Materialsandmethods

2.1. Participants

ThelocalEthical Committeeof AnkaraYıldırımBeyazıt

Uni-versityMedical School hasapproved thestudy.All participants

provided writtenconsentafterthestudyprocedureswere fully

explained. Remitted patients withschizophrenia (n=25),

bipo-lar I disorder (BD-I) (n=28), bipolarII disorder (BD-II) (n=20)

and a healthycontrol group(HC)(n=30) wereenrolled.

Socio-demographicfeaturesarepresentedinTable1.Exclusioncriteria

werehistoryofbraindamageorsurgery,MRincompatiblemetallic

implantsorprosthesis,systemicdiseases,hearingdisability,

life-timehistoryofpsychiatriccomorbidityand/orsubstanceabuse.All

medicationswereallowedexceptbenzodiazepines.Thefollowing

clinicalevaluationswereadministeredbyMIA:StructuredClinical

InterviewaccordingfortheDSM-IV(SCID-I)[19],YoungMania

Rat-ingScale(YMRS)[20],HamiltonDepressionRatingScale(HDRS)

[21],ScalefortheAssessmentofPositiveSymptoms(SAPS)[22],

ScalefortheAssessmentofNegativeSymptoms(SANS)[23]and

BriefPsychiatricRatingScale(BPRS)[24].Allsubjectscompleted

anMRdataacquisitionsessionimmediatelyfollowingtheclinical

evaluations.

2.2. Magneticresonanceimagingdataacquisition

Datawereacquiredona3.0TSiemensMAGNETOMTIMTrio

whole-bodyMRsystem(Siemens,Erlangen,Germany)withathirty

two-channelphased-arrayheadcoilattheUMRAMNational

Mag-neticResonanceResearchCenter,Ankara,Turkey.

T1-weighted anatomical MRI (MPRAGE sequence, 256×256

voxels,TR:2000msec,TE:3.02msec,FOVread:215,FOVphase:

100, slice thickness: 0.84, 192 slices) were collected for

diag-nostic and localization purposes. Proton Magnetic Resonance

Spectroscopy(1_H_MRS)_data_was_acquired_using_the_single_voxel

Point REsolved Spectroscopy Sequence (PRESS) (TE=30 msec,

TR=2000msec)toquantifybraincreatine(Cr)levelsand

MEscher-GArwood Point-REsolved Spectroscopy Sequence (MEGAPRESS)

[25,26](TE=68msec,TR=2000msec)toquantifybrainGABA

lev-els.Voxels(PRESS:20mmX20mmX20mm;MEGAPRESS:30mm

X30mmX20mm)wereplacedinthestructuresaroundSylvian

Fissureincludingsuperiortemporallobeandinferiorparietallobe.

2.3. Magneticresonanceimagingdataanalysis

TheprotonspectrawereﬁtusingLCModel(Version6.3.0)to

quantifythecreatinelevels[27,28]andGANNETsoftwareto

quan-tifytheGABA-to-creatineratio(GABA/Cr)[29–34].

ThestructuralT1-weightedimagesweresegmentedusingSPM8

[StatisticalParameterMapping–Welcome Departmentof

Imag-ingNeuroscience,London,UK;(http://www.ﬁl.ion.ucl.ac.uk/spm/

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Table2

GABAlevels.

SZ BD-I BD-II HCs ␹2_(df) _P

LeftGABA 0.12(0.11–0.17) 0.11(0.09–0.14) 0.13(0.11–0.16) 0.12(0.10–0.14) 1.63(3) 0.652 RightGABA 0.23(0.20–0.27) 0.18(0.16–0.22) 0.18(0.15–0.21) 0.18(0.15–0.20) 9.62(3) 0.022

Kruskal-WallisTest.Median(25–75percentiles)valuesarereported.SZ:Schizophrenia,BD-I:BipolarIDisorder,BD-II:BipolarIIDisorder,HCs:HealthyControls.

Fig.1.GABAlevelsingroups.Therewassignificantdifferencebetweengroupsatrighthemisphere.SchizophreniagrouphadsignificantlyhigherGABAlevelsincomparison tohealthycontrols.Therewasnosignificantdifferencebetweengroupsatlefthemisphere.BD-I:BipolarIDisorder,BD-II:BipolarIIDisorder,SZ:Schizophrenia,HC:Healthy Controls.GABAlevelsareininternationalunits(IU).

CSFcontributionstothevoxelofinterest.AbsoluteCrvalues[16]

werecorrectedforvoxeltissuecontentandthenmultipliedwith

theGABA-to-CrtodeterminetheabsoluteGABAlevels[35].

2.4. Statisticalanalysis

StatisticalanalyseswereperformedusingSPSS22.0software

(Chicago,Illinois,USA).OutlieranalysiswasconductedandGABA

valuestwostandarddeviationsawayfromthemeanofthe

corre-spondinggroupswereeliminatedfromfurtheranalysis.Chi-square

testwasusedforthecomparisonofcategoricalvariables.

Shapiro-Wilk’stestsfornormalitywereperformedforcontinuousvariables.

Twotailed independentsamplest-testorMann-WhitneyUtest

wereusedforcomparisonsbetweenindependentgroups.Group

comparisonsincludingmorethantwogroupswereperformedby

UnivariateANOVAorKruskal-Wallistests.Mann-WhitneyUtests

wereperformedforpost-hoccomparisonsafterKruskal-Wallistest.

Sincewehad4groupsandperformed6Mann-WhitneyUtestsfor

posthoccomparisonsbetweengroups,wedeterminedsigniﬁcance

levelas0.0083(0.05/6=0.0083)accordingtoBonferroni

correc-tion. In addition, Pearson’s correlation analysis was performed

todeterminetherelationshipbetweenGABAlevelsandclinical

assessments.

3. Results

Thedemographicandclinicalcharacteristicsofthesampleare

listedinTable1.Therewerenosigniﬁcantdemographicdifferences

insociodemographicvariables.Allpatientswereclinicallystable.

However,schizophreniapatientsscoredsigniﬁcantlyhigherthan

thebipolardisordergroupsonBPRS(F(2,63)=21.76,p<0.0001).

GABA levels at the right hemisphere signiﬁcantly differed

betweenthegroups[␹2₌_9.62,_df:_3,_p₌_0.022]₍_Table₂_)._Posthoc

comparisonsrevealedthatGABAlevelsintheschizophreniagroup

weresigniﬁcantlyhigherthantheBD-I(p=0.02),BD-II(p=0.02)

andHC(p=0.002,Z=−3.08) groups(Fig.1).Differencebetween

thegroups wassigniﬁcantonlybetween schizophreniaand HC

afterBonferronicorrection(p=0.002).Therewerenosigniﬁcant

differencesinthelefthemisphereGABAlevelsbetweenthegroups

[␹2₌_1.63, _df: _3,_p₌_0.652]₍_Table₂_)._GABA_levels_did_not _differ

betweenthehemisphereswithineachgroup(p>0.05).

Patientswithschizophreniawereonsigniﬁcantlymore

atypi-calanti-psychoticsthantheBD-IorBD-IIgroups(␹2_(2,73)₌_8.874,

p<0.012)(Table3).Chlorpromazineequivalentsofantipsychotic

doses were correlated positively with right hemisphere GABA

levels (r2₌_0.68, _p₌_0.006,_n₌_33:_{schizophrenia,} _BD-I _and _BD-II

groups). Serum valproate levels correlated positively with left

hemisphereGABAlevels(r2₌_0.8,_p₌_0.016,_n₌_14:_BD-I_and_BD-II

groups).

TherewasacorrelationbetweenlefthemisphereGABAlevels

andthealogiasubscaleoftheSANS(r2₌_0.8,_p_<_0.05,_n₌_10)._There

wasnosigniﬁcantcorrelationbetweenGABAlevelsandYMRS(r

2₌_0.48,_p₌_0.158,_n₌₃₉₎_however,_there_was_a_trend_for_a

nega-tivecorrelationwithHDRS(r2₌_0.53,_p₌_0.08,_n₌₃₉₎_in_the_bipolar

disordergroups.

4. Discussion

GABA levelsin the right perisylvian structures were higher

inschizophreniapatientsincomparisontobipolardisorderand

healthycontrol groups.Therewas positivecorrelation between

antipsychoticmedicationsandGABAlevelsatrighthemisphere.

Previous1_H_MRS_studies_have_reported_inconsistent_results

regard-ing GABA levels in schizophrenia. In ﬁrst episode psychosis

patients, GABAlevelswere lowerwithin leftbasal ganglia [38]

and bilateral calcarine sulci [37] and approximately the same

withinfrontalandparieto-occipitallobes[35] incomparisonto

healthycontrols.Moreover,astudycomparingyoung

schizophre-nia patients and healthy controls reported that GABA levels

werelowerwithinanteriorcingulateregionforthe

schizophre-niapatientsandsamewithincentrumsemiovale[38].Whereasin

chronicschizophreniapatients, GABAlevelswerehigherwithin

anteriorcingulateand parieto-occipitalcortices[9],and normal

withinanteriorcingulatecortexandleftbasalgangliaregions[39].

VariationsoftheGABAlevelsmightbeduetodifferencesinbrain

regions,psychotropicmedications,andclinicalstatesinthe

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Table3

Medicationstatusesofthepatientgroups.

SZ (n=25) BD-I (n=28) BD-II (n=20) ␹2_/Z _P AtypicalAntipsychotics(n) 22 14 12 8.87 0.012 ChlorpromazineEquivalent(mg) 225(145.75–400) 267(133–400) 150(50–267) 6.39(2) 0.041 Lithium(n) 0 11 10 0.54 0.461

SerumLithiumLevels(mEq/L) 0.70(0.45–0.85) 0.70(0.45–0.85) −0.47 0.658

Valproate(n) 0 11 7 −0.86 0.650

SerumValproateLevels(䊐g/ml) 72.2(56–99.35) 57.3(44.8–83.6) 0.91 0.386 Kruskal-Wallistest,Chi-squaretestandMann-WhitneyUtest.Median(25–75percentiles)valuesarereported.Inthepost-hoccomparisonsofthechlorpromazineequivalent dosesofantipsychotics,therewerenosigniﬁcantdifferencesbetweenthegroups.

The balance of the excitatory and inhibitory impulses may

determinetheGABAergiccellactivity[18,41].Correlationbetween

GABAandglutamatelayers inprefrontalcortices[41]mightbe

anindicatoroftherelationshipbetweenexcitatoryandinhibitory

neurotransmission. Since the excitatory neurotransmission is

degradedinneurodevelopmentaldisorders,activityofthe

GABAer-gic cells and GABAlevels might be altered in order to protect

thebalancebetweenexcitatoryandinhibitoryneurotransmission

[41–43].

In addition, GABA receptors are highly susceptible to rapid

neuroplasticchangesandvariousmechanismssuchas

phospho-rylationofsynapticproteins[44].Theseﬁndingsaresuggestiveof

dynamicmodulationofGABAergicneurotransmissionaccordingto

thedynamicsofthesynapseorthenetwork.Takentogether,these

ﬁndingsmayalsoexplainthevariabilityofGABAlevelsreported

inpreviousstudiesusing1_H_MRS,_as_GABA_{neurotransmission}_is

modulatedbyseveralclinicalfactorspronetorapidchanges.On

theotherhand,GABAreceptorsareoftennotsaturated[45]and

thereforethedeterminantofGABAergicsignalingissynthesisof

GABAfromglutamate[46].Therefore,activityleveloftheenzyme

glutamic-aciddecarboxylase(GAD)65and67isoenzymes,which

catalyzetheratelimitingstepofGABAsynthesis,determinethe

level of GABAergicactivity. Althoughpostmortem studies have

reporteddecreasedexpressionofGAD67[47],severallongterm

modulationsmayalsoalterGABAergicsignalingaswellasshort

termchanges[48]anddeﬁciencyofGAD67mightbecompensated

uponlongtermmodulations[46].

Abnormalities in the left hemispheric auditory cortices are

associatedwithlinguisticfunctionsandspeciﬁcsymptomsof

psy-choticspectrum disorders [15,16]and developmental disorders

[18].However,GABAlevelswerehigherin righthemispherein

schizophreniaandwerepositivelycorrelatedwithantipsychotic

dosesinthisstudy.Thisﬁndingmightbesuggestingthat

antipsy-choticscouldhaveenhancedGABAlevelsonlyatrighthemisphere

and couldnot enhanced lefthemisphere GABA levelsdue to a

strongerneuropathologyinlefthemisphere.Inaddition,valproate

serum levels were correlated with GABA levels at right

hemi-sphereinbipolardisorder.Thisisinlinewithapreviousstudy[8],

whichhasreportedthatmoodstabilizeranticonvulsantsadjunctive

toantipsychoticshaveincreasedGABAlevelsatparieto-occipital

lobeinschizophrenia.Ontheotherhand,studiesinvestigatingthe

relationshipbetweenantipsychoticsandGABAlevelshavebeen

indicatedbothdecrease[39,49]andnoeffect[9,36]in

schizophre-nia,asaresultofthemedication.Furthercontrolledstudieswith

speciﬁcdesignstoinvestigatetheeffectsofmedicationsonGABA

levelsareneededtoobtainmoreconsistentand reliableresults

using1_H_MRS._A_current_concept_suggests_that_{antipsychotics}_may

restorethedisturbances(disruptedmyelination,reversethelossof

dendriticspines,enhancesynapticconnections)oftheexcitatory

neurotransmissionthatprojectstoGABAergiccellsandstimulate

oligodendrocytematurationandincreasetheefﬁciencyof

GABAer-giccells [43,49].Tothisend, antipsychoticsmayamelioratethe

pathology of the GABAergic cells in schizophrenia and bipolar

disorder.However,itisnotpossibletopredicttheultimateeffects

ofantipsychoticsonGABAergicfunctionscurrently,asthereare

severalotherdeterminantsforGABAergicfunctions(suchas

exci-tatory/inhibitorybalance,receptorphosphorylation,ionchannel

physiology),butyetGABAleveliscurrentlytheonlymeasurable

invivoresponseofthecell.

AlthoughcorticalGABAcontentasquantiﬁedby1_H_MRS_has

been found to predictthe functional status of GABA-mediated

processesinpreviousneurophysiologyandpharmacological

stud-ies[40],normal GABAlevelsdonot implyregulatedGABAergic

function.DeterminantsofGABAlevelsandmechanismsof

com-pensatorychangesinGABAergicactivityarefuturedirectionsfor

further clariﬁcation of GABAergic abnormalities in

schizophre-nia and bipolar disorder. While 1_H _MRS _utilizing _edited _pulse

sequencessuchasMEGAPRESSisconsideredareliableand

repro-duciblemethodformeasuringbrainGABA[50],1_H_MRS_cannot

discriminatebetweenintraandextracellularGABAlevels.

There-fore,theseresultsshouldbeviewedcautiously.

Toconclude,higherGABAlevelsobservedintherightauditory

cortexofschizophreniapatientscouldbeacompensatory

mech-anism toobtainthe balancebetween excitatoryand inhibitory

impulsesinthecerebralcortex.Duetopharmacologicaland

phys-iopathologicalinﬂuencesonthisbalance,inthisinvestigation,we

maybecapturingacertainphaseofGABAmetabolismthatcould

bemodulatedinadynamicprocess.Dynamicmodulationofthe

GABAergicactivitymightbetheunderlyingreasonofthevariable

resultsofthe1_H_MRS_studies_measuring_GABA_levels.

Funding

ThisstudywasfundedbyScientiﬁcResearchProjects

Commit-teeoftheAnkaraYıldırımBeyazıtUniversity(ProjectNo:803),and

NIMHgranttoCMM(MH073998)andK24MH104449fromthe

NIHtoDÖ.Dr.PhillipsacknowledgedthesupportofthePittsburgh

Foundation.

Acknowledgement

We would like to thank Prof. Dr. Ergin Atalar from Bilkent

University(Turkey)andAliAvcıfromSiemens,Turkey.We also

appreciatetechnicalhelpregardingvoxelsegmentationprovided

byDineshDeelchand, Dr.UzayEmir andDr.Gülin Özfromthe

CenterforMagneticResonanceResearch,Minneapolis,MN,USA.

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