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NeuroImage 13, 433–446 (2001)doi:10.1006/nimg.2000.0699, available online at http://www.idealibrary.com on

Functional Neuroanatomy of Auditory Working Memory inSchizophrenia: Relation to Positive and Negative Symptoms

V. Menon,*,†,‡ R. T. Anagnoson,*,‡ D. H. Mathalon,§ G. H. Glover,¶ and A. Pfefferbaum§*Departments of Psychiatry and Behavioral Sciences, ¶Department of Radiology, and †Program in Neuroscience, Stanford University

School of Medicine, Stanford, California 94305-5719; ‡VA Palo Alto Health Care System, Palo Alto, California 94304;and §SRI International, Menlo Park, California 94025

Received June 19, 2000

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Functional brain imaging studies of working memory(WM) in schizophrenia have yielded inconsistent resultsregarding deficits in the dorsolateral prefrontal(DLPFC) and parietal cortices. In spite of its potentialimportance in schizophrenia, there have been few inves-tigations of WM deficits using auditory stimuli and nofunctional imaging studies have attempted to relatebrain activation during auditory WM to positive andnegative symptoms of schizophrenia. We used a two-back auditory WM paradigm in a functional MRI studyof men with schizophrenia (N 5 11) and controls (N 53). Region of interest analysis was used to investigateroup differences in activation as well as correlationsith symptom scores from the Brief Psychiatric Ratingcale. Patients with schizophrenia performed signifi-antly worse and were slower than control subjects inhe WM task. Patients also showed decreased lateraliza-ion of activation and significant WM related activationeficits in the left and right DLPFC, frontal operculum,

nferior parietal, and superior parietal cortex but not inhe anterior cingulate or superior temporal gyrus. Theseesults indicate that in addition to the prefrontal cortex,arietal cortex function is also disrupted during WM inchizophrenia. Withdrawal-retardation symptom scoresere inversely correlated with frontal operculum acti-ation. Thinking disturbance symptom scores were in-ersely correlated with right DLPFC activation. Ourndings suggest an association between thinking distur-ance symptoms, particularly unusual thought content,nd disrupted WM processing in schizophrenia. © 2001

cademic Press

INTRODUCTION

Schizophrenia is characterized by broad range ofcognitive impairments (Heinrichs et al., 1998). Work-ng memory (WM), the ability to hold and manipulatenformation online in the brain (Baddeley et al., 1974;oldman-Rakic, 1994; Smith et al., 1999), is among the

most significantly disrupted cognitive functions in
schizophrenia (Goldman-Rakic, 1994; 1991; Spindler et
433

al., 1997; Salame et al., 1998; Stone et al., 1998). Theomponent processes involved in WM—encoding, re-earsal, storage, and executive processes on the con-ents of stored memory—represent key cognitive oper-tions of the human brain. Smith and Jonides (Smitht al., 1999) have argued that analysis of WM is criticalor understanding not only memory systems, buthought itself. Goldman-Rakic (1994) has hypothesizedhat WM dysfunction may be a fundamental feature oformal thought disorder, a predominant positive symp-om of schizophrenia.

Functional and structural neuroimaging in subjectsith schizophrenia suggests that cognitive deficits re-

ult from prefrontal pathophysiology (Weinberger etl., 1996; Shenton et al., 1997; Nestor et al., 1998;cCarley et al., 1999). Regional cerebral blood flow

rCBF) studies have found evidence for decreased pre-rontal cortex blood flow (“hypofrontality”) in subjectsith schizophrenia (Weinberger et al., 1988), with the

argest decreases occurring during cognitive tasks in-olving executive function (Young et al., 1998). A num-er of previous imaging studies of prefrontal cortexeficits in schizophrenia have used neuropsychologicalasks that have a WM component (Schroeder et al.,994; Volz et al., 1997, 1999; Andreasen et al., 1992).lthough these studies have found deficits in prefron-

al cortex function in schizophrenia, they have usedasks, such as the Wisconsin Cart Sorting Test, whichre generally quite complex and engage a number ofognitive processes that are unrelated to WM per se.More recently, researchers have focused attention on

asks that are generally considered to involve the coreperations underlying WM (Carter et al., 1998). Theseasks can be generally categorized into two types (1)elayed matching to sample tasks involving WM de-ays of 3–5 s and (2) n-back tasks generally involvinghorter delays (Gevins et al., 1993). For example, one

study (Stevens et al., 1998) used auditory word andtone recognition in a delayed matching to sample taskdesign and found decreased fMRI activation in subjects
with schizophrenia in the lateral frontal cortex and
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434 MENON ET AL.

anterosuperior temporal gyrus, but not in the dorsolat-eral prefrontal cortex (DLPFC) or parietal cortex. How-ever, Manoach et al. (1999) found no decrease in pre-frontal cortex activation in subjects with schizophreniaduring digit matching to sample. Instead, they foundgreater activation in subjects with schizophrenia thanin control subjects in the left DLPFC, but did not in theright DLPFC. Using a visual 2-back task designedspecifically to manipulate contents of WM, Carter et al.(1998) found significantly decreased PET activation inthe right DLPFC and right posterior parietal cortices ofsubjects with schizophrenia. An fMRI study using asimilar visual 2-back task also found less DLPFC acti-vation in subjects with schizophrenia (Callicott et al.,1998). Both of these studies used visual stimuli withWM delays of 2 s. Overall, functional imaging studiesof WM in schizophrenia have yielded variable and con-flicting results. These inconsistencies may be related todifferences in paradigm and type of operations involv-ing WM. The delayed matching to sample tasks gener-ally emphasize prefrontal cortex function during delay(Elliott et al., 1999), while the n-back WM tasks involvedelay as well as more dynamic updating of informationvia executive functions of the prefrontal cortex (Cohenet al., 1997; Smith et al., 1999). More detailed analysisf auditory processing by Javitt et al. (1997) have sug-ested that auditory WM deficits in schizophrenia mayot be dependent on the duration for which memoryraces are retained.

Attempts to relate cognitive and behavioral deficitsn schizophrenia have focused on the characterizationf symptom types, such as the dichotomy between pos-tive and negative symptoms (Toomey et al., 1997). Theositive symptoms of schizophrenia include disorgani-ation of thinking and planning, and loss of ability toistinguish between real and imagined events as ex-mplified by hallucinations and delusions (Liddle et al.,994; Carpenter et al., 1994). The negative symptoms

include blunted affect, poverty of speech and content,avolition and apathy, social withdrawal, and anhedo-nia (Andreasen, 1982). More recently, investigatorshave used correlational and factor analytic approachesto examine in greater detail the interrelationships be-tween positive and negative symptoms (Andreasen etal., 1999). These studies have suggested that positivesymptoms can be further subdivided into two dis-tinct dimensions—psychosis and disorganization (An-dreasen et al., 1986; Liddle, 1987; Lenzenweger et al.,1989; Schuldberg et al., 1990; Arndt et al., 1991; Minaset al., 1992).

Dimensional and categorical approaches to investi-gation of the psychopathology of schizophrenia haverelied on a number of specific rating scales. Of these,the Brief Psychiatric Rating Scale (BPRS) (Overall etal., 1988) has been widely used to examine schizophre-nia symptomatology both in clinical and research set-
tings (Bishop et al., 1983; Faustman, 1994; Lauriello et p
l., 1998; Cabeza et al., 2000). The BPRS provides aeliable measure of both the positive and negativeymptoms (broadly defined) as well as the more dis-inct dimensions that researchers have now begun tonvestigate in greater detail, including psychosis, con-eptual disorganization, withdrawal-retardation, andnxiety-depression. The BPRS is more widely usedcross a range of psychiatric disorders, it provides aotential for generalizing the present results beyondchizophrenia (Dell’Osso et al., 2000; Varner et al.,000). Although there exists a fairly extensive clinicalharacterization of these dimensions in schizophrenia,esearch on the neural correlates of underlying deficitsas been limited.Frontal lobe dysfunction is known to be associatedith the negative symptoms of schizophrenia (Breier etl., 1991). However, a recent behavioral study thatarsed out different components of frontal lobe func-ion found that positive symptoms are related to fron-al executive tasks, whereas negative symptoms areelated to mental tracking tasks that require motoricnd dexterous manipulation (Zakzanis, 1998). Al-hough a number of rest state rCBF studies (Shioiri etl., 1994; Suzuki et al., 1992; Wolkin et al., 1992) havenvestigated the effect of positive and negative symp-oms on hypofrontality, few neuroimaging studies toate have examined the relation between symptomsnd brain activation during cognitive activation para-igms. Andreasen et al. (1992) reported that decreasedctivation during a Tower-of-London task was ob-erved only in subjects with high scores for negativeymptoms. McGuire et al. (1998) found that verbalisorganization, a feature of thought disorder, corre-ated inversely with temporal, cingulate, and frontalctivation. Further, subjects with schizophrenia pre-isposed to hallucinations activated temporal and fron-al regions less than non-hallucinating patients withchizophrenia or controls (McGuire et al., 1996).To date, no study has investigated auditory verbalM in schizophrenia using an n-back task. In the

resent study we used fMRI to specifically examinerain activation in schizophrenia in several prefrontalnd parietal cortex areas known to be involved in WMnd further examined the relationship of the activationo BPRS scores. In order to control for factors unrelatedo WM, we compared activation between WM and alosely matched control condition. We hypothesizedhat, compared to control subjects, patients withchizophrenia would perform worse and have signifi-antly reduced activation in the DLPFC, ventrolat-ral prefrontal cortex and inferior parietal cortexD’Esposito et al., 1998; Smith et al., 1998; Owen,997). We also investigated brain activation in thenterior cingulate since it has been linked to executiveontrol of the WM system (D’Esposito et al., 1995) ands thought to be involved in cognitive deficits in schizo-
hrenia (Dolan et al., 1995). While hypofrontality

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435fMRI OF WORKING MEMORY IN SCHIZOPHRENIA

across broad regions of the frontal lobe has also beenreported in schizophrenia (Buchsbaum, 1990; An-dreasen et al., 1992; Weinberger et al., 1996, 1988), thespecific involvement of the anterior cingulate in WMdeficits in schizophrenia is not known. Thus, the majorobjectives of this study were to investigate regionalbrain activation during auditory verbal WM in schizo-phrenia and to examine the relationships of observedactivation abnormalities with symptoms.

MATERIALS AND METHODS

Subjects

Eleven men with schizophrenia (8 outpatients and 3inpatients), and 13 physically and mentally healthymen recruited from the local community participatedin the study after giving informed consent. Subjectswere recruited from the VA Palo Alto Health CareSystem, were in good physical health, and met theDSM-IV criteria for schizophrenia based on a consen-sus of a research psychiatrist or psychologist perform-ing a clinical interview and a trained research assis-tant performing the Structured Clinical Interview forDSM-IV (First et al., 1995). All patients were on astable dose of medication for at least 2 weeks prior tothe MRI scan. Exclusion factors were the DSM-IV cri-teria for Alcohol or Substance Abuse or Dependencewithin 3 months prior to scanning, a history of headinjury with loss of consciousness greater than 30 min,and neurological illness or trauma that could affect thecentral nervous system. Eight patients were on atypi-cal and three were on typical anti-psychotic medica-tion.

Clinical ratings using the BPRS (Overall et al., 1988)were obtained for patients at or close to the day of thescan (eight subjects were rated on the day of the scan,three were rated within 1 week of the scan). The BPRSis a clinician-rated instrument based on a semistruc-tured interview yielding measures of symptomatologyon 18 items. Two trained raters administered theBPRS, and the averages of their ratings were used.

Task

Subjects performed a 2-back continuous performancetask (Gevins et al., 1993) involving the numbers zerothrough nine spoken in a female voice with an ISI oftwo seconds. In the WM condition, subjects were in-structed to press a button with their right hand indexfinger every time the current number presented wasthe same as the number presented two stimuli prior. Inthe control condition, subjects were instructed to re-spond immediately after hearing the number “3.” Asequence of 11 stimuli comprised a single epoch. A totalof 12 epochs, 6 of each condition, were alternated
(ABAB . . .), beginning with the control condition. The
number of responses was balanced across conditions.All subjects were trained with 3 epochs of each condi-tion prior to scanning to ensure that they understoodhow to do the task.

Due to technical problems, behavioral data was notacquired concurrently with fMRI data. Subjects (10patients with schizophrenia and 8 normal controls)were brought back several months after the scan andwere tested on the same experiment with an identicalstimulus sequence. Six subjects could not be located orwere unable to return for this second session. There isevidence in the literature to suggest that workingmemory performance is stable for patients with schizo-phrenia and control subjects over long time periods(Rund et al., 1995). It was assumed that learning ef-fects would have been lost during this period. Responseaccuracy and reaction time were recorded.

Behavioral Data Analysis

Subject performance was gauged using reaction time(RT) and sensitivity (d9), a measure of response accu-acy that subtracts false-positive responses from hitsalso referred to as “risk difference”) (Macmillan et al.,

1991). d9 minimizes bias with subjects who respond toearly every stimulus.

MRI Data Acquisition

Images were acquired on a conventional 1.5T GEcanner using a quadrature whole head coil. Subjectsay supine in the scanner with their head restrainedsing a bitebar (Menon et al., 1997b). Functional im-ges were acquired using a T2*-weighted gradient echopiral pulse sequence with a temporal resolution of 4 st 132 time points (TR 5 1000 ms, TE 5 40 ms, flip

angle 5 40°, and 4 interleaves) (Glover et al., 1998). Ateach time point, 12 axial slices, 210 to 162 mm withrespect to the anterior commissure, were imaged. Slicethickness was 6 mm, interslice thickness was 0 mm,field of view was 310 mm, with an effective in-planespatial resolution of 4.35 mm. A single k-space imagefile was written to disk and images reconstructed, byinverse Fourier transform for each of the 132 timepoints, into 256 3 256 3 12 image matrices (resolution:1.21 3 1.21 3 6 mm).

The task was programmed using Psyscope (http://poppy.psy.cmu.edu/psyscope) on a Macintosh notebookcomputer. Onset of scanning and task were synchro-nized using a TTL pulse delivered to the scanner tim-ing microprocessor board from a “CMU Button Box”microprocessor connected to the Macintosh with a se-rial cable. Audio signals from the Macintosh were am-plified using an audio receiver and transmitted to apiezo-electric speaker placed near the head of the scan-ner. Sound was piped binaurally to the subjects bymeans of a plastic headset connected with a plastic
tube to a funnel placed over the piezo-electric speaker.

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436 MENON ET AL.

MRI Data Acquisition

High resolution whole brain images were acquired toassist localization of activation foci. These images wereacquired using a T1-weighted spoiled grass gradientrecalled (SPGR) 3-D MRI sequence with the followingparameters: TR 5 24 ms; TE 5 5 ms; flip angle 5 40°;4 cm field of view; 124 slices in sagittal plane; 256 392 matrix; acquired resolution 5 1.5 3 0.9 3 1.2 mm.he reconstructed image was a 124 3 256 3 256 ma-

trix (resolution: 1.5 3 0.9 3 0.9 mm).

fMRI Data Processing

fMRI data were pre-processed using SPM96(http://www.fil.ion.ucl.ac.uk/spm). Images were firstcorrected for movement using least square minimi-zation without higher-order corrections for spin his-tory (Friston et al., 1996). Images were then normal-ized to stereotaxic Talairach coordinates (Friston etal., 1995b), resampled every 2 mm using sinc inter-polation and spatially smoothed with a uniformthree dimensional Gaussian filter with a full widthat half maximum of 4 mm.

To determine activation during the WM comparedto the control condition, regression analysis, and thetheory of Gaussian random fields as implemented inSPM96 was used (Friston et al., 1995c). Voxel-wise tstatistics were computed using multivariate linearregression for the individual data of each subject(Worsley et al., 1995). A delayed box-car hemody-namic response function (HRF) was used to deter-mine activation directly related to the difference be-tween the WM and control task conditions. Thepredictor reference waveform consisted of a series of21 for images corresponding to the control conditionand 11 for images corresponding to the WM condi-tion, convolved with a 6-sec delay Poisson function totake into account delay and dispersion in the hemo-dynamic response. Low frequency noise was removedwith a high pass filter (0.5 cycles/min) applied to thefMRI time series at each voxel. The confounding

TAB

Demographic Data (Mean and Sta

Subject group Age Education

Control (n 5 13) 42.46 6 3.93 14.65 6 1.0337–49 14–17

Schizophrenic (n 5 11) 44.55 6 4.61 13.82 6 1.6637–49 11–17

a Fourteen to 32 signified right-handedness and 50 to 70 left-handb Based on seven subjects.c Based on 10 subjects.

effects of fluctuations in global mean were removed

with a scaling model. A temporal smoothing function(Gaussian kernel corresponding to dispersion of 8 s)was applied to the fMRI time series to enhance thesignal to noise ratio. The degrees of freedom wereadjusted to take into account autocorrelations in thefMRI time series (Friston et al., 1995a). The t statis-tics were normalized to Z scores.

ROI Analysis

Statistical analysis of subject groups was conductedusing regions of interest (ROIs). Based upon previouslypublished studies (Braver et al., 1997; Cohen et al.,1997; Carter et al., 1998; Jonides et al., 1997), 12 mu-tually exclusive ROIs were constructed: The left andright hemispheres of the DLPFC (Brodmann Areas(BA) 9/46), inferior parietal cortex (BA 39/40), frontaloperculum (BA 44/45), superior parietal cortex (BA 7),and anterior cingulate (BA 24/32); a region not knownto be involved in WM, the superior temporal gyrus(STG; BA 22/42), was also included for comparisons.Regions of interest were constructed based upon theparcellation of Brodmann areas in the Talairach ste-reotaxic system (Talairach et al., 1988).

Group Analysis of Brain Activation

The mean Z score of voxels activated above a Z 52.33 threshold (P , 0.01) was used to measure activa-tion intensity within each ROI. An analysis of variancemodel was used to investigate differences betweengroups and ROIs.

Clinical State and Brain Activation

Spearman correlations were used to relate both func-tional measures with clinical measures in patientswith schizophrenia. Four subscales of the BPRS wereused (Overall et al., 1972; Faustman, 1994): ThinkingDisturbance (assessing positive symptoms), With-drawal-Retardation (assessing negative symptoms),

1

ard Deviation) for Subject Groups

NART IQ Parental SES Handednessa

113.92 6 7.27 2.79b 6 0.64 19.54 6 7.48104–125 2–4 14–39

110.45 6 9.65 2.82 6 0.98 15.50c 6 2.6488–124 2–5 14–22

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RESULTS

emographic Measures

The two groups did not differ significantly in aget(22) 5 21.196, P 5 0.244), years of education (t(22) 5

1.507, P 5 0.146), intelligence as indexed by the Na-tional Adult Reading Test (t(22) 5 1.004, P 5 0.327)(Nelson, 1982), parent/caregiver socioeconomic status(t(16) 5 20.077, P 5 0.939) (Hollingshead, 1975), orhandedness (t(21) 5 1.624, P 5 0.119) (Crovitz et al.,1962) (Table 1).

Behavioral

Patients with schizophrenia performed significantlyworse than control subjects and had significantlylonger RTs for both the WM and control tasks (Table2). Repeated measures ANOVA of RT showed a signif-icant Group 3 Task condition interaction (F(1,16) 57.731, P 5 0.013), indicating that the patients weresignificantly more impaired during WM than controlconditions (Fig. 1). A similar analysis with d9 showedgroup and condition effects but no significant interac-tion (F(1,16) 5 2.069, P 5 0.170).

Head Movement during fMRI Scan

Functional brain images were corrected for move-ment using least square minimization. Mean displace-ment (root-means-squared) needed to realign the im-ages was used as measure of head movement. Headmovement for both control subjects (1.12 6 0.73 mm)and patients (1.50 6 1.31 mm) was small and did not

TABLE 2

Group Differences in Behavioral Measures

Behavioral measureControl(n 5 8)

Schizophrenic(n 5 10) P

d9 (WM condition) 0.832 6 0.090 0.636 6 0.150 0.00249 (Control condition) 0.997 6 0.006 0.877 6 0.176 0.0364

T (WM condition) 822 6 55 ms 1107 6 140 ms ,0.0001T (Control condition) 721 6 37 ms 847 6 119 ms 0.0057

FIG. 1. Behavioral performance in patients with schizophrenian 5 10) compared to control subjects (n 5 8) during the auditory

working memory and control conditions.

differ significantly between groups (t(22) 5 20.887;P 5 0.385).

Group Average Activation

Averaged group data for control subjects and pa-tients are shown in Figs. 2 and 3. These data suggestthat patients with schizophrenia had marked deficitsin activation in the DLPFC and the inferior parietallobe. In control subjects, activation foci were found atthe following locations in the left DLPFC (Talairachcoordinates: 56, 24, 34), right DLPFC (56, 28, 34), leftfrontal operculum (258, 24, 2), right frontal operculum(60, 22, 20), left inferior parietal (246, 258, 42), rightinferior parietal (50, 258, 42), left superior parietal(232, 258, 54), right superior parietal (34, 276, 44),left anterior cingulate (24, 24, 34), right anterior cin-gulate (2, 22, 24). Note that these figures do not repre-sent a statistical comparison of the groups. We describebelow regional differences in the pattern of activationbetween groups.

Group Comparison of Activation by ROI

Repeated measures analysis of variance was used to

FIG. 2. Surface rendered average group activation the controlsubjects and patients with schizophrenia. This figure is not a statis-tical representation of the data—an ROI analysis was used to deter-mine regionally specific group differences.

investigate group differences in fMRI activation across

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438 MENON ET AL.

ROIs. Factors used were Group (two levels: control,patient), ROI (five levels: DLPFC, frontal operculum,inferior parietal, superior parietal, anterior cingulate),and Hemisphere (two levels: left, right). Mean valueswith standard error are illustrated in Fig. 4.

Group differences. Significant effects were foundwith activation intensity for Group (controls . pa-ients), ROI (DLPFC . inferior parietal . frontal oper-ulum . superior parietal . anterior cingulate),roup 3 ROI (described below), and Group 3 Hemi-

sphere (right . left in controls, left 5 right in patients).Trends toward significance were found for ROI 3Hemisphere and Group 3 ROI 3 Hemisphere interac-tions (Table 3). To verify that these results did notarise from systematic group differences in head move-ment, we conducted a follow-up ANCOVA with thesame effects as above, using overall degree of move-ment as covariate, as suggested by Callicott et al.(1998). This procedure yielded results nearly identicalto the above ANOVA analysis, with all the same sig-nificant effects. The same findings were true whenactivation in a non-WM region, the STG, was used as acovariate, suggesting that regionally specific group dif-ferences do not result from movement.

Follow up analysis of the Group 3 ROI interactionevealed significantly reduced activation in patientsith schizophrenia in the following ROIs: DLPFC

F(1,22) 5 28.163, P , 0.001), frontal operculumF(1,22) 5 5.201, P 5 0.033), inferior parietalF(1,22) 5 8.391, P 5 0.008), and superior parietal

(F(1,22) 5 14.151, P 5 0.001). Anterior cingulateshowed no difference between groups (F(1,22) 5 0.002,P 5 0.962).

Group differences in STG. To confirm that groupdifferences in activation did not arise from global re-ductions in the patients with schizophrenia, we exam-ined activation in the STG. Group differences in acti-vation intensity within this region were not significant(F(1,22) 5 1.530, P 5 0.229).

Correlation with symptoms. Thinking Disturbancescores of patients correlated significantly with activa-tion intensity in the right DLPFC (rho 5 20.711, P 50.014; Fig. 5), but not in any other ROI. When theindividual items on this scale were correlated withright DLPFC activation intensity, unusual thoughtcontent showed a significant relationship (rho 520.648, P 5 0.031), while hallucinatory behavior(rho 5 20.503, P 5 0.115) and conceptual disorganiza-tion (rho 5 20.498, P 5 0.119) did not. Withdrawal-Retardation scores correlated significantly with activa-tion in the left frontal operculum (rho 5 20.897, P ,0.001; Fig. 6) and right frontal operculum (rho 520.661, P 5 0.038; Fig. 6). The Hostility-Suspicious-ness and Anxiety-Depression scores showed no signif-
icant relationship to activation in any ROI.
DISCUSSION

Although patients with schizophrenia were not sig-nificantly different in IQ and a number of demographicvariables from control subjects, they showed signifi-cant behavioral deficits as well as deficits in brainactivation during WM task performance. Patients withschizophrenia were significantly less accurate andslower than control subjects in the 2-back WM task.Additionally, patients were significantly more im-paired in the WM condition. Our results are consistentwith previous reports of WM deficits in patients withschizophrenia based on other paradigms and stimulusmodalities including a visual 2-back WM task (Carteret al., 1998), spatial and object WM (Spindler et al.,1997), and verbal free-recall WM (Flemming et al.,1995; Ganguli et al., 1997). To our knowledge, this isthe first demonstration of behavioral deficits during anauditory verbal 2-back WM task in schizophrenia.

Patients with schizophrenia showed significant acti-vation deficits in the left and right DLPFC, left andright inferior parietal cortex, but not the anterior cin-gulate or the superior temporal gyrus. A significantGroup 3 ROI interaction further underscored the pro-file of regionally specific deficits in schizophrenia. Themost significant differences were found in the DLPFC,inferior and superior parietal cortex, while the frontaloperculum showed less significant group differencesand the anterior cingulate was not different betweengroups. Patients with schizophrenia also showed de-creased lateralization of activation, in agreement withprevious hypotheses (Maher et al., 1998; Crow et al.,1989). Together, these results suggest that the ob-served decreases in activation do not arise from globaldeficits in blood flow in schizophrenia patients. Fur-thermore, head movement during the task was small (1mm or less in each axis) and did not differ betweengroups, nor did head movement or STG activation af-fect observed group differences when used as a covari-ate, as suggested by Callicott et al. (1998). Along withour finding of regionally specific group differences, thissuggests that the observed brain activation deficits inschizophrenia patients are related to functional andbehavioral differences rather than an artifact arisingfrom differences in head movement.

Patients with schizophrenia showed no deficits ineither the left or right STG, suggesting that deficits inearly auditory stimulus processing are unlikely to un-derlie the observed WM deficits in schizophrenia.Rather, our results point to prefrontal and parietalcortex deficits underlying disruptions in the executiveand storage components of WM (Smith et al., 1998).

The largest brain activation differences between thegroups occurred in the DLPFC, a subregion of theprefrontal cortex that has been implicated in executivefunctions involved in verbal working memory (Cohen et
al., 1997; Smith et al., 1999). Our results suggest that

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DLPFC deficits occur in both hemispheres. There wereno hemispheric differences in activation in eithergroup of subjects. This is consistent with fMRI studiesindicating that both hemispheres, rather than just theleft hemisphere, are involved in verbal working mem-ory processing (Rypma et al., 1999; Schumacher et al.,1996). Further, several PET and fMRI studies haveshown a correlation between left and right DLPFCactivation and increased memory load (Smith et al.,1998).

Although the DLPFC is known to be critically in-volved in verbal WM, Stevens et al. (1998) did not finddifferences between patients with schizophrenia andcontrols in this region, a result that they attributed totheir task’s strong subvocal rehearsal element. Ourresults converge with previous studies of visual 2-backWM tasks which found decreased DLPFC activation inpatients with schizophrenia (Carter et al., 1998; Calli-ott et al., 1998). The discrepancy in these findings mayrise from the fact that the 2-back task may havenvolved more frequent and dynamic manipulation ofhe contents of WM compared to the delayed match toample tasks used by Stevens et al. (1998). If thisnterpretation is correct, these findings would suggesthat it is manipulation of WM, compared to mainte-ance of the contents of WM, which is most affected inhe DLPFC of patients with schizophrenia. Patientslso showed decreased activation in the frontal oper-ulum, although this deficit was not as large as that inhe DLPFC. The left frontal operculum is thought to benvolved in the rehearsal and inhibitory processes as-ociated with WM (Smith et al., 1998), while the rela-ive contribution of the right frontal operculum, whichppears to have greater deficits in patients with schizo-hrenia (Fig. 4), is poorly understood (Smith et al.,999).Patients with schizophrenia also showed significant

ctivation deficits in the parietal cortex. Differencesere found in the inferior as well as the superior pa-

ietal lobe. Recent imaging studies suggest that thenferior-posterior parietal cortex is involved in thehort-term storage and retrieval of verbal materialJonides et al., 1998) as well as the active maintenancef phonological stimulus representations (Smith et al.,998). Furthermore, our finding of conjoint parietalnd prefrontal cortex deficits in schizophrenia is con-istent with findings from metabolic studies of coacti-ation in the parietal and prefrontal cortex duringorking memory (Friedman et al., 1994; Ungerleider etl., 1998). The neuroanatomical connection betweenhe prefrontal and parietal cortices is well documentedSelemon et al., 1988; Cavada et al., 1989). Electro-hysiological studies in monkeys have shown changesn firing patterns of prefrontal cortex neurons during

M delay periods when the parietal cortex is cooledQuintana et al., 1989). Chafee et al. (2000) have re-
ently shown that the reciprocal projections between O
arietal and prefrontal neurons tightly entrains theirarallel activation. Together, these findings suggesthat deficits in integration of frontal and parietal cir-uits may underlie working memory deficits in schizo-hrenia.Control subjects and patients did not show any dif-

erences in the anterior cingulate. The only previoustudy to examine activation of the anterior cingulate inatients with schizophrenia during a WM taskStevens et al., 1998) also found no deficits in thisegion. Previous imaging studies have suggested thatnterior cingulate cortex deficits may underlie impair-ent in verbal fluency (Dolan et al., 1995) and declar-

tive memory (Fletcher et al., 1999). The lack of signif-cant differences in the present study may have arisenrom use of a closely matched control condition, therebyesulting in smaller activation in this region (see Fig.). The anterior cingulate has been postulated to con-rol inhibition of preprogrammed responses to stimuli,uch as in the Stroop task (Smith et al., 1999) and to benvolved in detecting and responding to salient targettimuli (Menon et al., 1997a; Posner et al., 1990). Inhis regard, a potential issue with the control task usedn the present experiment as well as other n-backorking memory studies is worth noting. The control

ask requires the subject to respond to the number 3.his builds up a preprogrammed response bias to thisumber. A response bias during the WM condition andesponse inhibition associated with a “No-Go” type ofituation, when it is not an appropriate response tar-et, could be potentially contribute to the activation.owever, only 6% of the stimuli during the experimen-

al condition were No-Go stimuli (the number 3) tohich the prepotent response bias had been createduring the control condition. Thus, it is unlikely that areprogrammed response bias could have a significantffect on the activation, and group differences in brainctivation during the experimental, compared to theontrol, condition are likely to be dominated by pro-esses related to WM rather than response inhibition.he lack of differential activation of cingulate cortex isoteworthy, as postmortem studies have implicated it

n the pathophysiology of schizophrenia (Benes, 1993).he present findings indicate that the anterior cingu-

ate is not the critical locus of auditory working mem-ry disruption in schizophrenia.This is the first study to investigate the relation

etween clinical symptoms in schizophrenia and brainctivation during an auditory WM task. Our resultsomplement and extend the findings of Carter et al.1996) who suggested that behavioral deficits duringhe 2-back visuospatial WM were related to negativeymptoms. In the present study, negative symptoms,s indexed by the withdrawal-retardation subscale ofhe BPRS, were associated with left and right frontalperculum activation in patients with schizophrenia.
ur results further support the hypothesis of a strong

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440 MENON ET AL.

relationship between the negative symptoms of schizo-phrenia and prefrontal lobe dysfunction (Mattson et

l., 1997). To date the majority of this evidence haseen based on neuropsychological assessment duringasks that involve memory and other cognitive func-ions. Imaging studies have investigated the relationetween negative symptoms in schizophrenia and fron-al lobe dysfunction mainly with resting state cerebrallood flow using PET and SPECT (Shioiri et al., 1994;

Suzuki et al., 1992; Wolkin et al., 1992). These studieshave generally shown that decreased frontal brain ac-tivity is associated with the severity of negative symp-toms in schizophrenia. Our results are in good agree-

FIG. 3. Averaged group activation for (A) control subjects and (B)superposed on the mean T1-weighted normalized structural MRI sc

ment with the findings of Andreasen et al. (1992), who

reported decreased PET activation in the prefrontalcortex during the Tower-of-London task only in pa-tients with high scores for negative symptoms. Thepresent fMRI findings suggest that negative symptomsmay be more specifically related to frontal operculumdysfunction in schizophrenia. In particular, left frontaloperculum dysfunction may be related to poverty ofspeech because this region, which encompasses classi-cal Broca’s language area, is known to be involved inspeech production and rehearsal.

Positive symptoms, indexed by the thinking distur-bance subscale of the BPRS, were associated with theintensity of right DLPFC activation. The correlation

ients with schizophrenia (Z . 2.33; P , 0.01). Activations are shown. Coronal slices from y 5 280 to 160 mm are shown.

pat

was strongest with unusual thought content and non-

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Co


significant with conceptual disorganization or halluci-natory behavior. Our results are in agreement withMcGuire et al. (1998), who reported an inverse corre-ation between thought disorder and baseline PET lev-ls in the right middle frontal gyrus (Brodmann area). Our results are also in agreement with behavioraltudies which have linked frontal lobe executive cogni-ive tasks to positive symptoms (Zakzanis, 1998; Mor-ison-Stewart et al., 1992), and previous research has

found a relationship between thought disorder andtests of verbal memory and working memory in pa-tients with schizophrenia (Nestor et al., 1998). Theseresults suggest that unusual thought content, such asdelusional thinking, might interfere with WM-related

FIG. 3—

activation. Previous imaging studies of positive symp- a

toms have generally focused on hallucinations usingspeech or verbal imagery or on formal thought disor-der. These studies have shown that functional andstructural dysfunction is related to deficits in the su-perior and middle temporal gyri (Shenton et al., 1992;

uretsky et al., 1995; McGuire et al., 1996, 1998). Pos-tive symptoms have also been linked to the temporalortex in schizophrenia in rCBF resting state studiesKlemm et al., 1996). In the present study, no activa-ion deficits were found in the STG in patients withchizophrenia. The present study does not access STGunction directly because auditory stimuli were com-letely balanced between WM and control conditions.hus, no relation was found between STG activation

ntinued

nd thinking disturbance, which includes hallucina-

GRH

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442 MENON ET AL.

tory behavior. The evidence in this study for a commonDLPFC neural substrate for working memory andthinking disturbance supports the hypothesis origi-nally proposed by Goldman-Rakic (1987, 1999).

The right DLPFC is thought to be more involved inintentional than incidental memory (Rugg et al., 1997).There has been speculation that the right DLPFC isinvolved in successful memory retrieval (Rugg et al.,1996) and memory retrieval attempt (Wagner et al.,1998). We suggest that thinking disturbance symp-toms, particularly unusual thought content, interferewith the conscious, effortful, processing of the contentsof WM, disrupting activation and impeding cognitiveperformance. These results, together with previousand current findings of right DLPFC deficits underly-ing WM dysfunction in schizophrenia, support the hy-pothesis that WM deficits and thinking disturbancesymptoms share similar neural substrates. There issome evidence to suggest that psychotropic medicationcan cause “hypoperfusion” in patients with schizophre-nia (Sabri et al., 1997), however, subjects in the present

TABLE 3

Results of ANOVA

Effect

Activation intensity

df F P level

roup 1, 22 13.9889 0.0011*OI 4, 88 6.9469 0.0001*emisphere 1, 22 0.4361 0.5159

roup 3 ROI 4, 88 4.4559 0.0025*roup 3 hemisphere 1, 22 9.1992 0.0061*OI 3 hemisphere 4, 88 2.2129 0.0740

roup 3 ROI 3 Hemisphere 4, 88 2.2998 0.0650

FIG. 4. Activation intensity, as measured by mean Z score ineach ROI, in control subjects and patients with schizophrenia.

study were all being treated with a stable dose ofanti-psychotic medication, and therefore it is unlikelythat the present finding of an inverse correlation be-tween right DLPFC and thinking disturbance is due todifferences in medication status. The lack of correla-tion in the DLPFC with withdrawal-retardation isequally notable and warrants further investigation.

Although frontal lobe dysfunction is widely sus-pected to underlie negative symptoms of schizophrenia(Breier et al., 1991), a number of studies have failed tofind specific relation between negative symptoms andperformance on specific cognitive tasks. For example,Morrison-Stewart et al. (1992) failed to find correla-tions between frontal lobe neuropsychological test per-formance and negative symptoms. In their study ofchronic patients with schizophrenia, Wolkin et al.(1992) reported that while the severity of negativesymptoms was a strong predictor of global cognitiveabilities, it was a poor predictor for tasks assessingmemory and planning functions (WCST and CategoryRetrieval). Our results suggest that positive and neg-ative symptoms may be related to specific componentsof cognitive deficits, as correlations with symptom se-verity were regionally specific. Further studies areneeded to investigate the relation between specific cog-nitive operations and specific symptoms in differentbrain regions.

All patients in the present study were medicated,and different types of antipsychotic medication wereused. Possible confounding effects of medication onfMRI activation in specific brain regions is somewhatdifficult to address given the lack of adequate informa-tion in this area. Typical and atypical anti-psychoticmedication have been shown to have different effectson fMRI signal during a motor task (Braus et al., 1999);decreased activation was seen in sensorimotor cortices

FIG. 5. Scatterplot of activation intensity in the right DLPFC, asmeasured by mean Z score and thinking disturbance (positive symp-tom) subscale scores for patients with schizophrenia.

(contra- and ipsilateral) in subjects with schizophrenia

sacncpnmh

bfrcttnnWartbfvd


under stable medication with typical, but not atypical,antipsychotics. There have been few studies of the pre-cise effects of specific drugs on fMRI activation duringcomplex cognitive tasks. In one of the few studies todate, Honey et al. (1999) found that during a WM task,risperidone (an atypical antipsychotic) increased fMRIactivation in right prefrontal cortex, SMA, and poste-rior parietal cortex, compared with a baseline on typi-cal antipsychotic drugs; no such effects were noted inthe patients whose medication status remained un-changed. The increased activity during risperidonetreatment was not associated with improvement inworking memory, perhaps because of the ease of thetask which the patients were already performing atnormal levels while receiving typical antipsychoticdrugs (Meltzer et al., 1999). Only 3 of the 11 patients in

FIG. 6. Scatterplot of activation intensity in the left and rightoperculum, as measured by mean Z score versus withdrawal-retar-dation (negative symptom) subscale scores for patients with schizo-phrenia.

the present study were on typical medication and it is

unlikely that the effects of medication itself are themajor cause of the decreased activation seen in thetarget brain regions in the present study.

Finally, we address limitations and potential exten-sions of the present study. With regard to the scanningacquisition, 4 s per image during a task with a 2-s ISIwould not seem to be ideal sampling of brain activityduring a complex task involving several processes. Theblock design makes this less of an issue, but it is worthpointing out. More rapid event-related approaches arenow needed to determine which basic processes under-lying WM are more affected in schizophrenia. It shouldalso be noted that patients with schizophrenia werealso mildly impaired in the control condition, raisingthe possibility that some of the group differences arisefrom differences in the control, rather than the exper-imental, condition. This is an important issue thatwarrants further investigation. On the other hand, thestrategy taken in the present study was to investigatethe Group 3 ROI 3 Task interaction. This interactionhowed significant effects on both the patterns of brainctivation as well as performance measures (both ac-uracy and reaction time). Given the loud fMRI scan-ing environment, performance of auditory WM taskould be impaired, particularly in a distractible patientopulation. Although the ROIs used in this study areot as precise as parcellation of individual anatomicalaps, the present methodology has strength in being

ighly replicable (e.g., Stevens et al., 1998).In summary, patients with schizophrenia showed

ehavioral deficits and a regionally specific profile ofunctional activation deficits in the prefrontal and pa-ietal cortex regions during WM. No WM related defi-its were found in the anterior cingulate or the superioremporal gyrus. The pattern of activation indicateshat patients with schizophrenia showed the most sig-ificant deficits in neural systems underlying mainte-ance, storage, and rapid updating of the contents ofM components of WM. Deficits in frontal operculum

ctivation were related to the severity of withdrawal-etardation symptoms and deficits in right DLPFC ac-ivation were related to the severity of thinking distur-ance symptoms. Our findings suggest that combiningunctional activation with symptom ratings can pro-ide new insight into the neural correlates of cognitiveeficits in schizophrenia.

ACKNOWLEDGMENTS

This research was supported by the Department of Veterans Af-fairs, grants from NIH (AA05965, AA10723, MH30854, MH58007),and a NARSAD Young Investigator Award to Vinod Menon. Theauthors thank Bill Faustman for patient rating, Christopher Gallo-way for help with demographic data, Jennifer Johnson for assistancewith scanning, Sarah Rawson for help with subject recruitment, and
Margaret Rosenbloom for editorial comments.

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