Pettersonn 2011 Review

Journal Identication = NBR Article Identication = 1383 Date: March 3, 2011 Time: 8:4pm

Neuroscience and Biobehavioral Reviews 35 (2011) 11101124

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l homepage: www.e lsev ier .com/ locate /neubiorev

Review

Dyscon

WilliamDepartment of

a r t i c l

Article history:Received 3 AuReceived in reAccepted 20 N

Keywords:SchizophreniaPsychosisConnectivityFunctional ma(fMRI)Diffusion tensGenetic high rUltra High RisFirst-episode (Early-onset schizophrenia (EOS)Positron emission tomography (PET)

Contents

1. Introd2. What3. Is dys4. Metho5. Resul

5.1.5.2.

5.3.

5.4.

5.5.

5.6.

CorresponTel.: +44 207 8

E-mail add

0149-7634/$ doi:10.1016/j.uction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111is dysconnectivity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111connectivity related to the stage of the disorder? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112ds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112

ts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112fMRI methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112HGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11125.2.1. Functional connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11125.2.2. Structural connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113UHR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11135.3.1. Functional connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11135.3.2. Structural connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113FE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11135.4.1. Functional connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11135.4.2. Structural connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113EOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11145.5.1. Functional connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11145.5.2. Structural connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114ChSZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11145.6.1. Functional connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11145.6.2. Structural connectivity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114

ding author at: Department of Psychosis Studies, PO Box 67, Institute of Psychiatry, Kings College London, De Crespigny Park, London SE5 8AF, UK.48 0833; fax: +44 207 848 0287.resses: [email protected], [email protected] (A. Mechelli).

see front matter 2010 Elsevier Ltd. All rights reserved.neubiorev.2010.11.004nectivity in schizophrenia: Where are we now?

Pettersson-Yeo, Paul Allen, Stefania Benetti, Philip McGuire, Andrea Mechelli

Psychosis Studies, Kings College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

e i n f o

gust 2010vised form 2 November 2010ovember 2010

gnetic resonance imaging

or imaging (DTI)iskk (UHR)FE)

a b s t r a c t

The disconnection hypothesis suggests that the core symptoms of schizophrenia (SZ) are related to aber-rant, or dys-, connectivity between distinct brain regions. A proliferation of functional and structuralneuroimaging studies havebeen conducted to investigate this hypothesis, across the full course of thedis-order; from people at Ultra-High-Risk of developing psychosis to patients with chronic SZ. However theresults of these studies have not always been consistent, and to date, there have been no attempts to sum-marise the results of bothmethodologies in conjunction. In this article, we systematically reviewboth thestructural and functional connectivity literature in SZ. The main trends to emerge are that schizophreniais associated with connectivity reductions, as opposed to increases, relative to healthy controls, and thatthis is particularly evident in the connections involving the frontal lobe. These two trends appear to applyacross all stages of the disorder, and to be independent of the neuroimaging methodology employed. Wediscuss the potential implications of these trends, and identify possible future investigative directions.

2010 Elsevier Ltd. All rights reserved.


W. Pettersson-Yeo et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 11101124 1111

6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11177. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .A.1. . . . . . .A.2. . . . . . .A.3. s . . . .Refer . . . . . .

1. Introdu

The lastareas of funapplicationmethodologto explain tgressive sup

Outlinedand Frith,functional dregions in S(Frith et al.,can be descbetween di

Since itsnetic resonaand descrip(DCM), Psydent Comphypothesis.functional ca host ofto chronicsubgroups.

In the lahas been mtural correl(WM) connnicant factensor imagof WM trawater.

To date,that summaable (KanaaWinterer, 22009a). Witare evidentreviewing ttural neuro

In this cpublishedtural and/owith SZ (aTo our knosuch we inevident inbetween sumore, we share presenprogresses.

For theused electrexamine co

otal npatien

nal craphntaineliabh regard to those structural studies presented, only thoseusing DTI and reporting fractional anisotropy (FA) valueselected for inclusion. This is based on the premise that FAcurrently represent the most commonly reported structuraltivity scale, relative to either mean diffusivity or relativeopy for example.

at is dysconnectivity?

theme of this review is dysconnectivity, fundamentally,ere to refer to an abnormal (rather than decreased) integra-etween anatomically distinct brain regions (Stephan et al.,2009a) (N.B. the term is used in isolation from the associ-echanistic hypothesis outlined by the group in the samereferenced). As the denition suggests, dysconnectivity

fer to either a hypo- or hyper-integrative/connective staten distinct brain regions. Specically it is used here as a sub-for disconnection, a term with the implicit implication ofd connectivity and one which would thence automaticallyhose ndings where increased, as opposed to decreased,tion between regions was discovered. Given that aberranttivity between distinct brain regions can occur both at aAbbreviations of brain regions reported . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Abbreviations of fMRI paradigms reported . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Abbreviations of Methodologies used for functional connectivity analyse

ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ction

two decades have seen signicant leaps forward in thectional and structural neuroimaging, not least in theirto the eld of schizophrenia (SZ) research. Astride thisical progression, one conceptual framework proposedhe core decits of the illness has been gathering pro-port: the disconnection hypothesis.in the early, 1990s (Friston and Frith, 1995; McGuire1996), the hypothesis was based on an observedisconnection between prefrontal and temporal brainZ patients relative to a group of healthy controls (HCs)1995). Specically it suggests that SZs core symptomsribed in terms of an abnormal functional integrationstinct brain regions.

initial inception, a proliferation of functional mag-nce imaging (fMRI) studies using increasingly sensitivetive techniques (including Dynamic Causal ModellingchoPhysiological Interaction (PPI) and Indepen-onent Analysis (ICA)) have been used to test thisTogether, these studies have reported a variety ofonnectivity alterations occurring within, and between,different brain regions when comparing HCs bothSZ patients as well as a range of SZ diagnostic

st 1015 years the focus on functional connectivityatched by a concurrent search for potential struc-

ates and/or distinct abnormalities in the white matterections in the brains of those suffering SZ. One sig-tor underlying this has been the advent of diffusioning (DTI), a technique able to quantify the integritycts in vivo by utilizing the diffusion properties of

a number of informative reviews have been publishedrise many of the functional, or structural, studies avail-n et al., 2005; Begr and Koenig, 2008; Konrad and008; Ellison-Wright and Bullmore, 2009; Stephan et al.,hin and amongst the results a range of inconsistencieshowever, and to date, no paper has been published

he connectivity eld, from both a functional and struc-imaging perspective as a whole.ontext, what follows is a systematic review of papersto date that report, specically, contrasts in struc-r functional connectivity estimates between patientsnd preceding aberrant states) and HCs (see Fig. 1).wledge this review is the rst of its kind and as

tend to highlight connectivity alterations that may beand between studies either methodologically and/or

Fig. 1. Tfor each

functiotomogto maimore r

Witpaperswere svaluesconnecanisotr

2. Wh

Theused htion b2006,ated mstudiescan rebetweestitutereduceomit tintegraconnecbjects in different phases of the illness. Further-all elucidate where possible whether these alterationst from onset, or instead emerge as the disorder

purposes of this paper, functional studies that haveoencephalography and magnetic-encephalography tonnectivity have been omitted, and instead only those

functional ahere.

In functfunctional iacterised iconnectivitbetween ac. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121

umber of functional and structural connectivity publications foundt group.

onnectivity studies using fMRI and positron emissiony (PET) imagingwill be reviewed. This isdone inanefforta level of consistency between studies, and hence a

le analysis.nd/or structural level, both aspects shall be considered

ional neuroimaging studies, it should be claried thatntegration within a distributed network can be char-n terms of functional connectivity and effectivey. Whilst the former refers to a correlation over timetivity in spatially remote brain regions, the latter refers


1112 W. Pettersson-Yeo et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 11101124

to the impact that activity in one region exerts over activity inanother. To date however the majority of studies including thosepresented here, have assessed functional as opposed to effectiveconnectivity with few exceptions (Schlsser et al., 2003; Mechelliet al., 20072010) and athe type of

It shouldtively generconnectivittive correlafromvoxelwtype of corridentied ricant correconnectiontivity, it istwo positivelying mechbetween twity thereforreported btable.

In the cotivity is infealternative,connectivitregions andet al., 2005results howthe purposeby DTI.

Consideand Pierpasent greatethe same feither be reHCs.

Whilst dthe use ofways, the dent conceptpresented.

3. Is dysco

To dateresearcheprecisely hoHowes andpapers includifferent starisk of deveAs such thebasis of therst episodUltra-Highchangeably2002; Yungmore rst dGenetic Risorganised inconnectivitwe aim towith frankillness onse

4. Methods

In order to identify suitable publications, an online search of thePubmed,Medline andPsychInfo. databases, using the search terms;

zophraphndued, oon cpatiee whstic dsearicancedwithld (Krer, 2. PETationeal ing thnalralwhi

ry). Rin eaableonne2B), 1en tandwiders an319r thehe Dns exmenor thet a

ults

RI m

Tablesed be, w

g mal, epslowomped toan ined. Acangm u

GR

FuncpiteR grty in; Benetti et al., 2009; Crossley et al., 2009; Allen et al.,s such we do not distinguish between studies based onconnectivity they report.also be made explicit that dysconnectivity is a rela-

al term, in that it can refer to a range of distinct aberranty patterns. For example, both positive and/or nega-tions contribute to the connectivity estimates derivedise functional activity correlationanalyses. The specicelation however is irrelevant with respect to whetheregions are hypo- or hyper-connected. Whilst signif-lation alterations of either type indicate an aberrantand are hence consistent with the term dysconnec-true that an increased connection observed betweenly correlated regions is likely to reect a distinct under-anism of action relative to an increased connectiono negatively correlated regions. For the sake of clar-

e, where the type of connectivity modulation has beeny a particular study, this has been indicated in the

ntext of the structural studies presented here, connec-rred from each participants WM specic FA value. Analbeit more indirect, method of estimating structural

y would be to look at volumetric co-variation betweenhow this varies between experimental group (Mechelli). Whilst this approach has yielded some interestingever (Mitelman et al., 2005; Modinos et al., 2009), fors of the present review we focus on FA values obtained

red to reect the underlying structural integrity (Basseroli, 1996), greater FA values are believed to repre-r WM integrity (Kubicki et al., 2007) and in exactlyashion as functional connectivity, these values canduced and/or increased in patient groups relative to

ysconnectivity is a general term therefore, that throughdifferent methods may be characterised in differentenition we describe is used to encompass the differ-ualisations of connectivity across the different studies

nnectivity related to the stage of the disorder?

, there remain substantial divisions within the SZldas to theaetiologyof the illness and,more specically,w it originates and develops (Fatemi and Folsom, 2009;Kapur, 2009; Stephan et al., 2009a). Given this fact, theded for review here reect a range of patient groups atges of illness; from those with a signicantly increasedloping psychosis, through to patients with chronic SZ.studies reported here have been sub-divided on their clinical categorisation, namely: chronic SZ (ChSZ),

e SZ (FE), early onset SZ (EOS), those diagnosed with anRisk (UHR) of developing psychosis (used here inter-with the At-Risk Mental State (ARMS)) (Miller et al.,et al., 2003; Cannon et al., 2008) and those with one oregree relatives diagnosed with SZ, and hence at Highk (HGR) of developing it themselves. With the reviewthis way, it is intended that the temporal course of any

y alterations within SZ can be elucidated. Specically,establish if dysconnectivity is present only in patientspsychosis or whether such alterations are evident att, or earlier.

(schiTomogwas coreturninclusiity inor thosdiagnoonlineof signreferentermsthe eWinte2009a)publicgreat d

Usifunctiostructustudiescategoresent7 FE (Ttural c(Table

Givdosagevaried18 yeaaged 1teria fousing ttigatioAssess2004)(Miller

5. Res

5.1. fM

Aswere ution timworkinretrievversustence cDesignused cobservbelowparadi

5.2. H

5.2.1.Des

the HGnectivireniaORpsychosis)AND(MRIORPositron-Emissiony OR diffusion tensor imaging) AND (connectivity)cted on 14th October 2010. A total of 254 hits weref which we included 73. Those studies not matching ourriteria were, for example, those examining connectiv-nts with respect to medication (Goghari et al., 2010),ose patient groups did not strictly meet our operatingenitions (e.g. Modinos et al., 2010). In addition to the

ch criteria described, in order to ensure that no studiesce were omitted from the review, we also hand cross

the list of those studies gathered from our online searchthe bibliographies of the currently existing reviews ofanaan et al., 2005; Begr and Koenig, 2008; Konrad and008; Ellison-Wright and Bullmore, 2009; Stephan et al.,methodology was also used to ensure inclusion of key

s from the mid-late 1990s whose results contributed an guiding the eld to its present position.ese criteria a total of forty-seven papers reporting

connectivity studies, and fty-nine papers reportingconnectivity studies were identied (although somech used multiple patient groups fell into more than oneepresenting functional connectivity studies these rep-ch subject category; 5HGR (Table 1A), 4UHR (Table 2A),3A), 2 EOS (Table 4A) and 35 ChSZ (Table 5A). For struc-ctivity studies we identied 3 HGR (Table 1B), 5 UHR1FE (Table 3B), 5 EOS (Table 4B) and41ChSZ (Table 5B).

he expansiveness of the literature presented, types,duration of medication prescribed to patients, if any,ly. With respect to age, all patient groups were agedd above with the exception of the EOS group who wereyears old. In the case of ChSZ, diagnostic inclusion cri-studies representedwere in themajority of casesmadeSM-IV and, less frequently, the ICD-10. For those inves-amining UHR participants either the Comprehensive

t for the At-Risk Mental State (CAARMS) (Yung et al.,e Structured Interview for Prodromal Symptoms (SIPS)l., 2002) was generally used.

ethodology

s 1A5A show, a wide variety of different paradigmsy those studies using fMRI. These include, choice reac-orking memory, auditory oddball, verbal/visuospatialemory, voice recognition, verbal encoding and/orisodic memory, verbal uency, word generation, fastarticulation, retrieval and lexical decision making, sen-letion, short delay pattern recognition and resting state.activate specic a priorinetworks, the typeof paradigmherently bias the specic range of areas that might bes such, interpretation of the fMRI results summarisedbe further informed by knowledge of the particularsed (see Tables 1A5A).

tional connectivity studiesonly 5 studies investigating functional connectivity inoup (see Table 1A), all studies reported decreased con-HGRparticipants relative toHCs.Moreover, every study



Table 1AStudies investigating functional connectivity in those at HGR of SZ relative to HCs.

Author Sample size Method Task Regions Connectivity

HC HGR

Li et al. (2010)a 20 21 VCa VLD L.IFG - FL, R.ACG, L.CG, TL, MOL, L.PL, L.FusiformL.IFG - L.Olfactory, L.OL, R.MFG

Woodward et al. (2009) 32 12 VCa CRT R.MFG - L.MFGWhiteld-Gabrieli et al. (2009)b 13 13 VCa RS DMN - MPFC

R.DLPFC - MPFCWhalley et al. (2005)b 21 69 VCa SC R.Med.FG - L.Cerebellum

L.IPL - L.IFGSpence et al. (2000) 10 10 PCa VF L.DLPFC - PCu

n.s. = no signicant differences in connectivity between patient group and HCs; red downward arrow ( ) = refers to studies which reported (i) positive connectivity in HCsand less pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and less pronounced negative connectivity in patients. Green upward arrow( ) = refers to studies which report (i) positive connectivity in HCs and more pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and morepronounced negative connectivity in patients. See Appendices A.1A.3 for method, task and brain region abbreviations.

a Studies where regions of reported difference have been condensed into fewer representative areas.b Studies wh nd HC

also reportesubcorticalthe anterioet al., 2005;Li et al., 201studies alsoative to HCLi et al., 201

5.2.2. StrucConsiste

pants, all 3inHGRpartcal andmidin the right2009a).

Once agwith Hoptmincrease, buareas.

5.3. UHR

5.3.1. FunctAs with

number ofgroup (seewhich focualterationstwo studiesporal regionCrossley ettotemporalmiddle temUHR group

n ths (Sh

Strucsisteommwase stus theandgnistubjec

Functsistegatios, fourastnlyservdysctly sCrossui eti regn HC

Strucontrral c

Table 1BStudies invest

Author

Camchong eMunoz ManHoptman et

n.s. = no signiarrow ( ) = greexperimentalere differences in both positive and negative connectivity between patient group a

d frontal region dysconnectivity to other cortical andareas, such as the parietal cortex, the cerebellum andr cingulate gyrus (ACG) (Spence et al., 2000; WhalleyWhiteld-Gabrieli et al., 2009; Woodward et al., 2009;0). In addition to decreased connectivity, three of thesereport increased connectivity in HGR participants rel-

s (Whalley et al., 2005; Whiteld-Gabrieli et al., 2009;0).

tural connectivity studiesnt with the functional studies examining HGR partici-included structural studies report reduced connectivityicipants relative toHCs between frontal and other corti-brain regions (see Table 1B). Reduced FA is also reportedGenu of the corpus callosum (CC) (Camchong et al.,

ain however, these consistencies are not absolutean et al. (2008), not only reporting a connectivityt an increase between frontal, temporal and parietal

ional connectivity studiesstudies of HGR groups, there remain to date a limitedstudies published examining connectivity in the UHRTable 2A). All four studies included however, three ofs on frontotemporal interactions, report connectivityin the UHR subjects relative to HCs. Specically, whilstreport reduced connectivity between frontal and tem-s in the UHR group relative to HCs (Benetti et al., 2009;al., 2009) one study reports no change in left fron-connectivityandan increasedconnectivitybetween left

betweeregion

5.3.2.Con

most clationthe vreportfrontalwith si

TwoUHR su

5.4. FE

5.4.1.Con

investiandHCIn conttivity othat obreportexplici2009;ever, La priorbetwee

5.4.2.In c

structu

poral gyrus (L.MTG) and ACG (Allen et al., 2010) in the, whilst the last reports both increases and decreases

Whilst sixreduction i

igating structural connectivity in those at HGR of SZ relative to HCs.

Sample size

HC HGR

t al. (2009a) 30 22iega et al. (2008) 51 22al., 2008 37 22

cant differences in connectivity between patient group and HCs; red downward arrow (ater connectivity in patient group relative to HCs. Studies that have included schizoaffec

group: Hoptman et al. (2008). See Appendix A.1 for brain region abbreviations.s has been explicitly reported.

e posterior cingulate gyrus (PCG) and other corticalim et al., 2010).

tural connectivity studiesnt with functional studies examining UHR subjects, theon nding from structural studies of the same popu-

a FA reduction in frontal regions, reported by three ofdies included (see Table 2B). One of these studies alsosuperior longitudinal fasciculus (SLF), which connectstemporal regions (amongst others), as the only tractcant alteration (Karlsgodt et al., 2009).dies however report no signicant difference betweents and HCs whatsoever (Peters et al., 2008, 2010).

ional connectivity studiesnt with the studies detailed so far, the majority of the 7ns examiningpotential differences betweenFE subjectsnda reduction in functional connectivity (seeTable3A).

one study alone found an increase in functional connec-(Boksman et al., 2005). Furthermore, 5 of the studiesed signicant differences in FE patients relative to HCs,onnectivity between frontal andother regions,with twopecifying frontotemporal connections (Benetti et al.,ley et al., 2009). Inconsistent with these ndings how-al. (2009) who included frontotemporal regions asions of interest, reported no signicant differencess and FE participants.

tural connectivity studiesast to functional connectivity studies in FE patients,onnectivity studies are less consistent (see Table 3B).

of the eleven studies suggest a tentative trend of FAn patient group versus HCs, with four of the six also

Regions Connectivity

R.GenuALICL.IFG, L.PCG, angular gyrusL.ACG, pontine tegmentum, R.FG

) = lesser connectivity in patient group relative to HCs; green upwardtive, schizophreniform and/or schizotypal patients within their HGR



Table 2AStudies investigating functional connectivity in those with an UHR of becoming psychotic relative to HCs.


HC UHR

Shim et al. (2010)a 39 19 VCa RS

Allen et al. (2010) 15 15 DCM SC

Crossley et al. (2009) (ve) 13 16 DCM WMBenetti et al. (2009) 14 16 DCM SDPR

n.s. = no signicant differences in connectivity between patient group and HCs; red downward arrow (and less pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and less( ) = refers to studies which report (i) positive connectivity in HCs and more pronounced positive connepronounced negative connectivity in patients. Where studies have explicitly reported connectivity typconnectivity between regions in patients relative to HCs. See Appendices A.1A.3 for method, task and

a Studies where differences in both positive and negative connectivity between patient group and H

implicating frontal and temporal regions (Szeszko et al., 2005; Haoet al., 2006; Cheung et al., 2008; Luck et al., 2010) one study bySegal et al. (2010) found an increase alone. Furthermore, in additionto these conreport neithferences atet al., 2008)

5.5. EOS

5.5.1. FunctOf the tw

in this categbrain regionused ICA foustriatum (sthe temporfrontal andity (White eZhou et al.,left TL.

5.5.2. StrucTheve

FA value inparallel wittwo of the et al., 2007;Kyriakopoua particulahigh-risk gr

Table 2BStudies investpsychotic rela

Author

Peters et al.,Karlsgodt etBloemen etPeters et al.,Peters et al.,

n.s. = no signidownward arrupward arrowthat have inclwithin their Ufor brain regio

However, tdecit, withto the right

SZ

Funcsistet inveed inentstwo snlyelli etwo,s conbjeconly

ely laf theed ley onWhitShimseened r

alonermorncreral as (M

Strucicting ndings, the remaining four studies presenteder increase, nor decrease, but instead, no signicant dif-all (Price et al., 2005, 2008; Friedman et al., 2008; Peters.

ional connectivity studieso studies (see Table 4A) thatwere suitable for inclusionory one reported dysconnectivity in multiple, distinct,s having used the CG as a seed region. The other havingnd reducednetwork connectivity between cerebellum,

tri.) and occipital lobe (OL), and between the ACG andal lobe (TL). In common with FE and HR groups, bothtemporal areas are identied as showing dysconnectiv-t al., 2010a; Zhou et al., 2010). Inconsistently howeveralso report an increased functional connectivity in the

tural connectivity studiesstructural studies in EOS showaclear patternof reducedEOS subjects relative to HCs (see Table 4B). One notableh the results from UHR and FE studies is the report byve investigations of frontal lobe involvement (AshtariKyriakopoulos et al., 2008). Furthermore, of these two,los and colleagues specically detail the right SLF asr region of decit consistent with studies in FE andoups reporting aberrant frontotemporal connection.

igating structural connectivity in those with an UHR of becoming

5.6. Ch

5.6.1.Con

subjecincludin patithirty-with o(Mechthirty-regionHGR su

Therelativteen oreportcated b2007;2010;

AsincreastivityFurthetivity itemporegion2009).

5.6.2.tive to HCs.

Sample size Regions Connectivity

HC UHR

2010 10 17 n.s.al., 2009 25 36 SLFal., 2009 10 37 SFL2009 10 10 R.SFL2008 10 10 n.s.

cant differences in connectivity between patient group and HCs; redow ( ) = lesser connectivity in patient group relative to HCs; green( ) = greater connectivity in patient group relative to HCs. Studies

uded schizoaffective, schizophreniform and/or schizotypal patientsHR experimental group: Peters et al. (2008, 2009). See Appendix A.1n abbreviations.

Reducednding of stwo groups(see Table 5different pastudies invAmongst thtemporal represent in ein the otheregion showpassing ndimplicatedin theACG,PCG - ACG, Med.PFC, PCu, PLPCG - DLPFC, IPL, MTG, L.Supp.Motor AreaL.MTG - ACGL.MTG - L.MFGMFG - STGPost.Hipp - IFL

) = refers to studies which reported (i) positive connectivity in HCspronounced negative connectivity in patients. Green upward arrowctivity in patients, and/or, (ii) negative connectivity in HCs and moree; (ve) = Studies in which differences were only found in negativebrain region abbreviations.Cs has been explicitly reported.

here is little overall trend in other reported regions ofareas ranging from the left ACG (Ashtari et al., 2007)

SLF as noted above.

tional connectivity studiesnt with the functional ndings from HGR, UHR and FEstigations, the overwhelming majority of ChSZ studiesthis review (see Table 5A) report reduced connectivityrelative to HCs. In addition to this, it is noteworthy thattudies report signicant involvementof frontal regions,two studies alone observing no frontal involvementt al., 2007; Zhou et al., 2008b). Furthermore, of theseseventeen reporteddysconnectivity in frontotemporalsistent with the ndings seen in FE, EOS and UHR andts.other region showing dysconnectivity reported by a

rge number of studies is the CG highlighted in seven-thirty-ve papers. Interestingly CG dysconnectivity isss frequently in FE, EOS, UHR and HGR subjects, impli-ly seven other groups (Boksman et al., 2005; Zhou et al.,eld-Gabrieli et al., 2009; Allen et al., 2010; Li et al.,et al., 2010; White et al., 2010b).in the earlier stages of the illness and in those withisk however, not all 35 studies report reduced connec-, with eleven reporting both increase and decreases.e, the two studies that report a functional connec-ase only, implicated connections between frontal andreas, and, default mode network (DMN) and PCGeyer-Lindenberg et al., 2005; Whiteld-Gabrieli et al.,

tural connectivity studies

FA in patients relative to HCs was the most common

tudies investigating structural differences between the(seen in thirty-four of the forty-one studies included)B). This result is consistent both with studies utilizingtient groups (as detailed above) and also with thoseestigating functional connectivity in ChSZ patients.e thirty-four studies showing reductions, frontal andgionswere themost frequently reported areas affected,ighteen of the studies a trend previously highlightedr patient groups. The second most frequently reporteding reduced FA was the corpus callosum (CC) (encom-ings in the splenium, genu, and forceps minor/major)

byelevenof the studies (seeTable5B). Finally, altered FAimplicated sporadicallyby thedifferent studies covering



Table 3AStudies investigating functional connectivity in those with FE SZ relative to HCs.


HC FE

Woodward et al. (2009) (ve) 32 10 VCa CRT R.MFG - L.Med.FG, L.MFGCrossley et al. (2009) 13 10 DCM WM MFG - STG Benetti et al. (2009) 14 10 DCM SDPR R.Post.Hipp - R.IFLLui et al. (2009) 68 68 VCa RS n.s.Yoon et al. (2008) (+ve) 24 25 VCa WM R.IPL - L.Premotor CortexZhou et al. (2007)a 17 17 VCa RS R.DLPFC - IPL, L.Intraparietal Sulcus

L.DLPFC - R.Supramarginal Gyrus, Thal., Stri.,Post.TLR.DLPFC - PCGL.DLPFC - L.SPLL.DLPFC - Post.Ins

Boksman et al. (2005) 10 10 PPI VF R.ACG - R.Thal, R.Ins, R.ITG, R.Fusiform Gyrus, R.IOL, L.IFG

n.s. = no signicant differences in connectivity between patient group and HCs; red downward arrow ( ) = refers to studies which reported (i) positive connectivity in HCsand less pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and less pronounced negative connectivity in patients. Green upward arrow( ) = refers to studies which report (i) positive connectivity in HCs and more pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and morepronounced negative connectivity in patients. Where studies have explicitly reported connectivity type; (+ve) = studies in which differences were only found in positiveconnectivity between regions in patients relative to HCs. (ve) = studies in which differences were only found in negative connectivity between regions in patients relativeto HCs. Two black upward arrows () = refers to studies which reported a reversal of connectivity from negative in HCs to positive in patients. Studies that have includedschizoaffective oup: Yregion abbrevi

a Studies wh nd HC

Table 3BStudies invest

Author

Luck et al. (2Segal et al. (Gasparotti eFriedman etCheung et alPrice et al. (2Peters et al.Price et al. (2Hao et al. (2Price et al. (2Szeszko et a

n.s. = no signiarrow ( ) = greexperimental

the variousby ve of th

Howeveone investiparticipants

Table 4AStudies invest

Author

White et al.

Zhou et al. (2

n.s. = no signiand less prono( ) = refers to spronounced n, schizophreniform and/or schizotypal patients within their ChSZ experimental grations.ere differences in both positive and negative connectivity between patient group aigating structural connectivity in those with FE SZ relative to HCs.

Sample size Regions

HC FE

010) 30 44 SLF, UF2010) 38 6 ACGt al. (2009) 21 21 Spleniumal. (2008) 39 40. (2008) 26 25 L.OFF, L.ILF, Adj. R.PCu, R.PLIC, Adj. R.Su008) 23 19

(2008) 10 10007) 21 18 Genu

006) 21 21 Hipp., Cerebellar Peduncles, R.Corona R005) 29 20

l. (2005) 13 10 L.MFG, L.Post.STG, L.IC

cant differences in connectivity between patient group and HCs; red downward arrow (ater connectivity in patient group relative to HCs. Studies that have included schizoaffegroup: Price et al. (2008, 2007), Peters et al. (2008) and Szeszko et al. (2005). See Append

patient groups (see Tables 15A and B), was reportede forty-one investigations.r in comparison to the above ndings, six of the forty-gations found no signicant differences between ChSZand HCs. Furthermore, the study by Rotarska-Jagiela

et al. (2009ues, and sigFasciculus,a result thathe eightee

igating functional connectivity in those with EOS relative to HCs.

Sample size Method Task

HC EOS

(2010a) 14 14 ICA VeWM

010) 19 19 VCa RS

cant differences in connectivity between patient group and HCs; red downward arrow (unced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and lesstudies which report (i) positive connectivity in HCs and more pronounced positive conneegative connectivity in patients. See Appendices A.1A.3 for method, task and brain regiooon et al. (2008). See Appendices A.1A.3 for method, task and brain

s has been explicitly reported.Connectivity

n.s.bNigra, R.CC, L.Cerebral Peduncle

n.s.n.s.

adiate, Cu, PCu, Ins, L.OFL, ITG, R.ACG, R.MFLn.s.

) = lesser connectivity in patient group relative to HCs; green upwardctive, schizophreniform and/or schizotypal patients within their FEix A.1 for brain region abbreviations.

) found both a decrease and also an increase in FA val-nicantly, this increase was identied in the Arcuatea WM tract connecting frontal and temporal regions t not only differs from, but is in direct contradiction to,n studies reporting reductions in these regions.

Regions Connectivity

ACG - TLCerebellum - Stri, OLCG - Post.Cerebellum, SFG,MFG, Gyrus Recti, Hipp, Cu,Fusiform Gyri, MOL,IOL, R.ITG, R.MTG,R.Angular GyrusCG - L.MTG, L.ITG

) = refers to studies which reported (i) positive connectivity in HCspronounced negative connectivity in patients. Green upward arrowctivity in patients, and/or, (ii) negative connectivity in HCs and moren abbreviations.



Table 4BStudies investigating structural connectivity in those with EOS relative to HCs.

Author Sample size Regions Connectivity

HC EOS

Tang et al. (2010) 38 38 R.Ant.Cing.Kyriakopoulos et al. (2008) 20 19 PL, Splenium, R.SLFAshtari et al. (2007) 21 23 L.ILFKumra et al. (2005) 34 26 L.ACGKumra et al. (2004) 9 12 Ant./Post.Commissural Plane

n.s. = no signicant differences in connectivity between patient group and HCs; red downward arrow ( ) = lesser connectivity in patient group relative to HCs; green upwardarrow ( ) = greater connectivity in patient group relative to HCs. Studies that have included schizoaffective, schizophreniform and/or schizotypal patients within their EOSexperimental group: Ashtari et al. (2007) and Kumra et al. (2005). See Appendix A.1 for brain region abbreviations.

Table 5AStudies investigating functional connectivity in ChSZ relative to HCs.


HC SZ

Lynall et al. (2010)a (+ve) 15 12 IPRC RS FL - CG - OL - PCuWhite et al. (2010b) 19 19 ICA SS Ins. - ACG, VMFL

L.DLFL - PCu, PCG, PLLi et al. (2010)a 21 20 VCa VLD L.IFG - FL, L.Ins., TL, OL, Caudate, L.PL,Hoptman et al. (2010) 21 25 VCa RS Amygdala - ACG, L.IFG, Med.FG, L.MFG, L.Lentiform Nuc.Tu et al. (2010) 21 27 ICA VPAS R.Dorsal ACG - L.Thal., R.Pre-Supp.Motor Area, R.Ant.InsOngr et al. (2010) 15 14 ICA RS DMN - dorsal ACG

DMN - L.Frontal Polar cortex, R.DLPFC, Basal GangliaRotarska-Jagiela et al. (2010) 16 16 ICA RS PCG, Hipp., R.MFG,

L.FL - L.PL, R.FL - R.PL

L.PLVercammen et al. (2010) 27 27 VCa RS L.TPJ - R.IFGCamchong et al. (2009b) 29 29 ICA RS MFG - DMN, ACG - DMNWoodward et al. (2009)b 32 15 VCa CRT R.MFG - R.MFG, R.IPL

R.MFG - L.Med.FGWolf et al. (2009)a,b 16 16 ICA VeWM L.P/O - R.T/P

FL - L.T/PL.FL - TL - R.CerebellarFL - R.PL - Thal. - R.Post.Cing

Gavrilescu et al. (2009) 14 12 VCa RS L. - R. 1 Aud.CortexL. - R. 2 Aud.Cortex

Bluhm et al. (2009)a,b 17 17 VCa RS Retrosplenium - PL, FL, TL, OL, CerebellumRetrosplenium - L.IFG

Henseler et al. (2009)b 12 12 PPI Ve/ViSp WM R.Frontal Operculum - Post.Hipp, L.Intraparietal Sulcus

R.SPL - L.SPL, L.OLR.Frontal EyeField - R.OLR.Frontal Operculum - L.MFGR.SPL - Fusiform Gyrus, L.SPLR.Frontal EyeField - Aud.Cortex

Meda et al. (2009)b 54 37 ICA ViSp WM L.Post.PL - L.D/VLPFC - CG - Bas.GangR.Post.PL - R.DLPFC, PCG - Cu. - Hipp.CG - MFG - IPL

Kim et al. (2009)a (+ve) 66 63 ICA AOP TL - PL, CG - OL, FL - TL, CG - PL - OLWhiteld-Gabrieli et al. (2009) 13 13 VCa WM DMN - MPFC, PCG

R.DLPFC - MPFCZhou et al. (2008b)a,b 14 17 VCa RS L.Ant.Hipp - PCG, R.STG, Parahipp.,

L.Med.Temporal PoleR.Ant.Hipp - R.MOLL.Ant.Hipp - L.Cerebellum

Zhou et al. (2007)a,b 18 18 VCa RS R.DMPFC - R.Inf.TG, L.DMPFC - L.DMPFC,L.DMPFC - L.MFGR.Premotor Cortex - PCuL.Ins - L.DMPFC

Mechelli et al. (2007) 10 21 DCM VR STG - ACGWolf et al. (2007) 14 14 VCa VE L.DLPFC - L.STG, L.DLPFC - L.Parahipp.

L.VLPFC - L.STG, L.VLPFC - L.ParahippGarrity et al. (2007)a,b 22 21 ICA AOP FL - PL - OL

FL - CG - TL - OLLiang et al. (2006)a 15 15 VCa RS Cerebellar - Stri. - Ins - TL - PFC

PFL - Ins - TL - Stri. - CerebellarHoney et al. (2005) 11 22 PPI WM ACG - R.Pre/Post Central Gyrus, L.Cerebellum

L.Cerebellum - L.Med.SFGL.Cerebellum - R.MFG

Foucher et al. (2005) 11 13 VCa RLD ITG - RetrospleniumR.FL - L.FL



Table 5A (Continued)


HC SZ

Meyer-Lindenberg et al. (2005) 22 22 PCa WM R.DLPFC - L.Hipp.FormationSchlsser et al. (2003) 6 12 SEM WM R.Cerebellum - L.DLPFC, Thal., R.DLPFC - L.DLPFC, R.PL -

L.PL, R.VLPFC - R.DLPFC,R.VLPFC - L.CerebellumThal. - L.DLPFC, VLPFC

Shergill et al. (2003) 8 8 VCa FSA L.IFG - R.Parahipp., R.Ins, R.Precentral Gyrus,L.Med.PL, R.STG, R.MTG

Kim et al. (2003) 12 12 PCa WM R.DLPFC - L.Frontal Pole, IPLLawrie et al. (2002) 10 8 VCa SC L.DLPFC - L.MTG, L.STGSpence et al. (2000) 10 10 VCa VF L.DLPFC - ACGFletcher et al. (1999) 7 12 PCa VE/VRet ACG/PFC - STG Andreasen et al. (1996) 13 14 PCa EM PFL - Thal - CerebellumFriston et al. (1996)a 6 18 PCa WG L.PFL - TL Friston and Frith (1995) 6 18 PCa VF L.PFL - STG

n.s. = no signicant differences in connectivity between patient group and HCs; red downward arrow ( ) = refers to studies which reported (i) positive connectivity in HCsand less pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and less pronounced negative connectivity in patients. Green upward arrow( ) = refers to studies which report (i) positive connectivity in HCs and more pronounced positive connectivity in patients, and/or, (ii) negative connectivity in HCs and morepronounced n ity tyconnectivity b re onlyto HCs. Two b ty froschizoaffective oup: H(2008). See Ap

a Studies wh areasb Studies wh nd HC

6. Discussi

Our syststudies thatand relatedto increaseinvolvementrends are rappear to bndings areconnectivit

The rstdecreasedarelative toconictinghyper-integthe formerbe further uferences nogroups. In pferences ba(or absence2004; MechVercammensuch correl

s ofainst to dfactHCshe inalte thultsstudeurocentd coatiendistsults

on anchesseco

Fig. 2. Graphstructural conegative connectivity in patients. Where studies have explicitly reported connectivetween regions in patients relative to HCs. (ve) = studies in which differences welack upward arrows () = refers to studies which reported a reversal of connectivi, schizophreniform and/or schizotypal patients within their ChSZ experimental grpendices A.1A.3 for method, task and brain region abbreviations.ere regions of reported difference have been condensed into fewer representativeere differences in both positive and negative connectivity between patient group a

on

ematic review highlights some commonndings acrossare consistent with the notion of dysconnectivity in SZsubgroups. Namely, the report of reduced (as opposedd) connectivity in patients relative to HCs, and thet of frontal regions in dysconnectivity. Notably, theseeported inHGR, UHR, EOS, FE and ChSZ groups, and thuse evident at all stages of the disorder. Secondly, theseevident in studies of both functional and structural

y. In this context the results are discussed below.and most prominent trend is the prevalent report of

s opposed to increased connectivity in thepatient groupHCs (see Tables 15A and B and Fig. 2). In light ofreports of hypo- (Rotarska-Jagiela et al., 2010) versusrative (Wolf et al., 2009) states in SZ, this trend suggestsas widespread. Interpretation of this suggestion shouldnderstood in the context of reported connectivity dif-t just between patients and HCs, but also within patient

nuanceIt remsuppor

Thetive towith tfunctioelucidathe resfuturetiple nOne rereducein SZ pwith ation, reof actiapproa

The

articular, a number of studies report within-group dif-sed on specic symptom prole such as the presence) and severity of auditory hallucinations (Hubl et al.,elli et al., 2007; Henseler et al., 2009; Wolf et al., 2009;et al., 2010). Whilst not explored here, knowledge of

ations can contribute to greater understanding of the

reduced codisorder, inillness, butdevelop it (

Subtle dacross the c

showing proportion of papers that reported either an increase, a decrease, an increasenectivity between patient group versus HCs.pe; (+ve) = studies in which differences were only found in positivefound in negative connectivity between regions in patients relative

m negative in HCs to positive in patients. Studies that have includedoptman (2010), Ongr et al. (2010), Kim et al. (2009) and Yoon et al.

.s has been explicitly reported.

the disorder, and hence potential drivers of treatment.however that taken together all such results still addysconnectivity in SZ.that reports of reduced connectivity in patients rela-traverses methodological boundaries is also consistentdea of a strong association between structural andconnectivity alterations in SZ. Whilst not possible toe specic directionality of any such association from

here, it is a question that would be well informed fromies able to integrate, and thus directly compare, mul-imaging modalities within the same participant group.such study conducted in this way for example reportsherence between functional and structural modalitiests relative to HCs (Skudlarski et al., 2010). Consistenturbed interaction between brain structure and func-such as these can aid our understanding of SZs moded potentially contribute to guiding future therapeutic.nd salient trend is the observation that patterns ofnnectivity traverse across the different stages of thecluding those with an increased risk of developing theyet to become ill (and the majority of whom will neverYung et al., 2004)).ysconnectivity alterations therefore appear evidentourse of SZ, albeit to varying degrees. Moreover there

and decrease or no difference in (a) functional connectivity and (b)



Table 5BStudies investigating structural connectivity in ChSZ relative to HCs.

Author Sample size Regions Connectivity

Segal et al. (Camchong eOh et al. (20 IFGRotarska-Jag ract,

Sussmann e TRPeters et al.Phillips et alKubicki et alFriedman et , L.ILFMunoz ManSeal et al. (2 CKarlsgodt etRotarska-JagSkelly et al. .ATR,Seok et al. (2 .Ant.SLFujiwara et aManoach etShergill et alMori et al. (2 SplenWhite et al. ionTang et al. (2Schlsser etBuchsbaum , TGJones et al. (Kubicki et alHubl et al. (2Wang et al. (Okugawa etKubicki et alArdekani etSun et al. (20Wang et al. (Burns et al. (Minami et aKubicki et alFoong et al.Agartz et al.Steel et al. (2Foong et al.Lim et al. (19Buchsbaum

n.s. = no signiarrow ( ) = greexperimental

a Studies wh

is evidencethat illnessdysconnectthose vulnestrated a prHCs, to the

In termtheme to eextent, frontical and suinvestigatintoms, manyfrontal andand Bermaworks in pboundariesone of partiand producand speciplay a criticwith regardHC SZ

2010) 38 41 ACGt al. (2009a,b) 29 29 ACG09) 21 18 IC - DLPFC, ACG,iela et al. (2009) 24 24 R.EC, Pyramidal T

AFt al. (2009) 38 28 L. UF/Inf.OFF R. A(2009) 10 10 L. AF, ILF. (2009) 22 23 L.AF, ILF. (2008) 42 32 Ant.Frontal CCal. (2008) 40 40 R.Forceps Minoriega et al. (2008) 51 31 L.AF, UF, ALIC008) 14 14 SLF, UF, Inf.OFF, Ial. (2008) 17 12 SLFiela et al. (2008) 24 24 Genu/Splenium(2008) 25 25 R.Inf.OFF, Cing., L007) 22 30 L.Rostral Cing., Ll. (2007) 24 42 Cing.al. (2007) 19 17 R.ACG. (2007) 40 33 SLF, ILF, Genu007) 42 42 FG, TG, UF, Cing.,(2007) 15 14 L.Post.Limbic Reg007) 42 40 MTGal. (2007) 18 18 R.MTG, R.DLPFCet al. (2006) 55 64 CG, FG, ALIC, SLF

2005) 12 12. (2005) 26 21 Fornix, CC, Cing., Sup.O004) 13 26 AF, UF, ILF2004) 20 21 ACGal. (2004) 21 25 Middle Cerebral Pedun. (2003) 18 16 Cing.al. (2003) 14 14 CC, L.STG, Parahipp., M03) 19 30 Ant. Cing.2003) 20 292003) 30 30 L.AFl. (2003)a 11 12 FL, TL, PL, OL. (2002) 18 15(2002) 19 14(2001)a 24 20 Splenium OL001) 10 10

(2000) 25 20 Splenium99)a 10 10 Widespread -FL to OLet al. (1998)a 6 5 PFL, TL

cant differences in connectivity between patient group and HCs; red downward arrow (ater connectivity in patient group relative to HCs. Studies that have included schizoaffecgroup: Karlsgodt et al. (2008), Fujiwara et al. (2007), White et al. (2007) and Ardekani etere regions of reported difference have been condensed into fewer representative areas

extrapolated from cross sectional studies to suggestonset is associated with exacerbation of less severe

ivity (structural and functional) alterations seen inrable to SZ. Crossley et al. (2009) for example demon-ogressive increase in functional dysconnectivity fromUHR, to FE patients.s of dysconnectivity localisation, the most commonmerge is the nding of frontal lobe, and to a lessertotemporal, CC and ACG dysconnectivity to other cor-bcortical areas. This is a trend consistent with studiesg executive dysfunction in SZ, one of the core symp-of which report functional activation alterations in

pre-frontal regions inpatients relative toHCs (Eisenbergn, 2010). The report of altered frontotemporal net-atients relative to HCs, crossing both methodologicaland across the different stages of the disorder is alsocular interest. Dysfunction of language comprehensiontion centres located in frontal and temporal regions,cally dysconnectivity between the two, is thought toal role in the core pathophysiology of SZ, particularlyto the formation of auditory verbal hallucinations

another staet al., 20042009).

As mentspecic cocic symptMechelli etWolf et al.,2010). Onedorso-latertotal scorescale (Wolfdysconnect(Rotarska-J

Togethestructural aof the disorsuch alteratalthough dedo so. One iat least inCC, L.SLF, ILF, OFF

n.s.

PLIC, ILF, SLF, Forceps MinorF, Middle Cerebellar Peduncle

ium/Genun.s.FF, IC, R.Inf.OFF, L.AF

cles

TG, IPL, Med.OL, Deep Frontal Perigenual

n.s.

n.s.n.s.

n.s.

) = lesser connectivity in patient group relative to HCs; green upwardtive, schizophreniform and/or schizotypal patients within their ChSZal. (2003). See Appendix A.1 for brain region abbreviations..

ple symptom of the disorder (Fletcher et al., 1999; Hubl; Seok et al., 2007; Winder et al., 2007; Wible et al.,

ioned previously, a number of these studies also reportrrelations between dysconnectivity values and spe-om prole (Lawrie et al., 2002; Garrity et al., 2007;al., 2007; Zhou et al., 2007; Henseler et al., 2009;

2009; Rotarska-Jagiela et al., 2010; Vercammen et al.,study for example reports dysconnectivity of the rightal prefrontal cortex being positively correlated with therecorded by the patient on the brief psychiatric ratinget al., 2009), whilst another reports frontotemporalivity being inversely correlatedwithpositive symptomsagiela et al., 2010).r, these ndings are consistent with the concept thatnd functional braindysconnectivity represents a featureder, evident even prior to its onset. It is also true thations may present in truncated form in individuals who,emed at increased of developing SZ, will never actuallymplication of this fact is that altered connectivity does,part, reect genetic vulnerability to psychosis. Indeed



a number of studies have reported structural and/or functionalconnectivity alterations in those carrying risk-alleles for SZ, butwho have no personal or family history of the disorder (Bertolinoet al., 2006; Drabant et al., 2006; Buckholtz et al., 2007; Meyer-LindenbergMcIntosh et

From thcan extraposurementsalso to idenit. Althoughevidence ofpotential risure such alhas also betions includSussmann e2008; Mins2008a; Dam(Kenny et afore, dysconMoreover, tdifferent psple, given treportedlyder, a direcbetween thstudy byOnactivation cand patientreported inparison betIt follows tmust be relinoses overlthat such mhealthy consubgroups.

The relaindices to dfrom studiethat an obet al. (1999increased cospecializeding performchronic schsix studiesory and conpatients andit within thWolf et al., 2(Henseler eciation at afor an assocency perforcontrols (Lyonly (Boksmnectivity albeen observthese alteranitive stratthe cognitivtaken by Winvestigatetile stimuli

network connectivity during processing of the stimuli in chronicschizophrenic patients relative to healthy controls which, theysuggest, reects disturbances to the system effecting changesbetweencontextually relevant functional brain states (Whiteet al.,

). Thn dysing.piteemastuded. Wlike tyingr pos. ThSZ ptionsticalpreant

viateeurond. Tantas a rcedcher2009n mncesillnee etanoththe

ng fagatinatcheersp

furndinis mher

xperiphrenani ei et a20072008Whit010)perimifcre, tstic at gro2; Yry medgete thnt mto tion pradigaradareaet al., 2007; Tan et al., 2007a,b; Kempf et al., 2008;al., 2008; Esslinger et al., 2009).

e results of the studies presented here therefore welate the potential use of connectivity alteration mea-as biomarkers both for those with established SZ, andtify those with an increased risk of later developingin terms of predictive power, it is recognised thatsuch alterations may only confer a small increase in

sk for SZ given the sensitivity with which we mea-terations currently. Furthermore, aberrant connectivityen reported in a range of other psychiatric condi-ing bipolar affective disorder (Almeida et al., 2009;t al., 2009), autism spectrum disorder (Sundaram et al.,hew and Keller, 2010), Alzheimers disease (Zhou et al.,oiseaux et al., 2009; Caffo et al., 2010) and depressionl., 2010; Sheline et al., 2010). In this context there-nectivity cannot be considered a feature unique to SZ.hemanor inwhichdysconnectivity alterations betweenychiatric diagnoses differ remains unclear. For exam-he many clinical, cognitive, and genetic features thatoverlap between both SZ and bipolar affective disor-t comparison of structural and functional connectivitye two groups would be one of interest. One such recentgr et al. (2010) examined spatial extent and functionaloherence within the DMN, in HCs, patients with SZs with bipolar affective disorder. Dysconnectivity wasboth patient groups versus HCs, however, a direct com-ween the two suggested distinct regions of alteration.hat any attempt to use such measures as biomarkersably sensitive to inter- aswell as intra-psychiatric diag-ap. For the present time at least therefore, it is cleareasures cannot be reliably used to distinguish betweentrols and patients with schizophrenia or its associate

tionship between connectivity and specic cognitiveate also remains poorly understood. Evidence availables using healthy subjects has however demonstrated

servable association between the two exists. Bchel) for example report a signicant correlation betweennnectivity occurring between distinct cortical systemsfor spatial and object processing, and individual learn-ance. However reports from studies conducted usingizophrenic subjects has so far yielded mixed results. Ofthat examined an association between working mem-nectivity for example, one observed it in both chronichealthy controls (Medaet al., 2009), twoonly observed

e healthy control group (Meyer-Lindenberg et al., 2005;007), two only observed it in the chronic patient groupt al., 2009; Wolf et al., 2009) and one found no asso-ll (Kim et al., 2003). Similarly, two studies that testediation between functional connectivity and verbal u-mance found it in both chronic patients and healthynall et al., 2010), and in the healthy control groupan et al., 2005), respectively. Since signicant con-

terations in patients relative to controls have oftened without differences in task performance however,tions could reect either the use of alternative cog-

egies or differences in the neural implementation fore process under investigation. An alternative approachhite and colleagues used somatosensory stimulation tothe passive processing of information. Using vibrotac-to the right index nger, they report reduced salience

2010bbetweeproces

Desthere rferentreportmuchunderlof othendingand Cha funca statiresultssignicto alleious nconfousignicducedinuen1999; Set al.,betweediffereof theWillhitsentsexplainfoundiinvestiage-mdinal ptake.

Twoable analyssentedtheir eschizo(ArdekAshtaret al.,et al.,2009;et al., 2one exmore dthermodiagnopatienal., 200still veknowlstantiaaberraance inactivatball paeach pworks/is result therefore tentatively supports an associationsconnectivity in schizophrenia and altered information

the emergence of some clear trends in the ndings,ins a signicant amount of variability between the dif-ies, in terms of regions and types of dysconnectivityhilst feasible this may simply reect the fact that,

he clinical presentation of SZ, the causal mechanismsit are themselves heterogeneous, there are a numbertential factors that could realistically lead to variablee signicant difference in WM integrity between HCsatients has for example, been shown to diminish asof age (Jones et al., 2006), and unless factored in ascovariate, could feasibly have a biasing effect on the

sented in the studies here. A second factor also withpotential to convolute results is medication. Providedsymptoms through pharmacological alteration of var-transmitter levels, anti-psychotics represent a majorhis is evident from a number of studies which reportstructural and functional brain alterations being pro-esult of anti-psychotic application an outcome furtherby specic medication type and duration (Honey et al.,k andFalkai, 2006;Navari andDazzan, 2009; Smieskova). A third confounding factor is the simple divisionales and females, with a number of groups identifyingin the development, presentation and clinical coursess between the genders (Gearon and Bellack, 2000;al., 2008). Small and varied sample size also repre-er basic, but highly inuential confound that couldinconsistency between studies. To overcome these con-ctors therefore future studies would be facilitated byg larger cohorts of single gender, medication nave andd subjects, both from a cross-sectional and longitu-ective a direction many groups are now trying to

ther factors likely to contribute to the widely vari-gs are the differences in experimental design andethods used. For example, a number of studies pre-e combine a range of SZ diagnostic subtypes withinmental ChSZ cohort, including schizoaffective disorder,iform disorder and schizotypal personality disordert al., 2003; Kumra et al., 2005; Szeszko et al., 2005;l., 2007; Fujiwara et al., 2007; Price et al., 2007; White; Hoptman et al., 2008; Karlsgodt et al., 2008; Peters; Price et al., 2008; Yoon et al., 2008; Kim et al.,eld-Gabrieli et al., 2009; Hoptman et al., 2010; Ongr. The inclusion of different diagnostic categories withinental cohort makes any subsequent results inherently

ult to interpret. In the context of the UHR studies fur-here is signicant inconsistency with respect to thessessment tool used by different groups to assess theirup. A relatively recent diagnostic category (Miller etung et al., 2003), the UHR/ARMS classication is oneuch in development, and to the best of the authors

, there is currently no publication to conclusively sub-at the different diagnostic tools are assessing equivalentental states. Another factor likely to introduce vari-he ndings is the use of distinctly different cognitivearadigms, such as the resting state or auditory odd-ms for example, by different groups using fMRI. Withigm intended to activate specic known brain net-s, it follows that there will be an inherent bias in



the particular areas reported depending on the specic paradigmused.

Arguably the most signicant confounds however with respectto the connectivity inferences one can directly draw from the dataare the comseed regionaccuracy ofimages.

A practidescribed apotentiallyof-interesteldwith pdetected asexample thfrontoteminaccuracyular areas aa selection2009; Woo2010).

With resmates of strbasis that Fmatter tracthree criticareal anatomto changesvalues in soto carry infassumptiondeterministFA values talthough thpoints is hicorrespondverify non-ornot.Withchanges is mtracts in vivfan, in additcan lead towithout theThis is alsowe may infchanging FArying capacto these asthe denitiof DWI anasure the qudiameter, total axoncontributinstructural ccaution, an(such as FAlevel allowi(for an in-d

To datescopic changrey)mattemortem stuhave been ito reduced nies (Harriso

Schmitz, 2009; Garey, 2010; Kolomeets and Natalya, 2010). How-ever, the integration of micro- and macro-scale connectivity datawithin a unied neurobiological model has received little attentionuntil recent years.

y, myscoer abnatiouggesis inlnesssyna(seegestsult odiatetionnin asultto d

an etrall hial mough

appn wremedoloectivainedc traate aremetionn. Thotheconnizop

velop

clus

ilst oimilat acrl botiviturenterpFortivitorresucalte

Potetivitsideconcworkarraain.registigasivemon practice of selecting regions-of-interest (ROI) ass to examine a priori, and secondly, interpretationalconnectivity estimates made using diffusion weighted

ce intended to focus analytical resources to a pre-rea of interest to increase the chance of detectingsubtle results, the a priori selection of seed regions-to examine also by default leads to overall bias in theotentially highly signicant areas of alteration not beingthey are excluded from the networks of interest. Fore reported trend of dysconnectivity between frontal,poral, CC, ACGandother regions, is likely to be a skeweddue to a number of study groups using these partic-s a priori seed regions of interest thereby producingbias (Yoon et al., 2008; Bluhm et al., 2009; Oh et al.,dward et al., 2009; Segal et al., 2010; Vercammen et al.,

pect to DWI measures, according to Jones (2010) esti-uctural connectivity inferred from DTI are made on theA values represent the integrity of underlying whitets in the brain. These estimates are based however onl assumptions: (i) the WM tract(s) detected representical tract(s), (ii) detected changes in FA are solely linkedin integrity of the tract(s) in question, and (iii) that FAmeway reect the capacity of the tract(s) in question

ormation between two points. Taking the rst of theses, a number of the tracing methods used today (bothic and probabilistic) to identify tracts based on voxelend to be precise rather than accurate, meaning thate replicability of nding the same tract between twogh, it cannot be veried as to whether there is a realing WM tract, and to date, there is no proven way toinvasively whether the connection exists anatomicallyrespect to the secondassumption, interpretabilityof FAade difcult by the often complex organisation of WM

o. Specically, the tendency of bers to splay, twist andion to kissing or crossing with other bers, all of whichalteration of observed FA value of the visualised tract,actual integrity of the bers themselves being altered.relevant to the third assumption, in that the whilst

er connectivity changes in the supposed tracts due tovalue, the actual integrity, and hence information car-

ity of the real tract, is not actually altered. In additionsumptions, one must also be cautious with respect toon of connectivity when discussing DTI. The majoritylysis methods used today for example cannot mea-

antitative metrics of WM tract integrity, namely, axonalber density, inter-node spacing, level of myelination ornumber any, and all, of which could be considered asg to measures of structural connectivity. Estimation ofonnectivity fromDTImust thereforebe interpretedwithd future work will benet from macroscopic evidencechanges) being informed by data from the microscopicng one to truly associate WM diffusivity with structureepth analysis see (Jones, 2010)).much work has been done looking into the micro-ges occurring at the cellular level in the white (andr of patients sufferingwith schizophrenia throughpost-dies from which a number of cellular abnormalitiesdentied ranging from increases in microglia numbersumbers of dendritic spines found on neuronal cell bod-n, 2004; Voets et al., 2008; Beasley et al., 2009; Hof and

Briescale dof eithcombibeen spsychowith ilronal,inputsis sugthe restor meregulaserototurn releading(Steph

Ovepotentnia thrlevel.

Onequestiomeasumethoine effconstrabilistipredicmeasuintegrafunctioif anytionalthe schthe de

7. Con

Whthan sevidenologicaconnecTo ensones iations.connecative cand asgreatlylatter.connecfor con

Tocal neta vastthe brfrontalof inveimpresany of the mechanisms proposed to underlie macro-nnectivity in schizophrenia revolve around the concepterrant developmental wiring, synaptic plasticity or an of the two (Stephan et al., 2006). For instance it hassted that grey matter reductions in the ACG, precedingsome individuals at high-risk, and, thought to progressduration,maybe theconsequenceof reductions in neu-ptic and dendritic density as well as increased afferent(Fornito et al., 2009) for detail). One specic hypothe-that macro-scale dysconnectivity in schizophrenia is

f aberrant N-methyl-d-aspartate glutamatergic recep-d synaptic plasticity, itself a consequence of abnormalby neuromodulatory transmitters including dopamine,nd acetylcholine. This aberrant synaptic plasticity ins in alterations in gross brain structure and functionysconnectivity between spatially remote regions (seeal., 2009a) for detail).owever there have been few attempts to elucidate theechanisms underlying dysconnectivity in schizophre-reconciling information at both a cellular and a systems

roach that would contribute to the revelation of thisould be the integration of structural and functionalnts of connectivity at the same time. For example,gy developed by Stephan et al. (2009a,b) seeks to exam-e connectivity using functional models that have beenby anatomically informed priors obtained by prob-

ctography. The aim of this integration would be togreater coherence between structural and functionalnts facilitating greater interpretability and inform theof cellular level data with gross brain structure ande method described here however is one of very few,rs, to attempt to truly integrate structural and func-ectivity estimates, and has as yet not been applied tohrenic population. As such the eld remains open forment of alternatives.

ion

verall there remains a greater number of differencesrities, two clear trends emerge from the data that areoss the stages of the disorder, and also traversemethod-undaries. These are reduced (as opposed to increased)y, and the frequent involvement of frontal regions.reliability of extrapolations made from these trends,retation should be in the context of certain consider-example, the prevailing report of reduced functionaly includes ndings of both reduced positive and neg-lations between regions in patients relative to HCs,h any heuristic framework devised for SZ would bered depending on whether it was the former or thential within-group differences, selection bias, and/ory/symptom associations also represent further facetsration.lude it appears that there are no clear and unequivo-alterations in terms of connectivity in SZ, but instead,

y of subtly altered networks distributed throughoutHowever the data suggest that the connectivity ofons is particularly affected. Although the proliferationtions dealing with the subject has been increasing at anrate, future eld-wide analysiswould signicantly ben-



et fromamuchgreater cohesion in theapproach takenbydifferentgroups in their analyses of functional and structural connectivity inSZ.

Acknowled

Williamthe MRC. AnWellcome T

Appendix A

A.1. Abbrev

FLTLOLPLPFLFGTGOGPGMFG/TG/FL/Med.FG/TG/IFG/TG/FL/PSFG/TG/FL/PDLPFCVLPFCCGPCGACGCuPCuInsThal.P/OT/PStri.ECICPLICALICCCSLFILFOFFUFAFATRCing.DMN

A.2. Abbrev

CRTWMAOPRSVe/ViSp WMVRVE/VRetVEEMVFWGFSARLDSCSDPRVPASVLDSS

A.3. Abbreviations of Methodologies used for functionalconnectivity analyses

nces

., Andefusion, Stephy in pe, J.R.C.een ption laen, N.sitronbellari, B.AotropyM., CoitudinograpP.J., Pielucid219.C.L., Hin therder a, KoenroscieS.,Mecmpusthe ato, A., Rproces, 1250, O.J.Nspect.L., Mhiatryn, K., Td uenC., Couivity fum, MBiol. Pum, Mmetabtz, J.Wtional159

, Job, Dor maS., CranctionroImang, J.,pe forents nng, J.,ectiviT.D., Crisk: a), 28V., Chonnec), 877, N.A.,mporahosis.aux, Jeimer, E.M.type. Gen.gements

Pettersson-Yeo is funded by a PhD studentship fromdrea Mechelli is supported by a project grant from therust.

.

iations of brain regions reported

Frontal lobeTemporal lobeOccipital lobeParietal lobePrefrontal lobeFrontal gyrusTemporal gyrusOccipital gyrusParietal gyrus

PL/TL/OL Middle FG/TG/FL/PL/TL/OLFL/PL/TL/OL Medial FG/TG/FL/PL/TL/OLL/TL/OL Inferior FG/TG/FL/PL/TL/OLL/TL/OL Superior FG/TG/FL/PL/TL/OL

Dorsolateral prefrontal cortexVentrolateral prefrontal cortexCingulate gyrusPosterior CGAnterior CGCuneusPrecuneusInsulaThalamusParietaloccipitalTemporalparietalStriatumExternal capsuleInternal capsulePosterior limb of the ICAnterior limb of the ICCorpus callosumSuperior longitudinal fasciculusInferior longitudinal fasciculusOccipito-frontal fasciculusUncinate fasciculusArcuate fasciculusAnterior thalamic radiationCingulumDefault mode network

iations of fMRI paradigms reported

Choice reaction timeWorking memoryAuditory oddball paradigmResting stateVerbal/visuospatial WMVoice recognition taskVerbal encoding/retrieval taskVerbal encodingEpisodic memoryVerbal uencyWord generationFast versus slow articulationRetrieval and lexical decisionSentence completionShort delay pattern recognitionVolitional prosaccade and anti-saccadeVisual lexical decisionSomatosensation

SEMVCaPCaDCMPPIICAIPRC

Refere

Agartz, Ia dif

Allen, P.tivit

Almeidabetwemo

Andreasa pocere

Ardekananis

Ashtari,longtract

Basser,sues209

Beasley,turediso

Begr, S.Neu

Benetti,pocaand

Bertolinory(11)

Bloemena pro

Bluhm, RPsyc

Boksmawor

Bchel,nect

Buchsbania.

BuchsbaPET

Buckholfunc1584

Burns, J.tens

Caffo, B.of fuNeu

Camchonotypati

Camchoconn

Cannon,ical65 (1

Cheung,dysc38 (6

Crossleytotepsyc

DamoiseAlzh

DrabantgenoArchStructural equation modellingVoxelwise correlation analysisPET correlation analysisDynamic causal modellingPsychophysiological interactionIndependent component analysisInter-parcellated region correlation

rsson, J.L., et al., 2001. Abnormal brainwhitematter in schizophrenia:tensor imaging study. Neuroreport 12 (10), 22512254.an, K.E., et al., 2010. Cingulate activity and frontotemporal connec-oplewith prodromal signs of psychosis. NeuroImage 49 (1), 947955., Mechelli, A., et al., 2009. Abnormally increased effective connectivityarahippocampal gyrus and ventromedial prefrontal regions duringbeling in bipolar disorder. Psychiatry Res. 174 (3), 195201.C., OLeary, D.S., et al., 1996. Schizophrenia and cognitive dysmetria:-emission tomography study of dysfunctional prefrontal-thalamic-circuitry. Proc. Natl. Acad. Sci. U.S.A. 93 (18), 99859990.., Nierenberg, J., et al., 2003. MRI study of white matter diffusionin schizophrenia. Neuroreport 14 (16), 20252029.

ttone, J., et al., 2007.Disruptionofwhitematter integrity in the inferioral fasciculus in adolescents with schizophrenia as revealed by berhy. Arch. Gen. Psychiatry 64 (11), 12701280.erpaoli, C., 1996. Microstructural and physiological features of tis-ated by quantitative-diffusion-tensor MRI. J. Magn. Reson. B 111 (3),

onavar,M., et al., 2009. Two-dimensional assessment of cytoarchitec-superior temporal white matter in schizophrenia, major depressive

nd bipolar disorder. Schizophr. Res. 115 (23), 156162.ig, T., 2008. Cerebral disconnectivity: an early event in schizophrenia.ntist 14 (1), 1945.helli, A., et al., 2009. Functional integrationbetween theposteriorhip-and prefrontal cortex is impaired in both rst episode schizophreniarisk mental state. Brain 132 (Pt 9), 24262436.ubino, V., et al., 2006. Prefrontalhippocampal coupling during mem-sing is modulated by COMT val158met genotype. Biol. Psychiatry 601258.., de Koning, M.B., et al., 2009. White-matter markers for psychosis inive ultra-high-risk cohort. Psychol. Med., 18.iller, J., et al., 2009. Retrosplenial cortex connectivity in schizophrenia.Res. 174 (1), 1723.hberge, J., et al., 2005. A 4.0-T fMRI study of brain connectivity duringcy in rst-episode schizophrenia. Schizophr. Res. 75 (23), 247263.ll, J.T., et al., 1999. The predictive value of changes in effective con-or human learning. Science 283 (5407), 15381541..S., Friedman, J., et al., 2006. Diffusion tensor imaging in schizophre-sychiatry 60 (11), 11811187..S., Tang, C.Y., et al., 1998. MRI white matter diffusion anisotropy andolic rate in schizophrenia. Neuroreport 9 (3), 425430.., Meyer-Lindenberg, A., et al., 2007. Allelic variation in RGS4 impactsand structural connectivity in the human brain. J. Neurosci. 27 (7),

3.., et al., 2003. Structural disconnectivity in schizophrenia: a diffusiongnetic resonance imaging study. Br. J. Psychiatry 182, 439443.iniceanu, C.M., et al., 2010. Two-stage decompositions for the analysisal connectivity for fMRI with application to Alzheimers disease risk.

ge 51 (3), 11401149.Lim, K.O., et al., 2009a. Frontal white matter integrity as an endophe-schizophrenia: diffusion tensor imaging in monozygotic twins andonpsychotic relatives. Front. Hum. Neurosci. 3, 35.Macdonald, A.W., et al., 2009b. Altered functional and anatomicalty in schizophrenia. Schizophr. Bull..adenhead, K., et al., 2008. Prediction of psychosis in youth at high clin-multisite longitudinal study in North America. Arch. Gen. Psychiatry37.eung, C., et al., 2008. A diffusion tensor imaging study of structuraltivity in never-medicated, rst-episode schizophrenia. Psychol. Med.885.Mechelli, A., et al., 2009. Superior temporal lobe dysfunction and fron-l dysconnectivity in subjects at risk of psychosis and in rst-episodeHum. Brain Mapp. 30 (12), 41294137..S., Smith, S.M., et al., 2009. White matter tract integrity in aging ands disease. Hum. Brain Mapp. 30 (4), 10511059., Hariri, A.R., et al., 2006. Catechol O-methyltransferase val158metand neural mechanisms related to affective arousal and regulation.Psychiatry 63 (12), 13961406.



Eisenberg, D.P., Berman, K.F., 2010. Executive function, neural circuitry, and geneticmechanisms in schizophrenia. Neuropsychopharmacology 35 (1), 258277.

Ellison-Wright, I., Bullmore, E., 2009.Meta-analysis of diffusion tensor imaging stud-ies in schizophrenia. Schizophr. Res. 108 (13), 310.

Esslinger, C.,Walter,H., et al., 2009.Neuralmechanismsof agenome-widesupportedpsychosis

Fornito, A., Ygulate corneuropath

Fatemi, S.H., Fonia, revisit

Fletcher, P.,frontotem

Foong, J., Maielosum in sPsychiatry

Foong, J., Syter in sch333336.

Foucher, J.R.,too little o374388.

Friedman, J.I.,and chron

Friston, K., HschizophreSchizophr535.

Friston, K.J., Frrosci. 3 (2)

Frith, C.D., Frispatients d(3), 3433

Fujiwara, H., Nand their aimaging st

Garey, L., 2010rodevelop

Garrity, A.G., Ptivity in sc

Gasparotti, R.,callosum iSchizophr

Gavrilescu, Mtex in patiresonance

Gearon, J.S., Belevelof fun43 (1), 65

Goghari, V.M.,patientswJ. Psychop

Hao, Y., Liu, Z.,rst-episo

Harrison, P.J., 2logical evi(Berl.) 174

Henseler, I., Fanetworksschizophre

Hof, P.R., SchmNeuropath

Honey, G.D.,schizophre128 (Pt 11

Honey, G.D.B.,ences in frof risperidProc. Natl.

Hoptman,M.J.and aggres

Hoptman,M.J.in individu115124.

Howes, O.D., KIIIthe n

Hubl, D., Koenin auditory

Jones,D.K., 201with diffu

Jones, D.K., Caing studypsychosis.

Jones,D.K., Catimaging trHum. Brai

Kanaan, R.A.A., Kim, J.-S., et al., 2005. Diffusion tensor imaging in schizophrenia. Biol.Psychiatry 58 (12), 921929.

Karlsgodt, K.H., Niendam, T.A., et al., 2009. White matter integrity and predictionof social and role functioning in subjects at ultra-high risk for psychosis. Biol.Psychiatry 66 (6), 562569.

t, K.Hlongit. PsychL., Nicciatedand fuE.R., Ousinghiatry., Matdepezophr., KwoparietH2O Pts, N.ocamric stuA., Wprima2.M., MhizopM., Pysis oM.,

chizopzophrM., Wgneti820.M., W

zophrtry 54S., Aszophrlesc. PS., Aarly-o114oulos

ter inS.M., B

schiz, 1008nch,Cng semtic hi., Zhouith r

2092., Hedzophr3673, Buchoutc

.eng, Wntipsyphom(2), 19.-E., Bhizoph, D.S.te matadic la, P.K.,hol. Mh, A.Mhite m

i, A., An pati122

i, A., Frosci.A., Steng wo4 (11indenhum

6726variant. Science 324 (5927), 605.cel, M., et al., 2009. Anatomical abnormalities of the anterior cin-tex in schizophrenia: bridging the gap between neuroimaging andology. Schizophr. Bull. 35 (5), 973993.lsom, T.D., 2009. The neurodevelopmental hypothesis of schizophre-ed. Schizophr. Bull. 35 (3), 528548.McKenna, P.J., et al., 1999. Abnormal cingulate modulation ofporal connectivity in schizophrenia. NeuroImage 9 (3), 337342.

r, M., et al., 2000. Neuropathological abnormalities of the corpus cal-chizophrenia: a diffusion tensor imaging study. J. Neurol. Neurosurg.68 (2), 242244.mms, M.R., et al., 2002. Investigating regional white mat-izophrenia using diffusion tensor imaging. Neuroreport 13 (3),

Vidailhet, P., et al., 2005. Functional integration in schizophrenia:r too much? Preliminary results on fMRI data. NeuroImage 26 (2),

Tang, C., et al., 2008. Diffusion tensor imaging ndings in rst-episodeic schizophrenia patients. Am. J. Psychiatry 165 (8), 10241032.erold, S., et al., 1996. Abnormal frontotemporal interactions innia. In: Watson, S.J. (Ed.), ARNMD series, vol. 73, Biology of

enia and Affective Disease. ARNMD, Washington, DC, pp. 421449,

ith, C.D., 1995. Schizophrenia: a disconnection syndrome? Clin. Neu-, 8997.ton, K.J., et al., 1995. Regional brain activity in chronic schizophrenicuring the performance of a verbal uency task. Br. J. Psychiatry 16749.amiki, C., et al., 2007. Anterior and posterior cingulum abnormalitiesssociation with psychopathology in schizophrenia: a diffusion tensorudy. Schizophr. Res. 95 (13), 215222.. When cortical development goes wrong: schizophrenia as a neu-

mental disease of microcircuits. J. Anat..earlson, G.D., et al., 2007. Aberrant default mode functional connec-hizophrenia. Am. J. Psychiatry 164 (3), 450457.Valsecchi, P., et al., 2009. Reduced fractional anisotropy of corpus

n rst-contact, antipsychotic drug-naive patients with schizophrenia.. Res. 108 (13), 4148.., Rossell, S., et al., 2009. Reduced connectivity of the auditory cor-ents with auditory hallucinations: a resting state functional magneticimaging study. Psychol. Med., 110.llack, A.S., 2000. Sex differences in illness presentation, course, andctioning in substance-abusingschizophreniapatients. Schizophr.Res.70.Lang, D.J., et al., 2010. Anterior internal capsule volumes increase inith schizophrenia switched from typical antipsychotics to olanzapine.harmacol. (Oxford, England).et al., 2006. White matter integrity of the whole brain is disrupted inde schizophrenia. Neuroreport 17 (1), 2326.004. The hippocampus in schizophrenia: a review of the neuropatho-dence and its pathophysiological implications. Psychopharmacology(1), 151162.lkai, P., et al., 2009. Disturbed functional connectivity within brainsubserving domain-specic subcomponents of working memory innia: relation to performance and clinical symptoms. J. Psychiatr. Res..itz, C., 2009. The quantitative neuropathology of schizophrenia. Actaol. 117 (4), 345346.Pomarol-Clotet, E., et al., 2005. Functional dysconnectivity innia associated with attentional modulation of motor function. Brain), 25972611.Soni, E.T., Varatheesan, W., Williams, M., Sharma, S.C.T., 1999. Differ-ontal cortical activation by a working memory task after substitutionone for typical antipsychotic drugs in patients with schizophrenia.Acad. Sci. U.S.A. 96, 1343213437., DAngelo, D., et al., 2010. Amygdalofrontal functional disconnectivitysion in schizophrenia. Schizophr. Bull. 36 (5), 10201028., Nierenberg, J., et al., 2008. ADTI studyofwhitemattermicrostructureals at high genetic risk for schizophrenia. Schizophr. Res. 106 (23),

apur, S., 2009. The dopamine hypothesis of schizophrenia: versional common pathway. Schizophr. Bull. 35 (3), 549562.ig, T., et al., 2004. Pathways that make voices: white matter changeshallucinations. Arch. Gen. Psychiatry 61 (7), 658668.0. Challenges and limitations of quantifyingbrain connectivity in vivo

sion MRI. Imaging Med. 2, 341355.tani, M., et al., 2005. A diffusion tensor magnetic resonance imag-of frontal cortex connections in very-late-onset schizophrenia-likeAm. J. Geriatr. Psychiatry 13 (12), 10921099.ani,M., et al., 2006.Ageeffects ondiffusion tensormagnetic resonanceactography measures of frontal cortex connections in schizophrenia.n Mapp. 27 (3), 230238.

KarlsgodriorBiol

Kempf,assoture

Kenny,sionPsyc

Kim, D.Ian inSchi

Kim, J.-Jand(O)]

Kolomeehippmet

Konrad,nia729

Kubicki,in sc

Kubicki,anal

Kubicki,in sSchi

Kubicki,a ma813

Kubicki,schichia

Kumra,schiAdo

Kumra,in e1138

Kyriakopmat

Lawrie,ity in(12)

Li, X., Bradurigene

Liang,Mnia w(2),

Lim, K.Oschi(4),

Luck, D.termRes.

Lui, S., Din amor166

Lynall, Min sc

Manoacwhisacc

McGuirePsyc

McIntoson w

Mechellity i1213

MechellNeu

Meda, S.duriONE

Meyer-L32 in(3),., van Erp, T.G.M., et al., 2008. Diffusion tensor imaging of the supe-udinal fasciculus andworkingmemory in recent-onset schizophrenia.iatry 63 (5), 512518.odemus, K.K., et al., 2008. Functional polymorphisms in PRODH arewith risk and protection for schizophrenia and frontostriatal struc-nction. PLoS Genet. 4 (11), e1000252.brien, J.T., et al., 2010. Functional connectivity in late-life depres-resting-state functional magnetic resonance imaging. Am. J. Geriatr.: Off. J. Am. Assoc. Geriatr. Psychiatry.halon, D.H., et al., 2009. Auditory oddball decits in schizophrenia:ndent component analysis of the fMRI multisite function BIRN study.. Bull. 35 (1), 6781.n, J.S., et al., 2003. Functional disconnection between the prefrontalal cortices during working memory processing in schizophrenia: a[15ET study. Am. J. Psychiatry 160 (5), 919923.U., Natalya, 2010. Ultrastructural abnormalities of astrocytes in thepus in schizophrenia and duration of illness: a postmortem morpho-dy. World J. Biol. Psychiatry 11, 282292.interer, G., 2008. Disturbed structural connectivity in schizophre-ry factor in pathology or epiphenomenon? Schizophr. Bull. 34 (1),

cCarley, R., et al., 2007. A review of diffusion tensor imaging studieshrenia. J. Psychiatr. Res. 41 (12), 1530.ark, H., et al., 2005. DTI and MTR abnormalities in schizophrenia:f white matter integrity. NeuroImage 26 (4), 11091118.Styner, M., et al., 2008. Reduced interhemispheric connectivityhrenia-tractography based segmentation of the corpus callosum.. Res. 106 (23), 125131.estin, C.-F., et al., 2002. Uncinate fasciculus ndings i

Pettersonn 2011 Review

Documents

Transcript of Pettersonn 2011 Review