neurophysiological bio markers for drug development in schizophrenia. nat rev drug discov 2008

8/4/2019 Neurophysiological Bio Markers for Drug Development in Schizophrenia. Nat Rev Drug Discov 2008

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Schizphrenia is a ar ental isrer characterizeb psitie an negatie spts, as well as persistentnercgnitie eficits. All crrentl appre eica-tins fr schizphrenia fnctin b blcking paineD

2receptrs, an hae pre effectie priaril against

psitie spts. B cntrast, negatie an cgnitiespts freqentl persist, an lea t persistent is-abilit an pr lng-ter tce. Brain prcessesnerling persistent cgnitie eficits in schizphre-nia can be prbe sing aris techniqes, inclingstrctral an fnctinal iaging, psitrn eissintgraph an single phtn eissin cptetgraph receptr assas, an nerphsilgicaleasres sch as electrencephalgraph (EEG) aneent-relate ptentials (ERPs).

Nerphsilgical easres as a grp hae seeralcharacteristics that ake the well site fr se as

biarkers in rg eelpent sties. First, ancan be recre in passie paraigs in which n atten-tin, task engageent r behairal reat is reqire.These easres are therefre ieal fr se in pplatinsthat a be ifficlt t engage in behairal sties.Secn, becase f their high tepral resltin, ner-phsilgical biarkers can niqel be se t trace theflw f infratin in the brain fr sensr thrgh tassciatin brain regins, an hence can be se t eter-ine the earliest stages at which infratin prcessingis ipaire. Last, becase the inex nerling ne-rnal actiit, nerphsilgical biarkers a beseen as bectie inices f cgnitie sfnctin a

prinent featre f patients with schizphrenia. Here,we reiew the best aailable biarkers t ate, an thestrengths an liitatins f their se in the eelpentf rgs fr schizphrenia.

Nuphylgcl gnl

Nerphsilgical easres are generall recresing stanar EEG techniqes in which an arra f pt 256 electres are affixe t specific scalp lcatinsan the pattern f electrical actiit is nitre whilesbects participate in specific experiental paraigs.Scalp recre electrical actiit priaril representsspatial an tepral satin f snchrns crrentflw thrgh pstsnaptic enritic ebranes fcrtical praial nerns that, becase f their parallelalignent in the crtex an asetric rphlg,sere as pen fiel generatrs in the brain an gie rise

t local ild potntials.The basic phsilgical ata nerling st bi-

arkers that are presentl aailable are siilar t thatse in qalitatie r qantitatie EEG assessent. Acritical ifference is the se f signal aeraging. Brainrespnses t iniial sensr, cgnitie r treents are sall relatie t the backgrn EEG,whereas signal aeraging perits sch eents t stant. Nerphsilgical biarkers are tpicall tie-lcke t sensr eents (fr exaple, aitr r isalstili). Neertheless, ther tpes f eents can alsbe efine. Fr exaple, in respnse tasks, electricalrespnses can be back-aerage fr tr respnses

*Nathan Kline Institute

for Schizophrenia Research/

New York University

School of Medicine,140 Old Orangeburg Road,

Orangeburg, New York

10962, USA.Department of Psychiatry,

VA Boston Healthcare

System/Harvard Medical

School, Psychiatry 116A,

940 Belmont Street,

Brockton, Massachusetts

02301, USA.Maryland Psychiatric

Research Center,

Department of Psychiatry,

University of Maryland

School of Medicine, Baltimore,

Maryland 21228, USA.||Department of Psychiatry/

Heinrich Heine University,

Bergische Landstr. 2, 40629

Duesseldorf, Germany.Neuroscience Department,

CNS Discovery, Pfizer Global

Research and Development,

Groton, Connecticut 06340,

USA.

Correspondence to M.H.

email:

[email protected]

doi:10.1038/nrd2463

Publishd onlin

7 Dcmbr 2007

Neurophysiological biomarkers fordrug development in schizophreniaDaniel C. Javitt*, Kevin M. Spencer, Gunvant K. Thaker, Georg Winterer|| and

Mihly Hajs

Abstract | Schizophrenia represents a pervasive eficit in brain function, leaing to

hallucinations an elusions, social withrawal an a ecline in cognitive performance.

As the unerlying genetic an neuronal abnormalities in schizophrenia are largely

unknown, it is challenging to measure the severity of its symptoms objectively, or to esignan evaluate psychotherapeutic interventions. Recent avances in neurophysiological

techniques provie new opportunities to measure abnormal brain functions in patients

with schizophrenia an to compare these with rug-inuce alterations. Moreover,

many of these neurophysiological processes are phylogenetically conserve an can be

moelle in preclinical stuies, offering unique opportunities for use as translational

biomarkers in schizophrenia rug iscovery.

b i o m a r k e r s

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68 | jANuARy 2008 | voLumE 7 www.nat.m/w/
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=181500mailto:[email protected]:[email protected]://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=181500


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Local field potential

Th summd postsynaptic

potntials rcordd rom

nurons nighbouring a

microlctrod.

Prepulse inhibition

(PPI). Prpuls inhibition is amasur o snsory gating in

which a wak prstimulus

(prpuls) rducs th startl

rspons licitd by a

subsqunt intns auditory

stimulus.

P50

An arly auditory potntial

rlcting initial snsory

activation. P50 gating rrs

to th dcrasd P50

amplitud to th scond

stimulus in a paird click

compard to th irst.

an can be se t analse preceing actiit. In sthprsit ee eent (SPEm) tasks, nerphsilgicalactiit relate t ee eents can be back-aeragefr the nset f a saccae t etail nerling brainprcesses. Hweer, the absence f electrical actiitcannt be taken as eience f the lack f respnsef a gien regin as the arit f electrical actiitgenerate in the brain is inisible t srface recrings.Neertheless, er recent ears, nerphsilgicaleasres that prbe brain actiit in regins that are freleance t schizphrenia hae been eelpe.

T vu fquncy dn nly

once nerphsilgical ata hae been recre(BOX 1), tw cpleentar analtic appraches are sefr ata analsis. In the first apprach, brain actiatinsare iewe sipl as a series f aplite eflectinsthat ar in tie an space er the srface f the scalp.Analsis f respnse aplite er tie has traitin-all been referre t as a tie-ain analsis r, reaccratel, as tie-aplite ain analsis. The

seqence f eflectins triggere b a gien eent isreferre t as an ERP.

The secn apprach iews brain actiit as a sf speripse scillatins aintaine within anbetween brain regins giing rise t eent-relate eker ince scillatins1. This apprach, als knwn astie-freqenc analsis, captres re infratinn nerling brain actiit than the traitinal ERPapprach, bt is cptatinall re cplex an lessstanarize acrss sbects.

suc lclztn

Fr bth tie an freqenc ain analses, ai-tinal ata cncerning nerling echaniss can bebtaine sing srce analsis appraches that ealatethe electrical srces f scalp-erie actiit withinthe brain. Srce lcalizatin appraches ake specificassptins regaring the prpagatin f electricalactiit thrgh the brain an scalp, which a leat lcalizatin iprecisin. In practice, hweer, gspatial agreeent is tpicall btaine between fnc-tinal agnetic resnance iaging (fmRI) an ERP (frexaple, Ref. 2) r scillatin-base (fr exaple, Ref.3)easres f cnergent phenena.

valiatin f a nerphsilgical easre in thespatial ain with iaging eths that are base nbl flw ffers critical aantages: the signal-t-nise

rati ipres tenfl (when actiit is generate inthe crtex) an tie-freqenc infratin, which iscrrentl nt aenable t ther fnctinal iaging tls,beces aailable. B extensin, nerphsilgicalbiarkers a be re sensitie t rg-ince changescpare with ther fnctinal iaging alities.

mgntncphlgphy

Althgh st research with biarkers has beenperfre sing electricall base techniqes, agnet-encephalgraph (mEG) can be se instea t etect theagnetic fiels that accpan electrical crrent flwthrgh the brain. As agnetic fiels are less ssceptible t

istrtin b le cnctin f crrents than electricalfiels, recnstrctin f mEG srces is pssible withhigher spatial accrac than thse f EEG. Frtherre,mEG ffers the aantage f aiing cberse elec-tre fixatin t the scalp. As with EEG-base easres,mEG recrings can be analse in either the tie r thefreqenc ain. As a reslt f the electragnetic fielistribtin, hweer, mEG is liite b its insensitiitt srces raial t the scalp srface (that is, pinteperpeniclar, rather than parallel, t the skll srface)an b its cst: state-f-the-art mEG eqipent is stillre expensie than EEG-eqipent an ths its se iscrrentl liite t a few research centres. In cntrastt the ter ERP, which is se t refer t tie-lckeelectrical actiit, the ter eent-relate fiel (ERF) iscnl applie t mEG ata.

Nuphylgcl u

Becase f the wiesprea aailabilit f nerphsi-lgical eqipent an expertise, nerphsilgicaleasres hae been wiel applie in schizphrenia

research. Se well-aliate easres, sch as prpulsinhibition (PPI) r P50gating, reflect the gating t fparticlar sensr infratin4. Sch easres, hweer,reflect nl a prtin f the pschpathlg f schiz-phrenia, an are nt clsel linke t nercgnitie s-fnctin4,5. oer recent ears, newer nerphsilgicaleasres hae bece aailable that inex infratinprcessing abnralities an crrelate well with nega-tie spts an cgnitie eficits, as well as glbalfnctinal tce. Frtherre, these biarkersreflect the integrit f ifferential brain regins ancgnitie pathwas (fIG. 1), an s can be se t prbespecific nerling reginalize an nercheicalhptheses f schizphrenia.

Well-stie easres incle aitr P300 anisatch negatiit (mmN), bth f which are c-nl elicite sing an aitr ball paraig(that is, when a seqence f repetitie stanar stiliis interrpte infreqentl an nexpectel b a phsi-call eiant ball stils), as well as easres fipaire isal prcessing an SPEms. In aitin,significant aances hae been ae in recent ears inanalsing these eficits nt nl in ters f respnseaplite within the tie ain, bt als in ters fthe spectral cntent f nerling neral scillatinswithin the freqenc ain. These ifferent biarkershae ifferential strengths an weaknesses with regar t

sensitiit, specificit an tiing relatie t isease nset,an ths a be iewe as cpleentar apprachest nerphsilgical characterizatins f schizphreniaan f treatent respnses (TABLe 1).

Auditory P300. The earliest an best stie cgnitieERP abnralit in schizphrenia is the aplite rec-tin f the aitr P300 cpnent6. P300 is elicitest cnl in the cntext f the aitr ballparaig in which sbects are instrcte t atten tthe seqence f tnes, an either cnt the eiants rpress a bttn in respnse t the eiants. uner schcnitins, P300 ccrs apprxiatel 300 s fllwing

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0 200 400 600Time (ms)

0 200 400 600Time (ms)

0 200 400 600

Time (ms)

0 200 400 600

V

10

0

10 P1

N170

0

40

0 200 400 600

80

Evoked power (V2)

ms

0

40

0 200 400 600

80

Induced power (V2)

ms

0

40

0 200 400 600

80

Phase locking

ms

P1/N170

P1/N170

c Average ERP

Amplitude(V)

20

0

20

V

20

0

20

V

20

0

20

e

f

g

Frequency(Hz)

0

40

0 200 400 600

80

ms

Hz

0

40

0 200 400 600

80

ms

Hz

Hz

Hz

Hz

0

40

0 200 400 600

80

msTime (ms)

d Single-trial power (V2)

a EEG recording

b Single-trial recordings

h

Power/phaselocking values

+

Band

Frequency (Hz)

Type of activity

Delta

14

Theta

48

Alpha

812

Coordination across regions

Beta

1230

Gamma (low)

3070

Coordination within region

Gamma (high)

70300

Axonal activity

Back view Right view

Time/frequencyanalysis

Timedomainanalysis

Stimulusonset

eiant tne presentatin. P300 is tpicall iie inttw sbcpnents, an earl P3-like ptential (P3a)that is elicite b nel stili, een in the absence fa etectin task, an is lcate relatiel frntall, an alater, re parietal cpnent, P3b, that is elicite nlring target etectin.

Sbects wh are chrnicall ill with schizphreniashw a rectin f P300 aplite f apprxiatelne stanar eiatin relatie t health sbects7,8, anincle P3a as well as P3b cpnents9,10. Frtherre,eficits in P3b track the seerit f negatie sp-ts bth lngitinall an crss-sectinall9,10.

Box 1 | Nuphylgcl dt nly

Electroencephalography (EEG) data are recorded from an electrode array sampling the electric field across the scalp (a).In the classical event-related potential (ERP) approach, single-trial recording epochs (b) are averaged together ().The average ERP consists of voltage deflections that have been characterized as particular components, which are

typically defined by latency, polarity (P for positive, N for negative), scalp topography and variation with experimental

manipulations. For example, the P1 and N170 are occipito-temporal positive and negative components occurring early in

the stream of visual processing, approximately 100 ms and 170 ms following stimulation, and represent discrete stages of

sensory/perceptual processing (). The amplitude of the P1 is reduced in schizophrenia42, and this deficit represents onebiomarker for schizophrenia. Since the advent of signal averaging more than 40 years ago tens of thousands of ERP

studies have been published, providing a catalogue of components that are well-suited for probing the functioning of

specific brain regions and cognitive processes. In contrast to the classical ERP approach, which discards most of the

oscillatory information in the EEG through signal averaging, contemporary time-frequency approaches () representchanges in oscillatory activity as a function of time3, typically using Fourier or wavelet transforms1.

Interest in time-frequency analysis has been motivated by the hypothesis that synchronous neural activity, mediated

by oscillations in different frequency bands (h), enables information coded by individual neurons to be linked together(for example, Ref. 187). High-frequency oscillations (for example, gamma; 3070 Hz) may be predominantly relevant

for coupling local assemblies of neurons55,188,189, whereas low-frequency oscillations (for example, theta; 4-8 Hz) may

coordinate activity across widespread cortical regions. Very high frequency oscillations (70300 Hz) might reflect

axonal action potentials189.

Oscillatory responses are typically characterized by phase synchronization locking () and average power (V2) ()across trials. Evoked oscillations are strictly phase-locked to the stimulus (), whereas induced oscillations occur withvariable phase ()1.

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SPEM

Dorsalateralprefrontal

cortex Auditorycortex

Visualcortex

Parietalcortex

Auditory,visual P300

AX-CPT

Auditory,

visual P300

Visual N1, Ncl

Visual P1

MMN,auditory N1

Prodromal symptoms

Symptoms that aris bor

th onst o ully diagnosd

schizophrnia.

A liitatin f P300 is its relatie nnspecificit withregar t illness; schizphrenia-like P300 rectins areals bsere in alchl-epenent sbects11, biplarisrer12 an Alzheiers isease13 ang ther iag-nses. P300 is tpicall precee b an N200 cpnentthat lcalizes t secnar aitr regins. Like P300,generatin f N200 is tpicall rece in schizphrenia14.Deficits in P300 generatin are nt affecte b eithertpical r atpical antipschtics, althgh the a bepartiall aelirate b clzapine15,16.

Heritabilit f P300-aplite is high (7080%)17,sggesting that P300 a sere as a risk r trait arkerf the genetic risk fr schizphrenia18. In fact, seeralrecent sties hae reprte assciatins f P300abnralities with genetic ariatins that are thghtt cntribte t this genetic risk19,20. In cntrast t theparietal P300 aplite, which is rece in iniialsat risk fr schizphrenia, recent wrk sggests that earlprefrntal P300 aplite a een be increase 18.Despite the rectin f P300 in fail ebers withschizphrenia as a whle, negatie reslts with P300hae been reprte ang ffspring f schizphreniaprbans21.

MMN and additional sensory components. Cparewith P300, mmN is elicite b nattene, as well asattene, eiants within an aitr ball task, anths appears t reflect a pre-attentie stage f aitrinfratin prcessing22(fIG. 2). Fr mmN generatin,ball stili a iffer fr stanars in an f anber f phsical iensins, incling sensralit, freqenc, ratin, intensit r lcatin. Insties in which bth mmN an P300 are easresiltanesl, the latencies f the tw cpnentsincrease in parallel, sggesting that tw cpnents areseqentiall relate.

Like P300, eficits in mmN generatin hae beenextensiel replicate in schizphrenia, with eaneffect size f apprxiatel ne stanar eiatinacrss sties23. Cpare with P300, hweer, mmNeficits are relatiel selectie fr schizphrenia erther nerpschiatric isrers24. Deficits in mmNgeneratin persist fllwing treatent with bth tpicalan atpical antipschtics, incling clzapine15,16.Frtherre, in chrnicall ill patients the seerit fmmN eficits crrelates with seerit f negatie sp-ts25 an ipaire glbal tce26, sggesting that itinexes a cre eficit f the isrer.

Cpare with P300, which appears t be receeen at illness nset, three inepenent sties haebsere relatiel nral mmN generatin in ini-

ials at first presentatin f schizphrenia an well-establishe mmN eficits in patients that are 18 nthsr re int their illness14,2729, sggesting that eficitsa bece establishe ring the initial crse f theirillness. The heritabilit f mmN is als high, sggesting astrng genetic cntribtin17,30. Neertheless, f the tw

fail sties that hae been cncte with mmN tate, ne st fn a rectin in mmN generatinin naffecte fail ebers f patients with schiz-phrenia31, whereas the secn st i nt32. In bthsties, mmN was ecrease in patients with establisheschizphrenia. In ne st that ealate mmN inpatients shwing prodromal symptomsf schizphre-nia, n significant rectin was bsere, althghean mmN aplite ang prral patientswas intereiate between that f patients an cntrls.Frtherre, intersbect ariance was high, cnsistentwith the cncept that mmN eficits ight be present innl a sbset f patients befre the nset f illness33.

Priar generatrs fr mmN hae been lcalize tthe priar aitr crtex sing ltiple techniqesincling EEG an mEG iple lcalizatin, fmRI anirect intracranial recrings fr the aitr crtexf bth hans an nkes34. Deficits in aitrcrtical actiatin hae been enstrate in an fmRIaaptatin f the mmN paraig35, spprting the ieathat ipaire mmN generatin in schizphrenia reflectssfnctin at the leel f the priar aitr crtex.

Althgh mmN is the best-stie sensr easrein schizphrenia, ther easres that inex earl ai-tr an isal prcessing a als be affecte. Frexaple, eficits are als reprte in the generatin faitr N1003638, an aitr ptential that reflects

respnse t repetitie stanar stili, an t isal P1,a easre that reflects respnses within the rsal isalstrea3941(fIG. 3). Stea-state isal eke ptential(ssvEP) respnses t agncelllarl biase stili arebsere as well42,43. In all cases, ERP cpnents canbe easre een in the absence f a behairal task,renering these cpnents well site fr bth clinicalan translatinal biarker sties.

Visual P300. Althgh P300-like actiit has been beststie in the aitr sste, eficits hae als beenbsere in the isal sste. In the isal sste, eficitsin siple isal iscriinatin (fr exaple, ball44

Figure 1 | Th lt th mltpl ban n mplat n

hzphna, an ll nat p bma n th

t hzphna. AX-CPT, AX-type visual continuous performance task; MMN,

mismatch negativity; Ncl, closure negativity; SPEM, smooth pursuit eye movements.

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r eneratin45 tasks) are nt tpicall bsere inpatients with stabilize schizphrenia, an if a eficit isfn it is tpicall saller than that fn fr aitrP300 (Ref. 8). B cntrast, re rbst eficits in isalP300 hae been fn in tasks with greater cgnitieeans46,47.

Nerphsilgical eficits hae been enstrateparticlarl in cntins perfrance tasks (CPTs),sch as the AX-CPT in which sbects st press abttn wheneer the see the letter A fllwe b theletter X, bt withhl respnse t ther letter seqences.Patients with schizphrenia hae behairal eficits in

the abilit t withhl respnse fllwing inali ces(that is, letters ther than A), sggesting a preferentialeficit in the abilit t tilize cntext48. Sch eficitsare accpanie b rece aplite f the P300respnses t the inali ces46.

Behairal eficits are bsere in bth chrnic anfirst-epise treatent-naie patients, an are relatielselectie t schizphrenia erss nn-schizphrenicpschsis49,50. Generatrs f the isal P3 respnse inthe AX-CPT hae als been lcalize t prefrntal ancinglate crtex sing fmRI50,51 an ERP52 appraches, aswell as intracranial recrings in nkes53.

Table 1 | Chcttc f lctd n chzphn

Ma et nnatamlmmb

et npm

et att-p

et nsPd

etn th

rpntlzapn

Hmanhalln/lna t

Anmalml

Gating measures

Prepulseinhibition Abnormal192

ND Abnormal193

Normal192

Abnormal inAD194;BPD195

Yes130,196

DA197,198

;NMDA129,131,199 Roent128

;primate129,196

P50 gating Abnormal200 Abnormal201 Abnormal202 Abnormal203 Abnornalin AD204;BPD205;cocaineabuse92,206

Yes93 DA92,206,207;nACh7 (RefS 151,206,208);5-HT

3(Ref. 183);

NMDA130

Roent81,198,209

Information-processing measures

Auitory P300(P3)

Abnormal18,210 Abnormal/normal211

Abnormal212,213 Abnormal214 Abnormal inAD215;BPD64;ADHD216

Abnormal/normal15,217,218

DA19,96,98,219;ACh110; NMDA220

Mouse87 ;rat86

Mismatchnegativity

Normal31,221;abnormal32

Abnormal/normal33,211,222

Normal14,27,29 ND Normal inAD223;BPD24

No15,224 NMDA133135;5-HT

2A

(Ref. 137)Primate133,225;roent23

Auitory N1 Abnormal215,226 ND Abnormal37,38 Normal227 Abnornalin cocaineabuse228;normal inBPD229

ND ND Roent83,85;primate46

Visual P1 Abnormal41 ND ND ND ND ND NMDA43 Primate230

Neural-synchrony measures

Gamma:auitorysteay-stateresponse

Abnormal63 ND Abnormal62 Normal227 Abnormal inautism231;BPD62, 64;cannabisabuse182

ND ND Roent232

Gamma:Evoke/inuceoscillations

ND ND Abnormal233

ND ND ND mACh220

;DA234,235;NMDA236

ND

Prefrontalslow-wavesynchrony(noise)

Abnormal18,65 ND Abnormal60 Abnormal/normal60

Normal inAD60

ND DA19,101 Roent237

Other neurophysiological measures

Smoothpursuit eyemovements

Abnormal74,210,238 Abnormal239 Abnormal240,241 ND ND Worsens242 nACh164,243,249;NMDA138,139

ND

5-HT, 5-hyroxytryptamine (serotonin); Ach, acetylcholine; AD, Alzheimers isease; ADHD, attention-eficit/hyperactive isorer; BPD, bipolar isorer; DA,opamine; mACh, muscarinic acetylcholine; nACh, nicotinic acetylcholine; ND, not etermine; NMDA, N-methyl-d-aspartate; SPD, schizotypal personality isorer.

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DurationMMN

0 200 400

Time (ms)

0100 200100 400 500300

Time (ms)

PitchMMN

0 200 400

Time (ms)0 200 400

Time (ms)

+1 V

+1 V

Controlsc

V

V

Fzb

Recent-onset Chronic

4

2

0

2

4

4

2

0

2

4

0100 200100 400 500300

Time (ms)

V

V

LM

4

20

2

4

4

2

0

2

4

0100 200100 400 500300

Time (ms)

V

V

RM

4

20

2

4

4

2

0

2

4

ERP to standards

ERP to durationdeviant

ERP to frequencydeviantDuration MMN

Frequency MMN

Time (s)Typicalpitch

(Hz)

a

1,000

1,200

Deviant

StandardISI

Pitch

fDuration

+

Electrode

Parietalcortex

Occipitallobe

Frontallobe

Temporallobe

Cerebellum

Figure 2 | shmat aam mmath natt (MMN) nat n hzphna. a | MMN is elicite in an

auitory oball paraigm in which a sequence of repetitive stanar stimuli (blue boxes) are interrupte by stimuli that

iffer in a physical stimulus imension such as pitch or uration (green boxes). The eviant probability equals the numberof eviants ivie by the total number of stimuli. MMN reflects N-methyl-d-aspartate (NMDA)-epenent processing of

stimulus eviance within the auitory sensory cortex. b | Schematic iagram of MMN generators within the auitory

cortex (locate in the superior temporal lobe, shown in re). Because of the orientation of MMN generators, the MMN

reverses in polarity between the frontal miline electroe (Fz) an the left (LM) an right (RM) mastois. Because pitch

eviance can be etecte at stimulus onset, but uration eviance can only be etecte at the time of stanar stimulus

offset, uration MMN (pale blue line) is elaye relative to pitch (frequency) MMN (pink line). The ashe arrow inicates

the orientation of the electrical fiel originating from the auitory cortex. Activity from auitory cortex characteristically

inverts between the central miline electroe (Fz) an the mastois (RM, LM), relative to a nose reference (not shown).

| Characteristic waveforms at Fz from patients with recent onset or chronic schizophrenia versus controls. Peak MMN

responses (arrows) are significantly reuce in patients with schizophrenia relative to controls, for both pitch (top line)

an uration (bottom line). Dashe lines illustrate the latency shift in response to pitch versus uration to eviant stimuli25.

f, pitch ifference between stanar an eviant; ERP, event-relate potential; ISI, interstimulus interval. fIGS 2a an2c

are moifie with permission from Ref. 23 (2005) an Ref. 14 (2006) Elsevier Science, respectively.

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a Control b Patient

fast, an within 300500 s the ee atches the targetelcit. Paraxicall, this rees the retinal elciterrr (target iage elcit ins ee elcit) thatstilate the prsit respnse in the first place. unerthese circstances sbects elicit a preictie prsitrespnse base n the internal representatins f thetarget iage elcit71. These representatins are eriefr the efference cp f the tr can, as wellas the er trace f the earlier tin percept. Ths,SPEms are aintaine b the cbinatin f preictierespnse base n the internal representatin f the targettin an astents base n the isal feeback f

elcit an/r psitin errrs72.

SPEm is exaine in the labratr b asking sb-ects t fllw a sall ing target, an the ee psi-tin is recre sing electr-clgraph, agneticsearch cil, crneal reflectin tracker r high saplingrate ie caeras. Althgh initiatin an een laterrespnses are sei-atatic, the sbects cperatinis a ch larger isse than fr ERP easres. SPEmabnralities in schizphrenia were first bsereat the beginning f the 1900s73. Althgh the SPEmabnralit is bsere in relaties with n ert ps-chsis, it tens t c-aggregate with sbtle traits ancgnitie eficits in these iniials that are efine bschizphrenia spectr persnalit isrers. A recent

sibling-pair st estiate a heritabilit f arn 91%fr the preictie prsit abnralit in failies with ahistr f schizphrenia74.

There are ar generatr regins f SPEm: nerelate t the initiatin an the ther is assciatewith preictie prsit respnse. The tin f thetarget iage is prcesse b the ei-tepral (mT)regin, whereas the sth prsit initiatin respnseis eiate b neral circitr that inles the mTregin, the cerebell an the brain-ste cltrpathwas75,76(fIG. 6). The sbseqent preictie sthprsit respnse is base n the internal representatinf the preis target iage tin eiate b thepsterir parietal nerns, an the ei-sperir te-pral crtex that ences the efference cp f the trcan77,78. Frntal ee fiels integrate the extraretinaltin infratin int a preictie prsit respnse79.The eficit in schizphrenia is thght t be e t efi-cits in this extraretinal circitr80, with patients shwingecrease actiatin in ltiple brain regins inclingthe ei-sperir tepral crtex, the frntal ee

fiels an the secnar ee fiels (fIG. 6). In aitin,patients with schizphrenia wh hae enring negatiespts (an their relaties) shw eficits in sthprsit initiatin, which a be eiate b the mTcrtex an the cerebell eris.

Pclncl tnltn

In aitin t sering as rbst inices f brain sfnc-tin in schizphrenia, nerphsilgical biarkershae a istinct aantage f being translatable intanial els fr rg iscer. Fr an f theeasres, either hlgs r analgs prcesses canbe stie in rent r priate els. Frtherre,nerphsilgical easres can be btaine in awake,nrestraine anials, as well as restraine, anaesthetizer ex vivo preparatins.

Fr exaple, aitr easres resebling thsein hans hae been enstrate in bth rent anpriate els. In rents, aitr-gating phenenacan be stie sing EEG/fiel ptential recrings frthe crtex an hippcaps CA3 regin, r single-nitrecrings fr the agala, thalaic reticlar nclesan brain-ste reticlar fratin in respnse t acsticstilatin paraigs that are eqialent t thse seclinicall81. Althgh abslte latencies f crtical ansbcrtical aitr eke ptentials in rents (thatis, 1380 s) are tpicall ch shrter than thse in

hans (that is, 50300 s), the prcesses appear t beclsel siilar in respnse t paraetric aniplatinan respnse t pharaclgical agents81.

mmN-like23,82 an N1-like83,84 actiit can be recrein awake rents, spprting its rle in earl stage rgeelpent. Frtherre, in rents, generatin fmmN-like an N1-like actiit is inhibite b NmDA(N-ethl-d-aspartate) antagnists sch as ketaine,which is siilar t finings in hans85. Ptatie rentels f the P300 hae als been eelpe86,87. oerall,sbstantial ata enstrate that abnral infratinprcessing f schizphrenia cl be reprce in pre-clinical anial els sing pharaclgical, genetic r

Figure 4 | Tm/qn man ltnphalaph ma m a

ntl bjt an a patnt wth hn hzphna. The average event-

relate potential (ERP) (n= 88 trials) reveals that both P1 an N1 components are

markely reuce in the patient with schizophrenia compare with the control subject.

Reuce activity across the frequency spectrum is apparent in the maps of evoke

power, inuce power an phase-locking synchrony (colour scales same as in BOX 1).

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Delta0.55.5 Hz

Theta6.08.0 Hz

Alpha8.512.0 Hz

Controlsn = 89

Siblingsn = 115

Schizophrenicsn = 66

a b Left hemisphere

enirnental aniplatins. Ieall, these isrptingfactrs shl reflect genetic alteratins in schizphre-nia r replicate the sfnctinal nernal actiit rnertransissin that is bsere in patients withthe isease.

Aitr an isal prcesses siilar t thse bserein hans a als be reprce in priate els.Ths, bth mmN34,46 an aitr P300 (RefS 88,89)can be recre in nkes. Priates als shw isalsensr90 an AX-CPT53 respnses that are highl siilart thse in hans when siilar stilatin an recr-ing prceres are se. Althgh less aenable tgenetic aniplatin than rents, priate els fferthe aantage f extreel clse hlg betweenlabratr an clinical easres.

Undlyng pthphylgcl chn

In aitin t inexing the fnctin f specific brainregins, biarkers fr schizphrenia a be ifferen-tiall sensitie t the inleent f specific nerlingnercheical sstes. Schizphrenia has traitin-

all been linke t abnral painergic fnctin,althgh re recent theries ephasize aitinalistrbances in gltaatergic, GABA (-ainbtricaci)-ergic, sertnergic an chlinergic echaniss.The cntribtin f these easres t biarker eficitshas been ealate base n challenge sties, anialels an infratie genetic linkages.

Dopamine. Dpainergic els f schizphrenia arespprte b the abilit f painergic agents, sch asaphetaine, t stilate schizphrenia-like pschsis,as well as the abilit f paine D

2antagnists t ael-

irate sch spts. Hweer, acte aphetaine

ainistratin es nt case either negatie sptsr cgnitie eficits like thse bsere in schizphre-nia, leaing the rle f paine in nercgnitiesfnctin nresle.

Dpainergic hperfnctin is st releant t lerbiarkers, sch as PPIr P50 gating eficits, whicha be reprce in hans b aphetaine r therpaine agnists91,92. Aphetaine an ccaine alsisrpt aitr gating in the rat hippcaps, retic-lar thalas an crtex in a D

2-epenent anner81.

Hweer, eficits in P50 gating91,93 an PPI5 can bereerse in schizphrenia b atpical (especiall clzapine)bt nt tpical antipschtics, sggesting inleent faitinal nertransitter sstes.

Genetic sties hae prie frther insight intthe cnnectin between paine nertransissinan infratin prcessing94,95. Preliinar eienceassciates the late teprparietal P300 cpnentwith specific genetic ariatins in the paine D

3

an D2

receptr genes9699, whereas ariatins in thegene that ces fr the paine catablizing enze

catechl-O-ethltransferase (ComT) hae been ass-ciate with ariatins in prefrntal actiit (nise)19,100,101an SPEm102. Hweer, ther sties hae nt fn sig-nificant assciatins between paine-relate genesan P300-aplite103105. In line with these finings, ithas been arge that rece snaptic paine leelsa reslt in a iinishe signal-t-nise rati f pre-frntal nerns ring attentin-reqiring an wrkinger tasks60,101,106.

GABA. GABA istrbances hae been linke t schiz-phrenia n the basis f pst-rte finings f a rectinin the nber f paralbin-expressing internerns inthe hippcaps an frntal brain regins107,108, as well asspecific abnralities in the latin f praial cellspiking b paralbin-expressing, fast-spiking interne-rns. GABAergic nertransissin has been sggestet be a ar eterinant f the freqenc, pwer ansnchrn f gaa scillatins109.

Becase GABAergic prcesses hae a prinentrle in reglating excitatr nertransissin in thecrtex, it is nt srprising that GABAergic links can befn t st biarkers. GABAergic rgs hae beenshwn t alter P300 paraeters, with aplites beingrece an P300 latencies elae after the applica-tin f GABAergic rgs110. Siilarl, the generatin fmmN is thght t epen n intracrtical inhibitin,

reflecting GABAergic inhibitin f lcal GABAergicinternerns in the aitr crtex34. Siilarl, lcalGABAergic internerns in the mT crtical reginlate tin perceptin111,112, which cntribtes tthe cntrl f SPEm.

Ang neral scillatr easres, beta freqencies,een in backgrn EEG, a be relate t GABAergicfeeback. Benziazepines, sch as triazla, pr-ce a well-replicate increase in beta aplite thatinexes effects f these cpns n pschtrperfrance113. B cntrast, GABA inerse agnistsecrease beta aplite114. Assciatins between betaaplite an GABA

Areceptr plrphiss hae

Figure 5 | ctal pn aablt na n patnt wth

hzphna.a | Frequency omain analyses showing increase prefrontal noise,

that is, increase variability of slow-wave oscillations, in patients with schizophrenia

an their clinically unaffecte siblings60. Increase variability of slow-waveoscillations results from impaire phase-locking of these oscillations in schizophrenia65.

b | An analogous increase in variability of bloo-oxygen-level epenent response is

observe in patients with schizophrenia3: group contrast analysis compare with

controls. Prefrontal noise is moulate by synaptic opamine signalling (catechol-O-

methyltransferase (COMT)-genotype) as measure by electrophysiology an

functional magnetic resonance imaging3,60,101. This image is reprouce with permission

from Ref. 60 (2004) an Ref. 191 (2006) American Psychiatric Association.

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bFEFPutative retinal motion

processing areasSEF ACC MST

VermisPrimaryvisual

cortex Middletemporal lobe

D

egreespersecond

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Schizophreniaeye velocity

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Controls (n = 12) Patients with schizophrenia (n = 12)

als been escribe in health lnteers115an failialalchlics116, althgh the significance f these finingst schizphrenia reains t be eterine.

Glutamate. NmDA receptrs are ne f seeral recep-tr tpes fr the excitatr nertransitter gltaate.NmDA receptr antagnists sch as ketaine r phen-ccliine (PCP) ince spts an nerpschlgi-cal eficits that clsel reseble thse f schizphrenia,iplicating NmDA receptrs in the pathgenesis fschizphrenia117,118. Sch els hae been spprterecentl b enstratin f rece arkers fgltaatergic nernal integrit119, as well as rececncentratins f ain acis sch as glcine120,121 rd-serine122 in the plasa an/r cerebrspinal flif patients with schizphrenia. Seeral schizphrenia

ssceptibilit genes, sch as nereglin, ERBB4, sbin-in r d-ain aci xiase (DAOA; als knwn as G72)affect gltaate nertransissin an NmDA receptr

fnctin123. Siilarl, seeral enirnental alteratins,sch as rece gltathine leels124, increase knrenicaci125 r increase hcsteine leels121 als cnergen NmDA receptrs, sggesting a central rle f NmDAsfnctin in the isrer. Treatent with NmDAantagnists sch as ketaine r PCP leas t schiz-phrenia-like painergic sreglatin in han126an rent127 els, sggesting that istrbances inpainergic fnctin in schizphrenia ight be secn-ar t nerling gltaatergic sfnctin, cnsistentwith reciprcal interactin between sstes94.

NmDA antagnists, sch as ketaine, isrpt PPI inrents128 an priates129. Hweer, in hans, ketaine

Figure 6 | cmpnnt th mth pt mmnt: th nln nal t. The smooth

pursuit eye movement system functions to maintain the image of a moving object on the fovea by minimizing error

between the target velocity an the eye velocity. Broaly, the system is ivie into two components: the response

base on the internal representation of the target motion (that is, the extraretinal motion information), an the

corrections base on the visual feeback of iscrepancies between the eye an target velocities, the so-calle retinal

error. The pursuit maintenance in a control subject (re graph) an a patient with schizophrenia (blue graph) is shown

(a). The healthy iniviual is able to accurately match the target velocity, as this response is mostly riven by the

extraretinal motion signals uring the pursuit maintenance, whereas the patient with schizophrenia shows lower eye

velocity, because of inaequate extraretinal motion signals that create a retinal error. In response to the visual feeback

of the retinal error, the subject makes corrective responses in the form of a saccae or an increase in eye velocity

(marke by Z in panel a). However, this increase in velocity is transient as the retinal error signal becomes weak as the

eye velocity matches the target velocity. This interaction between the responses to retinal an extraretinal motion

signals is moelle by the regression equation72

: maintenance of eye velocity = be retinal error + ber extraretinalerror (where b

ean b

erare coefficients associate with retinal error an extraretinal error, respectively). Data suggest

that compare with control subjects, iniviuals with schizophrenia epen more on retinal error an less on

extraretinal motion signals to maintain pursuit72. When schizophrenia an control subjects were matche on how well

they maintaine pursuit, schizophrenia subjects showe more activation of the meio-temporal cortex (MT) (b), a

region known to process motion, than the healthy control subjects. However, these patients showe less activation of

the meio-superior temporal cortex (MST), the posterior-parietal cortex (PPC) an the frontal eye-fiel regions (FEF),

areas that are known to process extraretinal motion signals (); see Ref. 74 for more etails. ACC, anterior cingulate

cortex; SEF, supplementary eye fiels. fIG. 6c is moifie with permission from Ref. 80 (2005) Elsevier Science.

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es nt ince P50 gating eficits130 an a enhance,rather than inhibit, PPI131. Frtherre, in hans,PPI eficits are assciate with increase, rather thanecrease, plasa leels f the ain-aci glcine, whichseres as an NmDA c-agnist in vivo132. Ths, relatin-ships between phenenlg an NmDA sfnctinappear t iffer acrss species. In anials, NmDA antag-nist-ince PPI eficits are reerse b clzapine, btnt b st tpical r atpical antipschtics128,129.

of the cnsiere nerphsilgical easres, mmNhas been st extensiel inestigate with regar tgltaatergic echaniss, particlarl inling NmDAreceptrs. Deficits in mmN generatin a be ince inbth nkes133 an hans134,135 fllwing ainistra-tin f NmDA antagnists. Frtherre, in health l-nteers, mmN aplite preicts the egree f pschsisince b ketaine acrss sbects136. In cntrast teffects f ketaine, mmN was nt affecte b psilcbin,a pschtietic agent that fnctins ia stilatin f5-hrxtrptaine 2A (5-HT

2A) receptrs136. Deficits in

mmN generatin persist espite treatent with aailable

antipschtic agents, incling 5-HT2A-selectie c-pns sch as clzapine, lanzapine an risperine,sggesting that painergic an sertnergic sstesare nt clsel relate t mmN generatin.

Abnral gltaate transissin has been sg-geste in ther ipaire nerphsilgical easres inschizphrenia. Fr exaple, schizphrenia-like eficitsin AX-CPT prcessing are ince b ketaine, sp-prting a rle f NmDA sfnctin134. Hweer, scheficits are reprce b psilcbin as well, sggestingthat the are less specific fr NmDA sfnctin thanmmN137. Alteratin in isal P1-eke ptentials,which inicate abnral earl stage isal prcessingin schizphrenia, has als been linke t gltaatehpfnctin an/r rece NmDA receptr actiit43.Frtherre, ketaine ainistratin iics seeralfeatres f SPEm eficits in health sbects, sch as theinitiatin respnse138,139.

NmDA receptrs a als hae a rle in latinf scillatr actiit. Infsin f NmDA agnists int thehippcaps r sept irectl inces theta actiit,whereas NmDA antagnists sppress spntanes thetaactiit an actiit that is ince b behairalaniplatin, sch as tail pinch, while haing nn-significant effects n gaa actiit140,141. Siilarl,NmDA antagnists rece beta, bt nt gaa, actiitin the hippcapal slice142. In hans, ketaine atten-

ates the increases in crtical elta an beta actiit thatare bsere ring piate withrawal143. Ths, NmDAsfnctin in schizphrenia wl be anticipate tcase eficits in neral snchrn in schizphrenia,particlarl in slwer freqenc ranges.

Acetylcholine (ACh). Finall, istrbances in chlinergicfnctin hae been assciate with schizphreniabase n linkages t the 7 nictinic receptr, as wellas increase sking rates ang patients with schiz-phrenia144. Nictinic echaniss a be particlarlreleant t the phenenn f P50 gating, in that nic-tine ipres, althgh transientl, P50 aitr-gating

eficit in patients an their relaties145. In preclinicalanial els, pharaclgicall, geneticall an eni-rnentall ince gating eficits are nralize bnictinic receptr agnists an latrs146150, thscnfiring a rle f nictinic echaniss in aitrgating. Since it was shwn that a partial nictinic 7agnists ipres the gating eficit in patients withschizphrenia151, it appears that this nerphsilgicaleasre can be se as translatinal biarker, at leastfr nictinic targets.

Inleent f chlinergic echaniss in aitr-eke P300 has als been bsere. ACh an chlinergicrgs appear t strngl increase P300 aplite. Theppsite bseratin (a ecrease f P300 aplite) wasae fr antichlinergic sbstances. Bth effects are likelt be eiate b scarinic an perhaps als nictin-ergic receptrs152161. In line with these bseratins inhans, septal chlinergic lesins ablish aitr P300in cats162. As abnral chlinergic transissin appears tbe inle in aspects f schizphrenia pathphsilgan, in particlar, cgnitie eficits incling er an

attentinal eficits163, P300 a be cnsiere a seflbiarker t track pharaclgical interentins withchlinergic rgs. The ieiate respnse t a nelpresentatin f target tin, which is epenent n earltin prcessing, is als ipre b the ainistratinf nictine in patients with schizphrenia164, sggestingthat this arker cl be se as well.

Aitinall, chlinergic echaniss hae beeniplicate in nernal netwrk scillatins. visalleke gaa-ban scillatin patterns an nernalsnchrnizatin are greatl rece after intracrticalainistratin f the scarinic ACh receptr antagnistscplaine165. Frtherre, 7 nictinic ACh recep-trs appear t late theta an gaa-ban scilla-tins in bth in vitro an in vivo experients in anials,in part thrgh latin f GABA actiit146,166.Ths, een if eficits in chlinergic actiit are nt cas-atie in schizphrenia, nictinic receptrs, particlarl7, a sere as a target fr interentin.

In sar,seeral nertransitter sstes haebeen linke t schizphrenia, either thrgh the analsisf the actin f rgs f abse sch as PCP r apheta-ine, f thrgh the analsis f genetic plrphiss.Seeral f the prpse biarkers shw particlar sen-sitiit t eficits in specific nercheical pathwas,an ths ight cntribte t targete rg eelpent.The strngest assciatins are fn between P50 gating

an nictinic echaniss, paine an prefrntalnise easreents, an NmDA receptrs an sensristrbances in bth the aitr an isal alities.In general, later cpnents, sch as P300, hae a recplex pharaclg than earlier ptentials an arere likel t reflect an interpla between ltiplenertransitter sstes.

Futu dctn

At present, seeral escribe biarkers, sch as ai-tr mmN r P300, isal P1 r SPEm istrbances,appear sfficientl establishe s that the a sere asapprpriate translatinal easres fr rg iscer

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1. Tallon-Baudry, C. & Bertrand, O. Oscillatory gammaactivity in humans and its role in objectrepresentation. Trends Cogn. Sci.3, 151162 (1999).Reviews evidence for gamma-band synchrony in

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2. Sehatpour, P., Molholm, S., Javitt, D. C. & Foxe, J. J.Spatiotemporal dynamics of human object recognitionprocessing: an integrated high-density electricalmapping and functional imaging study of closureprocesses. Neuroimage29, 605618 (2006).

3. Winterer, G. et al. Complex relationship betweenBOLD signal and synchronization/desynchronization ofhuman brain MEG oscillations. Hum. Brain Mapp.28,805816 (2007).

4. Potter, D., Summerfelt, A., Gold, J. & Buchanan, R. W.Review of clinical correlates of P50 sensory gatingabnormalities in patients with schizophrenia.Schizophr. Bull.32, 692700 (2006).

5. Swerdlow, N. R. et al. Startle gating deficits in a largecohort of patients with schizophrenia: relationship tomedications, symptoms, neurocognition, and level offunction.Arch. Gen. Psychiatry63, 13251335 (2006).

6. Roth, W. T. & Cannon, E. H. Some features of theauditory evoked response in schizophrenics.Arch.Gen. Psychiatry27, 466471 (1972).

7. Ford, J. M. Schizophrenia: the broken P300 and

beyond. Psychophysiology 36, 667682 (1999).8. Jeon, Y. W. & Polich, J. Meta-analysis of P300 and

schizophrenia: patients, paradigms, and practicalimplications. Psychophysiology40, 684701 (2003).

9. Frodl-Bauch, T., Gallinat, J., Meisenzahl, E. M., Moller,H. J. & Hegerl, U. P300 subcomponents reflectdifferent aspects of psychopathology in schizophrenia.Biol. Psychiatry45, 116126 (1999).

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prects. In aitin, the se f nerphsilgicaleasres has been greatl extene er recent earsb the ealatin f neral snchrn easres alngwith siple respnse aplite. Acrss regins, actiitappears t be nis, reflecting the inabilit t snchr-nize brain scillatins apprpriatel acrss a wie fre-qenc range incling, bt apparentl nt liite t,the gaa freqenc ban.

Althgh nl a few biarkers hae prgresse tthe pint in which the can be reliabl applie in rgeelpent sties, nerphsilgical easres arenerging cntins eelpent, sggesting that thetpe an ariet f easres will increase in the cingears. mreer, targets fr rg treatent f schiz-phrenia are braening cntinall (fr reiews seeRefS 167,168). These targets incle specific sbtpes fnaine receptrs, sch as the 5-HT

2c(RefS 169,170),

5-HT3(Ref. 171), 5-HT

6(Ref. 172) an histaine (H

3)173

receptrs, aris ligans an latrs f gltaatereceptrs, sch as the etabtrpic (GlR2/3) glta-ate receptrs174, an ther ierse targets f intracell-

lar prcesses an/r secn essenger sstes, schas the phsphiesterases175. Se f these nel targetshae a strng assciatin with genes cnsiere t becaniate ssceptibilit factrs fr schizphrenia, schas phsphiesterase 4B (PDE4B) interacting with theisrpte in schizphrenia 1 (DISC1) gene176. othertargets hae eerge fr epieilgical sties,sch as the cannabini receptrs (fr exaple, CB

1) r

encannabinis177.mreer, it is knwn that an experiental

cpns acting n these targets prfnl affectnernal netwrk scillatins178185 r ther electr-phsilgical easres f infratin prcessing (schas aitr gating). Exaples incle ligans f 5-HT

3

,CB

1an H

3receptrs, as well as inhibitrs f PDE4 an

PDE10 enzes173,179,183185. once these rg caniatesenter clinical eelpent, nerphsilgical biark-ers iscsse here will prie a better nerstaningf the nerling nerphsilgical abnralities inschizphrenia, an their relatin t the aris psitie,negatie an cgnitie spts f the isease. Thesenel cpns esigne t treat a range f spts

f schizphrenia are crrentl being ealate in arispreclinical els f nerphsilgical biarkers.These finings, cbine with aitinal clinicalnerphsilgical biarker sties, will prie anpprtnit t aliate nt nl nel targets, bt als

aliate the therapetic preictie ale f these ner-phsilgical anial els.

Iprtantl, ifferent nerphsilgical easresprbe ifferent aspects f brain fnctin. Ths, biar-kers are prbabl best se in cncert with each ther,rather than in islatin. Fr exaple, althgh eas-res sch as P50 gating, mmN an P300 all shw highheritabilit an reprcibilit n their wn, the shwrelatiel lw crss-crrelatin17, sggesting relatiellittle genetic an echanistic erlap. Iniial eas-res a als iffer in ters f sensitiit an specificitfr schizphrenia, as well as nerling nercheicalechaniss. The se f cbine, rather than ini-

ial easres, has recentl been enstrate friagnstic prpses186. A siilar sitatin is likel thl fr rg eelpent. Finall, ltial iaging,

in which nerphsilgical biarkers are cbinewith strctre-base neriaging appraches (frexaple, fmRI), a prie re infratin thaneither alit alne.

Althgh brain actiit is ipaire in schizphreniaacrss a range f anatical regins an phsilgicalprcesses, nt all eicatins will affect all nerl-ing nercheical eficits eqall. Ths, the chicef biarkers in rg eelpent epens nt nln the pathphsilg f the nerling isrer, btals n the expecte echanis f actin f the rg tbe inestigate. The aailabilit f analgs easresin anial research represents an tstaning strengthf nerphsilgical biarkers, therefre perit-ting their se as translatinal easres ring earlrg eelpent, an as prf-f-cncept r prf-f-echanis easres in bth health sbects aniniials with schizphrenia.

oer the cing ears, aitinal refineents in bthbehairal paraigs an analtical appraches willnbtel lea t frther eelpent f biarkerappraches fr schizphrenia.

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