Altered Hippocampal-Parahippocampal Function During Stimulus Encodingn During Stimulus Encoding

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Copyright 2014 American Medical Association. All rights reserved.

Altered Hippocampal-Parahippocampal Function

During Stimulus Encoding

A Potential Indicator of Genetic Liability for Schizophrenia

Roberta Rasetti, MD,PhD; VenkataS. Mattay, MD; Michael G. White, BS; Fabio Sambataro, MD,PhD;

Jamie E. Podell, BS;BradZoltick, MA;Qiang Chen, PhD; Karen F. Berman,MD;

Joseph H. Callicott,MD; Daniel R. Weinberger, MD

IMPORTANCE Declarative memorythe ability to learn, store, and retrieve informationhas

been consistently reported to be altered in schizophrenia, and hippocampal-

parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible

role of genetic risk factors in such findings,it is necessary to study healthy relatives of

patients with schizophrenia who carry risk-associated genes but not the confounding factors

related to the disorder.

OBJECTIVE To investigate whether altered brainresponses, particularly in the hippocampus

andparahippocampus, duringthe encoding phase of a simpledeclarativememory task arealso observed in unaffected siblings whoare at increasedgenetic risk forschizophrenia.

DESIGN, SETTING, AND PARTICIPANTS Functional magnetic resonanceimaging was used with a

simple visual declarative memory paradigm to test for differences in neural activation across

normal control participants, patients with schizophrenia, and their healthy siblings. Thisstudy

wasconducted at a research center andincluded a totalof 308 participants (181 normal

control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants

were white of European ancestry.

MAIN OUTCOMESAND MEASURES All participants completed a declarative memory task

involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while

undergoing functional magnetic resonance imaging. Differences in hippocampus and

parahippocampus activation and coupling across groups and correlations with accuracy were

analyzed. Analyses were repeated in pairwise-matched samples.

RESULTS Bothpatients with schizophrenia and their healthy siblings showed reduced

parahippocampal activation (bilaterally) and hippocampal-parietal(BA 40) coupling during

theencodingof novelstimuli when compared with normalcontrolparticipants.There was a

significant positive correlation between parahippocampal activation during encoding and the

visual-memory score.

CONCLUSIONS AND RELEVANCE These results suggest thataltered hippocampal-

parahippocampalfunction during encoding is an intermediate biologic phenotype related

to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-

parahippocampal function with neuroimaging represents a potentially useful approach

to understanding genetic mechanisms thatconfer risk for schizophrenia.

JAMA Psychiatry. 2014;71(3):236-247. doi:10.1001/jamapsychiatry.2013.3911

Published onlineJanuary 1, 2014.

Supplementalcontent at

jamapsychiatry.com

Author Affiliations: Author

affiliations arelisted at theendof this

article.

Corresponding Author: Daniel R.

Weinberger,MD, Lieber Institutefor

BrainDevelopment, JohnsHopkins

Medical Campus,855 N Wolfe St,

Baltimore, MD 21205

([email protected]).

Research

Original Investigation

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Cognitive dysfunction is widely recognized as a consis-

tent and critical component of schizophrenia.1-4 Many

domains of cognitive function have been reported im-

paired inpatients withschizophreniaincludingdeficitsin work-

ing memory/executive function, verbal/visual memory, lan-

guage,attention, psychomotorskills,and generalintelligence.

The study of cognitive impairment in schizophrenia and its

neural correlates is proving to be an informative approach to

understanding geneticmechanisms of risk underlyingschizo-

phrenia. Evidence fromseveral recent meta-analyses andfrom

large family studies suggests that cognitive impairment is

familial and is likely genetically related to the risk for

schizophrenia.5,6 The evidence that cognitive impairment is

familial and related to genetic risk argues that it is an inter-

mediate phenotype on the pathogenic pathway from genetic

variation to the clinical syndrome.

Declarative memory is among the several cognitive do-

mains impaired in patients with schizophrenia.3 Human and

animal lesion studies implicate the hippocampal formation

(HF)which includes the entorhinal cortex; the dentate gy-

rus; Ammons horn subfields CA1, CA2, and CA3; the subicu-

lum;and the parahippocampal cortex7,8as a key structurein

declarative memory, together witha network of other brain re-

gionssuch as the prefrontal and parietal cortices.9 The role of

these brain regions in declarative memory has been impli-

catedthroughfunctional magneticresonance imaging (fMRI)

studies that have reported blood oxygenation level

dependent(BOLD) signal changes in the HF, dorsolateral pre-

frontalcortex(DLPFC),and parietal cortex,particularlythe in-

feriorparietallobule(IPL).9Specifically, theHF BOLDresponse

has been reported to correlate with effective encoding and is

purported to be linked to optimal integration of information

coming fromseveral cortical areas. Therole of theDLPFC dur-

ingdeclarativememory is relatedto theuse of different search

strategies, contextualization of events, and monitoring dur-ing retrieval. The IPL is thought to play a role in the modula-

tionof aninteractionbetween attentionand memory forform-

ing and retrieving memory traces.9

Declarative memory deficits in patients with schizo-

phrenia10,11 are thought to be due primarily to deficient

encoding12-14 through a mechanismnot fullyattributableeither

to deficits in IQ or executive function.15 The deficit likely re-

flects dysfunction in the HF, prominently implicated in the

pathophysiology of schizophrenia.16 Indeed, converging evi-

dencefrom differentlines of research,including postmortem,17

animal,18-20 and human neuroimaging studies,21,22 impli-

cates abnormal HF as a consistent pathological feature of

schizophrenia, although its role in memory dysfunction inschizophrenia is still under debate.22,23 Two recent meta-

analyses also reported decreased BOLD response in the IPL23

and DLPFC22,23 regions in patientswith schizophreniaduring

declarative memory tasks,suggesting a morewidespreaddys-

function of the declarative memory network.

Because many factors are likely to underlie declarative

memory dysfunction in patients with schizophrenia (includ-

ingseverity and type of symptoms,doseand durationof neu-

roleptic treatment, and numerous other confounding factors

associated with the experience of the disorder), the possibil-

itythat it is associated withgenetic riskfor schizophrenia can-

not be determined in studies of patients alone. To approach

this determination, it is crucial to define whether theimpair-

ment in declarative memory and in the underlying HF-

related network is a trait or a statefeatureof schizophrenia.If

an alteredHF-relatednetwork is a trait feature, andlikelyheri-

table with involvement of risk-associated genes, then pa-

tientswith schizophrenia and theirfirst-degreebiological rela-

tives, who share on average 50% of the risk genes, should

resemble oneanother more closely than they resemble unaf-

fected individuals.To ourknowledge,so far, only2 studieshave

reported impairment of HF recruitment in siblings of pa-

tients with schizophrenia during a declarative memory

task.24,25However,it is uncertainwhether theabnormality ob-

served in these prior studies represents a pure trait phenom-

enon or is confounded by other state variablesthatcould bias

the results such as risk for conversion to psychosis24 or poor

memory performance25 in these prior samples of siblings. It

also is preferable to study siblings rather than parents be-

cause ageis a state factorthat affectsmemory andbrainphysi-

ology. Nevertheless, morecompelling evidencefor a familial

likelygeneticimpairmentof declarative memory performance

in patients with schizophrenia is suggested from behavioral

studies,4-6,26,27 which report deficits in declarative memory

tasks in healthy relatives particularly siblings.

In the present study, we tested whether altered function

and connectivity of brain regions underlying declarative

memory, particularly during the incidental encoding of com-

plex visual scenes, fulfilled the characteristics of a potential

intermediatephenotype related to the genetic riskfor schizo-

phrenia.Differences of BOLD responseduring a visual scenes

memory task in the hippocampus-parahippocampus, pari-

etal, and DLPFC regions, as well as in posterior hippocampal

couplingwith DLPFC andIPL, wereexplored in a large sample

of patients with schizophrenia, unaffected siblings of pa-tients with schizophrenia, and normal control participants.

Methods

Subjects

WholeSample

Participants (patients with schizophrenia [PTs], their unaf-

fected siblings [SIBs], and normal control [NC] individuals)

were recruited through advertisements to participate in the

Clinical Brain Disorders Branch Sibling Study of schizophre-

nia at the National Institute of Mental Health (D.R.W., princi-

pal investigator). The study was approved by the institu-tional reviewboard of theIntramural Program of the National

Institute of Mental Health,and written informed consent was

obtained after complete description of the study was pro-

vided to the participants. Exclusionandinclusion criteriahave

been previously reported.28 A detailed description of thepar-

ticipants is reported in eAppendix 1 in Supplement. A total of

308 participants (NCs: 181, SIBs: 65, and PTs: 62) with good-

qualityfMRI data andwith recognitionaccuracyabovechance

(>50%) during the retrieval part of the task were included in

the whole-sample analysis. Two different analyses were per-

Altered Hippocampal-Parahippocampal Function Original Investigation Research

jamapsychiatry.com JAMA Psychiatry March2014 Volume 71,Number 3 237




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formed: (1)an analysisincludedall62 PTs, 65SIBsand181 NCs

and in which the variables that were significantly different

across groups were used as covariates of no interest (Table 1)

and (2) an analysis in which groups were matched for demo-

graphic and performance variables (described here).

Matched Sample

Toensure that theneuroimaging results were notdrivenby dif-

ferencesin demographic andperformancecharacteristicsacross

groups, all the analyses were repeated in pairwise-matched

samples (Table 2). Detailed description of the procedure andthe participants are reported in eAppendix 1 in Supplement.

Neuropsychological Data

Each participant was administered a battery of psychological

tests within a 1- to 2-day period of the fMRI scan. Factor

scores for several cognitive domains were obtained from fac-

tor analysis of 23 standard neuropsychological test scores, as

previously described.29 Because the fMRI protocol involves

primarily visual memory, a visual-memory-factor score

(Wechsler Memory Subscale Visual Reproduction I and II) was

used as an index of individuals visual processing/memory

ability. As a contrast, an N-Back factor score (1-, 2- and 3-back)

was used as an index of individuals working memory/executive function.

fMRI Simple Declarative Memory Paradigm

Participants underwent BOLD fMRI during a simple declara-

tive memory task (SDMT), which included incidental encod-

ingof neutral andaversive visualscenes selected from theIn-

ternational Affective Picture System.30 For boththe encoding

and retrievalsessions, the scenes werepresented in a blocked

fashion, with 4 blocks of neutral scenes (6 scenes for 3 sec-

onds perscene) and4 blocksof emotional/aversive scenes al-

ternatingwith 9 blocksof restingstate (participants wereasked

to attend to a fixation cross presented in the center of the

screen; 18 seconds). The order of the presentation of the im-

ageswas counterbalanced for emotionalvalence(neutraland

aversive) across individuals. The fixation blocks were treated

as a baseline in the fMRI analyses. Participants were not told

beforehand about thesubsequent recognitionphase, thusmak-

ingthe encodingincidental.During theencoding session, par-

ticipants were instructed to determine whether each picture

depicted an indoor or outdoor scene and were instructed to

respond via a button pressleftbuttonfor indoor andright but-tonforoutdoorthrough a 2-secondvisual instruction(indoor/

outdoor) on thescreenpreceding each block.The retrieval ses-

sion began after a brief delay (about 2 minutes) followingthe

encoding session. During the retrieval session, participants

wereinstructedto determine whether thescenepresented was

seen during the encoding session and were instructed to re-

spond viaa buttonpress (left buttonfor newand rightbutton

forold,as indicatedby the2-second instructionon thescreen

at the beginningof eachblock). During eachretrieval session,

half thesceneswere old(ie,presented duringtheencodingses-

sion),and half were new(ie, notpresented during the encod-

ing session).

In the current study, we limited our analyses to the en-coding phaseonly becauseinterpretation of theretrieval phase

is particularly complexbecause it includesboth encodingand

retrieval processes(since subjects viewed 50% of new scenes

duringretrieval, likelyengagingencoding processes). Further-

more, we also restricted our analyses to neutral scenes only

to circumvent potentialconfounds related todifferences across

groups in processing affective stimuli.

Both accuracy and reaction time (RT) were recorded dur-

ing the scan. Accuracy duringretrieval was calculated as per-

centage of correctresponses,dandresponsebias(criterionC).31

Table 1. Demographic and Performance Dataof the Whole Sample of 308

Characteristic

Mean (SE) PValue

NCs(n= 181)

SIBs(n = 65 )

PTs(n = 62)

Across Groups(ANOVAor 2)

NCsvs PTs

NCsvs SIBs

SIBsvs PTs

Sex, M/F, No. 86/95 27/38 43/19 .19 .005a .49 .003a

Age, y 34.9 (0.7) 36 (1.2) 33.8 (1.2) .35 .43 .33 .15

Years of education 17 (0.18) 16 (0.3) 14 (0.3)


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fMRI

Each subject wasscanned on a GE Signa3-Tscanner. Details on

fMRIdata acquisitionarereportedineAppendix1 inSupplement.

Analysis

Demographicand Behavioral Data

Analyses of variance, 2-sample ttests,and 2 tests were used

to compare continuousand categoricalvariables (thresholdfor

significanceP< .05).

Image Analysis

First-Level Processing| Imageswere processed usingSPM5 (http:

//www.fil.ion.ucl.ac.uk/spm). In the first-level analyses, lin-

ear contrasts were computed for each participant producing

t-statistical parameter maps ateach voxelfor encodingof neu-

tral visual stimulus relative to fixation. A detailed descrip-

tion of thepreprocessingmethodsis included in eAppendix1

in Supplement.

Table 2. Demographic and Performance Dataof thePairwise-MatchedGroups

Mean (SD) PValue

PTs vsNCs

Group NCs (n = 54) PTs (n = 54)

Sex, M/F 38/16 38/16

Age, y 34 (9.7) 34 (10.2) >.99

Years of education 16.9 (2.6) 14.3 (2.1) .99

False alarm 1.5 (1.3) 1.6 (1.5) .74

Hits 10 (1.5) 10 (1.8) .82

Criterion C 0.07 (0.39) 0.05 (0.05) .79

PTs vsSIBs

Group PTs (n = 38) SIBs (n = 38)

Sex, M/F 22/16 22/16

Age, y 34 (10) 34 (10) .82

Years of education 14 (2) 16 (2)


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Psychophysiological Interaction| Psychophysiological interac-

tion (PPI) analyses for encoding neutral greater than baseline

conditions were run with seeds placed separately in the left

and right posterior hippocampal regions. Specifically, we

created an anatomical mask of the hippocampus. This ana-

tomical mask was created using the Wake Forest University

PickAtlas toolbox version 2.4 (http://fmri.wfubmc.edu

/software/PickAtlas). We then divided the mask in 2 equalparts, and we used the posterior part as seed because the

main effect of activation during incidental encoding of the

visual scenes was predominantly in the posterior hippocam-

pus (vide infra). This procedure was done separately for the

left and right posterior hippocampus. A detailed description

of the PPI analysis procedure is included in eAppendix 1 in

Supplement.

Second-Level General Linear Model Analysis| For across-group

differences in the whole sample (including all NCs, PTs, and

SIBs with quality-controlscreened fMRI and performance

data, although not completely matched between groups

[Table 1]), individual contrasts were entered into random-effects analyses of covariance (ANCOVAs), with sex, years of

education, Wide Range Achievement Test score, and RT dur-

ing encoding as covariates of no interest. For the 3 pairwise-

matched group analyses (NCs vs PTs, NCs vs SIBs, and PTs

vs SIBs), individual contrasts were entered into ANCOVA

models in SPM5 (Wellcome Trust Centre for Neuroimaging;

http://www.fil.ion.ucl.ac.uk/spm/software/spm5/) using

years of education, the variable the groups were not

matched for, as a covariate of no interest. One-samplettests

were used as masks in the second-level analyses to identify

brain responses associated with task conditions across all

participants. A statistical threshold ofP< .05 with false-dis-

covery rate (FDR)32

at whole-brain level was used to identifysignificant differences in BOLD signal and coupling across

groups. Given our a priori hypothesis for altered function of

brain regions underlying declarative memory in PTs,9,22,23 a

statistical threshold ofP< .05, FDR corrected within regions

of interest (ROIs), was also accepted to investigate BOLD-

signal differences across groups in the HF (hippocampus

and parahippocampus), DLPFC (BA 9 and 46), and IPL (BA

40, inferior parietal lobule). These ROIs were created using

the Wake Forest University PickAtlas toolbox version 2.4.

We reported results obtained using separate ROIs for these a

priori brain regions, as well as those obtained using a com-

bined large ROI that included all these a priori brain regions

(HF-DLPFC-IPL).

Differences across groups in the functional coupling of

HF with other regions in the brain, and specifically with the

DLPFC and IPL, were explored. A statistical threshold of

P< .05, FDR corrected at the whole-brain level and within

the a prioridefined DLPFC and IPL ROIs, was used to signify

differences in functional coupling of the HF across groups.

We reported results obtained using separate ROIs for these a

priori brain regions, as well as those obtained using a com-

bined large ROI that included both DLPFC and IPL regions

(DLPFC-IPL).

Correlation of Hippocampal-Parahippocampal Activity

and HippocampalCoupling With Behavioral Measures

To explore the relationship between hippocampal-para-

hippocampal activity and hippocampal coupling with behav-

ioral measures, a simple regression analysis was performed

within SPM5entering single-subject first-level contrastmaps

for activation and PPI (for encoding neutral scenes > fixation

cross), with d, visual memory, and working-memory factor

scores as covariates of interest. Analyses withdincluded all

participants. Analyses with visual-memory factor scores and

working-memory factor scores were limited to participants

with available visual memory (NCs: 78,PTs: 50, and SIBs: 53)

and working memory (NCs: 78, PTs: 37, and SIBs: 48) scores.

Relationship Between Altered Hippocampal-Parahippocampal

Function DuringDeclarative Memoryand Other Cognitively Linked

Physiological Intermediate Phenotypes

We aimed toexplore whether thefindingof decreased activity/

coupling of HF during declarative memory, as tested during

incidental encoding of visual scenes (vide infra), is a unique

marker of increasedgeneticrisk forschizophreniadistinctfrom

the previously reported neuroimaging intermediate pheno-

types, such as altered DLFPC activity33 and DLFPC-HF

coupling28 during working memory and altered anterior cin-

gulatecortex activityduring response inhibition,34or whether

conversely it wasmappinga redundant phenomenon. Tode-

termine this,we investigateda subgroupof NCs andSIBswho

had fMRI data for both the working-memory task and the

SDMT, andfor boththe response-inhibitiontask andtheSDMT.

Details are reported in eAppendix 1 in Supplement.

Results

Whole SampleDemographic and Behavioral Results

Patients with schizophrenia differed from the other 2 groups

in sex, Wide Range Achievement Test score, years of educa-

tion, RT during encoding, and RT and accuracy during re-

trieval (Table 1). All these variables, except performance dur-

ingretrieval (RTand accuracy), wereincludedas covariatesof

no interest in analysis of the BOLD fMRI data.

Imaging Results: Activation

Consistent with previous studies, task-related activation in-

cludedbilaterally theHF, theDLPFC, theventrolateralprefron-

talcortex, themedial frontalcortex,the visual cortices,the pa-

rietal cortex, the basal ganglia, the thalamus, and the rightpremotor/motor cortices35,36) (eFigure1 in Supplement).Analy-

sisof covarianceFtestwith diagnosis asa factorrevealedBOLD-

signal differences acrossgroups in thebilateral parahippocam-

pus, in theleft inferiorand superior parietal lobules,and in the

left precentral and postcentral gyri (all PFDRwhole-brain< .05)

(Figure1Aand Table3). Specifically, bothPTs andSIBs showed

decreased BOLD signal in the parahippocampus when com-

pared with NCs (Table 3) (posthoc ttest NCS > SIBS: left HF:

x = 18, y = 36, z = 6 [Z= 4.02, PFDR_HF_ROI= .003, and

PFDR_HF_DLPFC_IPL_ROI = .009]; right HF: x = 30, y = 24, z = 15

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240 JAMAPsychiatry March 2014 Volume 71, Number 3 jamapsychiatry.com




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[Z= 2.77 andPFDR_HF_ROI= .03]; posthoc ttest NCs > PTs: right

HF: x = 24, y = 27, z = 9 [Z= 4.32, PFDR_HF_ROI = .002, and

PFDR_HF_DLPFC_IPL_ROI = .006]; left HF: x = 24, y = 39, z = 12

[Z= 3.42, PFDR_HF_ROI

= .004, and PFDR_HF_DLPFC_IPL_ROI

= .01]),

while only PTs showed increased BOLD signal in inferior and

superior parietal lobulesand in precentral andpostcentralgyri

when comparedwith both SIBs andNCs(posthocttests,Table3).

Matched Samples

Demographicand Behavioral Results

PTs vs NCs| A sample of NCs (n = 54) taken from the larger

sampleof 181participantswere strictly pairwisematched with

PTs (n = 54) in age, sex, and accuracy in retrieval of neutral

scenes (Table 2).Variables that differedbetween groups (years

of education)were used ascovariates of no interest in theneu-

roimaging analyses.

SIBsvs NCs | A subsample of NCs(n = 55) taken from thelarger

sample of 181 participants was strictly pairwise matched for

age, sex,and accuracy with SIBs (n = 55).The 2 groups didnot

differ in the other demographic variables, except for years of

education (P= .006), which were used as covariates of no in-

terest in the neuroimaging analyses (Table 2).

PTs vs SIBs | A subsample of SIBs (n = 38) taken from the larger

sample of 65 SIBs was strictly pairwise matched for age, sex,

andaccuracy, witha subsampleof 38 PTs(derivedby thelarger

Figure 1. MainEffect of Diagnosison Hippocampal Formation (HF) Activation

0.15Controls Patients

0.10

0.05

LeftHippopcam

palFormation

ParameterEstimates,au

0.00

0.05

0.10

Siblings

A

0.15 Controls Patients

0.20

0.15

0.10

0.05

L

eftHippopcampalFormation


0.00

0.05

0.10

Controls Siblings

0.20

0.25

0.30

0.15

0.10

0.05

LeftHippopcampalFormation


0.00

0.05

Controls Patients

0.20

0.25

0.30

0.15

0.10

0.05

RightHippopcampalFormation


0.00

0.05

Controls Patients

0.30

0.25

0.20

0.15

0.10

0.05

RightHippopcam

palFormation


0.00

0.05Siblings

Whole sample

Controls vs siblings vs patients

Z=12 12

T

0

BPairwise-matched sample

Controls > patients

Z=9 3.6

T

0

CPairwise-matched sample

Controls > siblings

Z=33.2

T

0

Thefigure illustratesblood oxygenation leveldependent(BOLD) signaldifferences acrossgroups. A, Theimage shows theeffectof diagnosisin HF

activationduring encoding of neutral scenesin thewhole sample(normal

control [NC] participants = 181, siblings [SIBs] = 65,and patients with

schizophrenia [PTs] = 62)(left HF:x = 24, y = 36, z = 12 [Z= 3.94 and

F= 10.46]; rightHF: x = 24,y = 27, z = 9 [Z= 3.80and F = 9.83];all

PFDRwhole-brain-corrected< .05;FDR indicates false-discoveryrate). Thegraphs of

contrastestimates fromthesignificantvoxels areshownin themiddle (for the

leftHF) andon theright (forthe rightHF). B, Theimage shows theeffectof

diagnosis inHF activation duringencodingof neutral scenesin the

pairwise-matchedsample of NCs(n = 54)and PTs (n = 54)(leftHF:x = 24,

y = 36,z = 9 [Z= 3.44 and PFDR_HF_ROI= .01, ROI indicates regionof interest];right HF: x = 24, y = 27, z = 9[Z= 3.59and PFDR_HF_ROI= .01]). The graphsof

contrastestimates fromthesignificant voxelsare shownin themiddle (forthe

leftHF) andon theright(forthe rightHF). C, Pairwise-matchedsample of NCs

andSIBs(n = 110). Theeffect of diagnosisin HFactivation duringencodingof

neutral scenesin thepairwise-matchedsampleof NCs(n = 55)and SIBs (n = 55)

(left HF: x = 18,y = 36,z = 3 [Z= 3.06 and PFDR_HF_ROI= .06]). Thegraph of

contrastestimates fromthesignificant voxel is shownon theright (left HF). For

illustrativepurposes,the mapsare thresholdedat P= .01, uncorrectedk>5.

au indicates arbitrary unit.






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sampleof 55). The 2 groupsstill differed in yearsof education

(P< .001), whichwas used asa covariate ofno interest(Table 2).

Imaging Results: Activation

PTs vs NCs | Patientswith schizophreniashowed lower activa-

tionin the parahippocampus bilaterally whencompared with

NCs (right HF: x = 24, y = 27, z = 9 [Z= 3.59, PFDR_HF_ROI = .01, and PFDR_HF_DLPFC_IPL_ROI= .06]; left HF: x = 24,

y = 36, z = 9 [Z= 3.44, PFDR_HF_ROI= .01, and PFDR_HF_DLPFC_IPL_ROI= .06]), despite similar accuracy and using similar

strategies as reflected by similar response bias (C, P= .62)

(Figure 1B and Table 2). No other differences were observed

across groups or with the opposite contrast (PTs > NCs).

SIBs vs NCs| Similar to PTs,SIBs showed lower activation in the

parahippocampus comparedwith NCs(left HF: x = 18, y = 36,

z = 3 [Z= 3.06 andPFDR_HF_ROI= .06]), despite performing as

wellasNCsandusingsimilarstrategies(responsebiasC, P= .79)

(Figure 1C and Table 2). No significant results were observed

in other brain areas or withthe oppositecontrast(SIBs > NCs).

PTs vs SIBs| There was a trend toward significance (FDR cor-

rected)for decreasedparahippocampalandincreasedIPLBOLD

signals in PTs when compared with SIBs (right HF: x = 21,

y = 39,z = 12 [Z= 3.15andPFDR_HF_ROI= .12]; left IPL: x = 54,

y = 33,z = 55[Z= 3.30andPFDR_IPL_ROI= .06]; rightIPL: x = 54,y = 36, z = 54 [Z= 2.82 and PFDR_IPL_ROI = .06]). This was

observed despite PTs performing and using strategies similar

to SIBs, as assessed using the response bias measure (perfor-

mance during encoding >91% in both groups and no differ-

ence in response bias,P= .26) (Table 2).

Functional Coupling of Hippocampal Regions (PPI)

Main Effect

The effect of the encoding process on coupling between the

left/right posterior hippocampal regions and the rest of the

brain is shown in eFigure 2 in Supplement (detailed descrip-

tion in eAppendix 2 in Supplement).

PTs vs NCs| Patients with schizophrenia demonstrated de-

creased right hippocampal/bilateral IPL functional coupling

whencomparedwith NCs(right hippocampal/leftIPL: x = 60,

y = 36, z = 45 [Z= 3.63, PFDR_IPL_ROI= .05, and PFDR_DLPFC_IPL_ROI= .10; righthippocampal/rightIPL: x = 54,y = 42, z = 51

[Z= 2.96andPFDR_IPL_ROI= .06]) (Figure2A).Asimilartrendwas

observed with theseedin thelefthippocampus, althoughit did

not survive correction for multiple comparisons (left hippo-

campal-leftIPL coupling:x = 51,y = 60,z = 48[Z= 2.93and

Puncorrected= .002]). No significant differences were observed

Table 3. MainEffect of Diagnosis on BOLDResponse During Encodingof Neutral Images

Region FDR whole-brain F Z MNICoordinates (X, Y, Z)

Ftest

Inferior parietal lobule 0.040 11.51 4.17 36, 48, 60

Precentral gyrus 0.040 11.22 4.11 30, 30, 72

Parahippocampal gyrus 0.040 10.46 3.94 24, 36, 12

0.042 9.83 3.80 24, 27, 9

Superior parietal lobule 0.042 9.51 3.72 18, 72, 60

Postcentral gyrus 0.042 9.06 3.61 45, 33, 63

Ttest

NCs>PTs

Parahippocampal gyrus 0.063 (0.002)a 4.39 4.32 24, 27, 9

0.112 (0.004)a 3.46 3.42 24, 39, 12

NCs>SIBs

Parahippocampus gyrus 0.089 (0.003)a 4.08 4.02 18, 36, 6

>0.15 (0.027)a 2.79 2.77 30, 24, 15

NCs


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in posterior hippocampal coupling with other brain areas, in-cluding the DLPFC, or with the opposite contrast (PTs > NCs).

SIBsvsNCs | Siblings demonstrated decreased lefthippocampal-

bilateralIPL couplingwhen comparedwith NCs, similar to the

pattern observed in PTs (left hippocampal-right IPL: x = 39,

y = 48, z = 42 [Z= 3.66, PFDR_IPL_ROI= .02, and PFDR_DLPFC_IPL_ROI= .09]; left HF/left IPL: x = 39, y = 48, z = 51 [Z= 2.81

andPFDR_IPL_ROI= .04]) (Figure 2B). No other differences were

observed.

PTs vs SIBs | No significant differenceswere observed between

SIBs and PTs.

Correlation of Hippocampal-Parahippocampal BOLD Signal

DuringEncoding of Neutral Scenesand Behavioral Outcome

Within eachsample,there was a positivecorrelation between

visual-memory factor scores and hippocampal-parahippo-

campalBOLD signal anda negativecorrelation between visual-

memory factor scores and IPL BOLD signal (Table 4; Figure 3

represents the scatterplot of this correlation in the sample of

NCs).Similarly,a negative correlationbetweend(accuracydur-

ingretrieval) andleft IPLBOLDsignalwas observed within each

sample (NCs: x = 36, y = 57, z = 48 [Z = 3.19 and PFDR_

IPL_ROI= .03];trendin PTs: x = 48, y = 45,z = 57 [Z= 2.81andPuncorrected= .002]; trend in SIBs: x = 57, y = 54, z = 39

[Z= 2.79 andPuncorrected= .003]).

Except for a trend for a positive correlation in the sample

of SIBs (SIBs: x = 15, y = 30, z = 15 [Z= 2.70 and Puncorrected= .004]), no significant correlations (positive or negative) were

observed between hippocampal-parahippocampal activation

and working-memory factor scores.

Relationship Between Altered Hippocampal-Parahippocampal

Function During Declarative Memoryand Other Cognitively Linked

Physiological Intermediate Phenotypes

The data on the SDMT suggest that reduction in parahippo-

campal BOLD signaland hippocampal coupling withIPL couldbe a potential intermediate phenotype related to genetic risk

for schizophrenia. We had previously reported parallel find-

ings in the prefrontal cortex and its coupling with the hippo-

campus during a working-memory task28,33 andin the cingu-

late cortex and its link to the prefrontal cortex during a

cognitive-control task.34 While these tasks engage relatively

segregated neural systems,many of the participants werethe

same across these studies. This raises the possibility that the

variousfindings maynot be independent. Toexplorewhether

altered parahippocampal activation and hippocampal

Figure 2. MainEffect of Diagnosison Posterior HippocampusInferior ParietalLobule(IPL) Couplingin Pairwise-Matched Samples

0.2

Controls Patients

0.3

0.1

CouplingRight

HF/RightIPL


0.0

0.2

0.4

0.1

0.3

A

0.2

Controls Patients

0.3

0.4

0.5

0.1

CouplingRigh

tHF/LeftIPL


0.0

0.2

0.1

0.3

0.2

Controls Siblings

0.3

0.4

0.5

0.1

Coup

lingLeftHF/RightIPL

Par

ameterEstimates,au

0.0

0.2

0.1

0.05

Controls Siblings

0.10

0.15

0.20

0.25

0.35

0.30

0.00

Cou

plingLeftHF/LeftIPL

Par

ameterEstimates,au

0.05

0.10

Pairwise-matched sample

Controls vs patients

B

Pairwise-matched sample

Controls > siblings

PPI seed right HFbilateral IPL

PPI seed left HFbilateral IPL

Between-groupdifferences in psychophysiologicalinteraction (PPI).

A, Pairwise-matched sample of normal control (NC)participantsand patients

withschizophrenia(PTs)(N = 108).Decreased rightposterior hippocampus/

rightIPL functionalcouplingwas observedin PTs whencompared withNCs

(rightIPL:x = 54,y = 42,z = 51 [Z= 2.96and PFDR_IPL_ROI = .06; FDR indicates

false-discoveryrate; ROI,region of interest]; graphin themiddle:contrast

estimatesfrom thesignificant voxel).A similar decrease wasobservedin the

rightposterior hippocampus/left IPLfunctional coupling (leftIPL: x = 60,

y = 36,z = 45 [Z= 3.63 and PFDR_IPL_ROI = .05]; graphon theright: contrast

estimatesfrom thesignificant voxel). Similar results wereobservedwhen seed

waslocated in theleft posterior hippocampus (seetext for details).

B, Pairwise-matched sample of NCsand siblings (SIBs) (N = 110). Decreasedleft

posterior hippocampus/rightIPL functionalcouplingwas observed in SIBswhen

comparedwithNCs (rightIPL: x = 39,y = 48, z = 42 [Z= 3.66 and

PFDR_IPL_ROI = .02]; graphin themiddle:contrastestimates fromthe significant

voxel).A similar decrease wasobservedin theleft posterior hippocampus/left

IPLfunctional coupling (leftIPL: x = 39, y = 48,z = 51 [Z= 2.81 and PFDR= .04;

graphon theright: contrastestimates fromthe significant voxel). Forillustrative

purposes,the mapsare thresholded at P= .05, uncorrected k>5.au indicates

arbitrary unit; HF, hippocampal formation.






9/12


coupling during the incidental encoding phase of SDMT is

independent from altered DLPFC activation and DLPFC-

hippocampal coupling observed during a working-memory

task,28,33we investigated a subgroupof NCsandSIBs that had

good-quality imaging datafor boththe working-memorytask

andthe SDMTand performedintraclass correlation (ICC)analy-ses. Specifically, within thisgroup, we explored whetherthere

were any correlations between the neuroimaging intermedi-

ate phenotypes observed with the working-memorytask and

the neuroimagingintermediatephenotype observed withthe

SDMT. Demographic and performance data of the 2 sub-

groups are reported in eTable 1 in Supplement. Briefly, the

groups consisted of 56 NCs and 44 SIBs with similar demo-

graphic andperformance (2-back fortheworking-memorytask

andd for the SDMT) characteristics. Although to a less sig-

nificant threshold given the small sample size, we observed

differences in DLPFC BOLD response and DLPFC-HF cou-

plingin thesampleof SIBs comparedwith NCsduringthework-

ing-memory task similar to the data previously reported (ie,

SIBs showed increased BOLD signal in the DLPFC and de-

creased couplingbetween therightDLPFC-hippocampuscom-pared with NCs; ANCOVA with years of education as the co-

variate of no interest; eTable 1 in Supplement), as well as

differences in parahippocampal BOLD signal and hippocam-

palcoupling in thesample of SIBs compared with NCsduring

theSDMT(ie,SIBsshowedreduced HFBOLDsignal andHF-IPL

coupling explored withPPI compared withNCs;ANCOVA with

years of education as the covariate of no interest; eTable 1 in

Supplement) similarto thedataobserved in thebigger sample.

We then performed correlation analyses (ICCs) on the signals

Table 4. Correlation of BOLDSignal During Encodingof NeutralScenesand Behavioral Outcome

(Visual-Memory Factor Scores)

Correlation MNI Coordinates (X, Y, Z) Z PValue

Positive correlation (contrast +1) for hippocampalformation

NCs 21, 15, 12 2.88 .002a

PTSs 12, 33, 18 2.78 .003a

24, 30, 18 2.55 .005a

SIBs 18, 15, 15 2.64 .004a

18, 36, 6 2.37 .009a

Negative correlation (contrast 1) for inferiorparietal lobule

NCs 45, 39, 51 4.00 .01b

PTs 51, 39, 51 3.11 .07a and.001a

SIBs 36, 51, 42 1.97 .03a

Abbreviations: BOLD, blood oxygen

leveldependent;MNI, Montreal

NeurologicalInstitute; NCs, normal

controls; PTs, patients with

schizophrenia; SIBs,siblings (healthy

siblings of PTs).

a Uncorrected Pvalue.

bPvalue false-discovery

ratecorrected within Inferior

parietal lobuleregions of interest.

Figure 3. Scatterplot

0.62.5

0.8 0.4 0.2 0.0 0.2 0.4 0.6

1.5

1.0

Visual-MemoryFactorScore

Left Hippocampus/Parahippocampus (First Eigenvalue), au

0.5

0.0

0.5

1.0

1.5

2.0 Scatterplotillustrates the positive

correlation between hippocampal

formation engagement and

visual-memoryscores in thesample

of normalcontrol participants.

au indicates arbitrary unit. N= 78,

r= 0.33, and P= .003.






10/12


extracted fromthese significantpeak voxels to explorepoten-

tial correlations between these intermediate phenotypes. We

repeated a similar analysis also on the first eigenvalue ob-

tained from the cluster. All ICCs (analyzed both with the sig-

nal extracted fromthe significant cluster andthe mostsignifi-

cantvoxelwithin the cluster)were nonsignificant (allP> .40;

ICC, 2 to 1; range, 0.4 to 0.4).

To explore whether altered parahippocampal activation

and hippocampal coupling during the incidental encoding

phase of SDMT is independent from altered anterior cingu-

late cortex activation observed during a cognitive-control

task,34 we investigated a subgroup of NCs and SIBs that had

good-quality imaging datafor both the cognitive-control task

and the SDMT, and we performed ICC analyses.Demographic

andperformance data of the2 subgroupsarereported ineTable

2 in Supplement. The groups consistedof 113NCs and38 SIBs

similar for demographic and performance (% correct for the

response-inhibition task andd for the SDMT) characteris-

tics. We observed differences in anterior cingulate BOLD re-

sponse in the sample of SIBs compared with NCs during the

response-inhibition task similar to the data previously re-

ported (ie, SIBs showed decreased BOLD signal in the ante-

rior cingulatecomparedwith NCs;2-samplettest; eTable 2 in

Supplement), as wellas differencesin parahippocampal BOLD

signal and hippocampal-IPL coupling in the sample of SIBs

compared with NCs during the SDMT (ie, SIBs showed re-

duced parahippocampal BOLD signal and hippocampal-IPL

couplingexplored withPPI comparedwith NCs;2-sample ttest;

eTable2 in Supplement)similar tothe data observed in thebig-

ger sample. We thenperformed correlation analyses(ICCs)on

the signals extracted from these significant peakvoxels to ex-

plore potential correlations between these intermediate phe-

notypes.We repeated a similar analysisalso on the first eigen-

value obtained from thecluster. All ICCs (analyzedboth with

thesignal extractedfrom thesignificant cluster andthe mostsignificant voxel within the cluster) were nonsignificant (all

P> .10; ICC, 2 to 1; range, 0.15 to 0.2).

Discussion

In this study, we found that activation of the parahippocam-

pus and hippocampal couplingwith IPL during the incidental

encoding phase of theSDMTare impaired both inPTs andtheir

healthy SIBs. These results suggest that hippocampal-

parahippocampal dysfunction in schizophrenia is a familial,

likely heritable, trait.

Hippocampal-Parahippocampal Functionand Visual-Memory CapacityConsistent with the long-standing and well-accepted view of

hippocampal-parahippocampal dysfunction in PTs,16 we ob-

served decreased posterior hippocampus-parahippocampus

function, reflected as decreased parahippocampal activity and

hippocampal coupling during the encoding of neutral visual

stimuli inour patient sample. This isconsistentwithmost fMRI

studiesreportingdecreased hippocampal-parahippocampal re-

cruitment during declarative memory tasks in schizophrenia

(for a meta-analysis, see article by Achim and Lepage22).

One crucial question is whether the hippocampal-para-

hippocampal dysregulationand memorydeficits observed in

schizophreniaare state or trait characteristics of the disorder.

Ourresults suggest thelatter.Indeed, ourfindings reported de-

creased hippocampal-parahippocampal function during en-

coding even in a sample of healthy SIBs of PTs well matched

for potential confounding factors with the sample of NCs. To

our knowledge, so far, only 2 studies have explored hippo-

campal-parahippocampal abnormalities during declarative

memory with fMRI in genetically high-risk populations.24,25

Both foundabnormalhippocampal-parahippocampalrecruit-

ment similar to our results, although the differences in clini-

cal status,24 sex, and performance25 of the high-risk partici-

pants vsthe comparisongroupof NCsleft unresolved whether

the observed deficit was due to familial/genetic background

or was due to these other confounding factors. Our findings

are also consistent with the results of 2 magnetic resonance

spectroscopic imaging studies that found reduced N-

acetylaspartatean in vivomarker for neuronal synaptic abun-

danceinthe hippocampus bothin PTsand their SIBs37,38 and

with those from behavioral studies that reported deficient

performance on declarative memory tests in unaffected

relatives.5

Ourconsistent observation in each participant group of a

positivecorrelationbetween thehippocampal-parahippocam-

pal BOLD response during our declarative memory task and

visual-memory abilitymeasuredwith standardneuropsycho-

logical tests suggests that the visual-memory network iden-

tified with our task has real-world implications for declara-

tive memory capacity. Our data also suggest that the

hippocampal-parahippocampal function deficit is a discrete

pathophysiological characteristic of the risk state indepen-

dent of the risk associated with working-memory function.

Studies of declarative memoryand executive cognitionin the

same patients also suggest that these deficits are indepen-dent phenomena.15,39 Our lack of finding a significant corre-

lation between the BOLD response elicited during working

memoryand declarative memory, as well as during response-

inhibitiontrials and declarative memory, support the conclu-

sion that these are not redundant physiologic characteristics

of the highergeneticriskstate. As previously, we haveshown

that these phenotypes are largely independent, with any re-

dundancy likely small, according to our ICC analyses. As we

have argued previously,28 this is not a surprising result be-

cause it is logical that theneuralsystemsmanifestations of in-

creased genetic riskfor schizophreniawill be diverse.This re-

sultalso suggeststhatindividualrisk factorsmay show effects

selectively on oneor anotherof these phenotypes.

28

Addition-ally, while the hippocampal-parahippocampal region showed

both reducedactivityand reduced couplingwith both IPL and

DLPFCin PTsand theirSIBs,these differences were observed

in the context of 2 very different cognitive processesthe re-

duced activation andcoupling withthe IPL wasobserved dur-

ing incidental encoding of complex scenes and the reduced

coupling with the DLPFC was observed during a working-

memory tasksupporting the notion that diverse neurobio-

logical mechanisms, presumably mediated by diverse ge-

netic mechanisms, could be involved.






11/12


Abnormal Posterior Hippocampal Coupling With Inferior

Parietal Lobule and Correlation With Cognitive Indices

Activation of the IPL was negatively correlated with visual-

memory performancewithin eachgroup(NCs, SIBs, andPTs),

and both patients and healthy SIBs showed a significant de-

creasein thecoupling between thehippocampus andIPL when

compared with NCs. There are studies reporting an associa-

tion between ventral parietal cortex (supramarginal and an-

gulargyrus, ie, IPL)functionand encodingfailure.During en-

coding of items that are subsequently forgotten, greater

activation of theIPL has been reported.40 It hasbeenhypoth-

esizedthatthisapparentincrease in activity of theIPL during

an attention-demanding task reflects a brief lapse in atten-

tionor mindwandering.41Thisinterpretationis consistent with

our results. Within each group, we found that greater IPL ac-

tivation was associated with worsevisual-memoryability (and

d), suggesting a disruptive effectof IPLactivationin theabil-

ity to effectively encode thevisual information. While it may

appearcounterintuitive thatIPL activationwas negativelycor-

related with visual-memory performance in the presence of

positive hippocampal-IPL coupling, it should be notedthatPPI

analysis measures the temporal coherence of the activity be-

tween brain regions across the time series irrespective of the

amplitudeof activityin thesebrainregions.Therefore,it ispos-

sible that while the averaged amplitude of IPL activity nega-

tively correlates withvisual-memory performanceacrosspar-

ticipants, its activity across the time series could positively

correlate with that of the hippocampus, reflecting positive

functional coupling.

Interestingly, in PTs,therewas increasedactivationin the

left precentral and postcentral gyri whencomparedwith SIBs

and NCs. This is in keeping with the previously reported in-

creased activation in the left sensorimotor cortexin PTs.42,43

It is likely the increased RT, reflecting the increased process-

ingtimein the PTsin the unmatched sample,may underliethis.

Limitations

Oneof thelimitationsin thecurrentstudywas theblockdesign

of theSDMT, whichlimited ourability to disentangle theBOLD

responserelatedto successful encodingfrom thatrelatedto un-

successful encoding. Future studiesusing an event-related de-

signmay helpdifferentiate these 2 processes in greater detail.

However,at thegrouplevel,our participantswerewellmatched

for overall performance. Another limitation was the relatively

low spatial resolution of the fMRI data acquisition precluding

usfrom clearly definingthe originof theBOLDsignalwhether

fromthehippocampusor parahippocampalregionduringthe

SDMT. Future studies with higher spatial resolution may help

studytheroleoftheseregions,whicharewellknowntobeana-

tomicallyand functionally distinct, in the pathophysiology of

schizophrenia. While decreased attentional and motivational

factors could contribute to reduced hippocampal-parahip-

pocampal engagement, it is a lesslikely explanationfor ourre-

sultsas all participants, includingpatientsand SIBs,performed

above chance(>50%accuracy) during boththe encodingand re-

trieval sessionsand werematchedforperformance, suggesting

thattheywereattending tothe taskas well asthe healthycon-

trolparticipants.Finally, we cannotexcludethe possibilitythat

our functional results couldbe drivenby structural differences

inhippocampus/parahippocampusvolumes acrossgroups.Fur-

ther studies using multimodal imaging techniques, including

fMRI, high-resolution structural MRI, and diffusion tensor

imaging, withinthe sameindividuals arerequiredto disentangle

thisissuein greater detail. However,we would notethat stud-

iesof hippocampal volume in healthy SIBs of PTs have not re-

vealed volume differences in the hippocampus.44-47

Conclusions

We reported evidence of impaired parahippocampal recruit-

ment and impaired posterior hippocampal coupling with the

parietal cortex duringvisual-memory encoding in PTsand in

their healthy SIBs. This impairment is related to visual-

memory ability and is not redundant with intermediate risk-

associated phenotypes linked to working memory and pre-frontal cortex andresponseinhibitionand thecingulatecortex.

Therefore, measuring hippocampal function through neuro-

imaging represents another potential intermediate pheno-

type that could prove useful in identifying neural system

mechanisms for genetic susceptibility and as a potential bio-

marker for intervention.

ARTICLE INFORMATION

Submittedfor Publication: March18, 2013;final

revision received August13, 2013;accepted August

15, 2013.

Published Online: January 1, 2014.

doi:10.1001/jamapsychiatry.2013.3911.

Author Affiliations: Clinical BrainDisorders

Branch, Genes, Cognition, and Psychosis Program,

National Instituteof Mental Health Intramural

Research Program, National Institutesof Health,

Bethesda, Maryland (Rasetti,Mattay, White,

Sambataro, Podell, Zoltick, Chen,Berman, Callicott,

Weinberger); Lieber Institutefor Brain

Development, JohnsHopkins Medical Campus,

Baltimore, Maryland (Mattay, White, Chen,

Weinberger); BrainCenter for Motorand Social

Cognition, Istituto Italiano di Tecnologia @ UNIPr,

Parma,Italy (Sambataro);Department of

Psychiatry, JohnsHopkins UniversitySchool of

Medicine,Baltimore,Maryland (Weinberger);

Departmentof Neurology, JohnsHopkins

UniversitySchool of Medicine,Baltimore,Maryland

(Weinberger);Solomon H. Snyder Departmentof

Neuroscience, JohnsHopkins UniversitySchool of

Medicine,Baltimore,Maryland (Weinberger);TheMcKusick-Nathans Instituteof Genetic Medicine,

JohnsHopkins UniversitySchool of Medicine,

Baltimore, Maryland (Weinberger).

Author Contributions: Drs Mattay and Weinberger

had full accessto allof the datain the study and

take responsibility forthe integrityof thedataand

theaccuracy of thedataanalysis.Drs Rasetti and

Mattay contributedequally to thiswork.

Study concept and design: Rasetti, Mattay, Berman,

Weinberger.

Acquisition of data: Rasetti, Mattay, White, Podell,

Zoltick, Berman, Callicott.

Analysis and interpretation of data: Rasetti, Mattay,

White, Sambataro, Podell, Chen,Berman, Callicott,

Weinberger.

Drafting of the manuscript: Rasetti, Mattay,

Weinberger.

Critical revision of the manuscriptfor important

intellectual content: Rasetti, Mattay, White,Sambataro, Podell, Zoltick, Chen,Berman, Callicott.

Statistical analysis: Rasetti, Mattay, White,

Sambataro, Podell, Chen.

Obtained funding: Weinberger.

Administrative, technical, and material support:

Podell, Zoltick, Callicott.

Study supervision: Mattay, Berman, Weinberger.

Conflict of Interest Disclosures: Nonereported.

Funding/Support: Thisresearch was supported by

the IntramuralResearchProgram of theNational

Instituteof Mental Health, National Institutesof

Health.






12/12

C i ht 2014 A i n M di l A i ti n All i ht d

Roleof the Sponsor: TheNational Instituteof

MentalHealthhad norole inthe designand conduct

of thestudy;collection, management,analysis,or

interpretationof thedata; andpreparation, review,

or approval of themanuscript; but approvedfinal

submissionof themanuscript for publication.

Previous Presentation: Thisstudy waspresented

as a posterat theAnnual Meeting of theSocietyfor

Neuroscience; October 15, 2012; New Orleans, LA.

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