288

Auditory Working Memory Impairments in Individuals at Familial HighRisk for Schizophrenia

Larry J. SeidmanHarvard Medical School and Beth Israel Deaconess Medical

Center, Boston, Massachusetts

Eric C. MeyerTexas A&M Health Science Center, College of Medicine,

Waco, Texas

Anthony J. GiulianoHarvard Medical School and Tewksbury State Hospital,

Tewksbury, Massachusetts

Hans C. BreiterHarvard Medical School and Northwestern University

Jill M. GoldsteinHarvard Medical School and Brigham and Women’s Hospital,

Boston, Massachusetts

William S. KremenUniversity of California San Diego

Heidi W. ThermenosHarvard Medical School and Beth Israel Deaconess Medical


Rosemary ToomeyBoston University

William S. StoneHarvard Medical School and Beth Israel Deaconess Medical


Ming T. TsuangHarvard Medical School and University of California

San Diego

Stephen V. FaraoneSUNY Upstate Medical University

Objectives: The search for predictors of schizophrenia has accelerated with a growing focus on earlyintervention and prevention of psychotic illness. Studying nonpsychotic relatives of individuals with schizo-phrenia enables identification of markers of vulnerability for the illness independent of confounds associatedwith psychosis. The goal of these studies was to develop new auditory continuous performance tests (ACPTs)

Editor’s Note. Eric Granholm served as the action editor for this arti-cle.—SMR

Larry J. Seidman and Heidi W. Thermenos, Department of Psychia-try, Harvard Medical School, Massachusetts Mental Health CenterDivision of Public Psychiatry, Beth Israel Deaconess Medical Center,Boston, Massachusetts; Eric C. Meyer, Department of Psychiatry andBehavioral Science, Texas A&M Health Science Center, College ofMedicine, Waco, Texas; Anthony J. Giuliano, Department of Psychia-try, Harvard Medical School, and Psychology Department, TewksburyState Hospital, Tewksbury, Massachusetts; Hans C. Breiter, Departmentof Psychiatry, Harvard Medical School, and Department of Psychiatryand Behavioral Sciences, Northwestern University; Jill M. Goldstein,Department of Psychiatry, Harvard Medical School, and Brigham andWomen’s Hospital, Boston, Massachusetts; William S. Kremen, De-partment of Psychiatry, Center for Behavior Genomics, and Institute ofGenomic Medicine, University of California, San Diego; RosemaryToomey, Department of Psychology, Boston University; William S.Stone, Department of Psychiatry, Harvard Medical School, and Mas-sachusetts Mental Health Center Division of Public Psychiatry, BethIsrael Deaconess Medical Center, Boston, Massachusetts; Ming T.Tsuang, Department of Psychiatry, Harvard Medical School, and De-partment of Psychiatry, Center for Behavior Genomics, and Institute ofGenomic Medicine, University of California, San Diego; Stephen V.

Faraone, Departments of Psychiatry and of Neuroscience and Physiol-ogy, SUNY Upstate Medical University.

Poster presentation by Eric C. Meyer, Anthony J. Giuliano, William S.Stone, Stephen J. Glatt, William S. Kremen, Heidi W. Thermenos, StephenV. Faraone, Ming T. Tsuang, and Larry J. Seidman. (2008, June). Auditoryvigilance and working memory in first-degree relatives of individuals withschizophrenia: Development and validation of the Auditory ContinuousPerformance Test (ACPT). Presented at the 6th annual Meeting of theAmerican Academy of Clinical Neuropsychology, Boston, MA.

We thank the patients with schizophrenia and their family members, controlfamilies, and project staff for their generous contributions to the study. Staffincluded Mimi Braude, Joanne Donatelli, Lisa Gabel, Stephen J. Glatt, JenniferKoch, Marc Korczykowski, Erica Lee, Virna Merino, Elon Mesholam, RaquelleMesholam-Gately, Caroline Patterson, Nicole Peace, Maryan Picard, LyndaTucker, Sharon White, and Peter Woodruff. This work was supported by thefollowing: Stanley Medical Research Institute (L.J.S.); National Association forResearch on Schizophrenia and Depression (NARSAD; L.J.S., M.T.T.); MentalIllness and Neuroscience Discovery (MIND) Institute (L.J.S.); MH- 43518 andMH65562 (M.T.T., L.J.S.); MH 63951 (L.J.S.); MH-46318 (M.T.T.); The Com-monwealth Research Center of the Massachusetts Department of Mental Health,SCDMH82101008006 (L.J.S.).

Correspondence concerning this article should be addressed to Larry J.Seidman, PhD, Massachusetts Mental Health Center, NeuropsychologyLaboratory, Commonwealth Research Center, 5th Floor, 75 FenwoodRoad, Boston, MA 02115. E-mail: [email protected]

Neuropsychology © 2012 American Psychological Association2012, Vol. 26, No. 3, 288–303 0894-4105/12/$12.00 DOI: 10.1037/a0027970

288

and evaluate their effects in individuals with schizophrenia and their relatives. Methods: We carried out twostudies of auditory vigilance with tasks involving working memory (WM) and interference control withincreasing levels of cognitive load to discern the information-processing vulnerabilities in a sample ofschizophrenia patients, and two samples of nonpsychotic relatives of individuals with schizophrenia andcontrols. Study 1 assessed adults (mean age ! 41), and Study 2 assessed teenagers and young adults age13–25 (M ! 19). Results: Patients with schizophrenia were impaired on all five versions of the ACPTs,whereas relatives were impaired only on WM tasks, particularly the two interference tasks that maximizecognitive load. Across all groups, the interference tasks were more difficult to perform than the other tasks.Schizophrenia patients performed worse than relatives, who performed worse than controls. For patients, theeffect sizes were large (Cohen’s d ! 1.5), whereas for relatives they were moderate (d ! "0.40–0.50). Therewas no age by group interaction in the relatives—control comparison except for participants #31 years of age.Conclusions: Novel WM tasks that manipulate cognitive load and interference control index an importantcomponent of the vulnerability to schizophrenia.

Keywords: CPT, working memory, schizophrenia, relatives, adolescence

The Importance of Neurocognition in Schizophreniaand the Family High Risk Approach

Schizophrenia is a serious, neurodevelopmental disorder with amultifactorial etiology, including both environmental and geneticinfluences (Tsuang, Stone & Faraone, 1999). Family, twin, andadoption studies provide strong evidence for a spectrum of disor-ders in which schizophrenia is the most severe expression of anillness that includes nonpsychotic features such as neurocognitivedeficits in addition to positive symptoms of psychosis (Faraone,Green, Seidman & Tsuang, 2001; Gottesman & Gould, 2003).Neurocognitive dysfunction has come to be regarded as a corecomponent of the disorder (Barch, 2005; Heinrichs & Zakzanis,1998; Seidman, 1983), supporting the original ideas of Kraepelin(1919) and Bleuler (1911) regarding the central role of cognitivedeficits. Neurocognitive dysfunctions are observed in the majorityof people with the illness and in all phases of the illness (Keefe,Beasley & Poe, 2005; Kremen, Seidman, Faraone, Toomey, &Tsuang, 2000; Palmer et al., 1997; Wilk et al., 2005). Amongpeople with schizophrenia, neurocognitive deficits aggravate over-all levels of disability and worsen functional outcomes (Green,1996; Green, Kern, Braff & Mintz, 2000). Moreover, the relativelymodest improvement in neurocognition after antipsychotic treat-ment (Harvey & Keefe, 2001; Mishara & Goldberg, 2004) sug-gests that neurocognitive impairments are largely independent ofpsychosis, thus underscoring the pressing need for effective inter-ventions to address cognitive impairments (Buchanan et al., 2011;Eack et al., 2010).

The “genetic” or family high-risk (FHR) approach is based onthe fact that genetic influences are among the best-established riskfactors for schizophrenia, with heritability estimated at approxi-mately 60–90% (Gottesman, 1991). Nonpsychotic first-degree rel-atives of people with schizophrenia, who on average share 50% ofgenes with their ill relatives, are typically unmedicated and free ofother confounds associated with psychosis. Thus, studying non-psychotic relatives provides a high fidelity window into under-standing the influence of genes on the pathophysiology of schizo-phrenia. Further, studying relatives at different time points (i.e.,during and after the peak risk for psychosis from ages 18–30)allows for identification of markers associated with vulnerabilityand risk in youth versus resilience among people who have passedthrough the peak risk period. Studying younger relatives (i.e., #age 31) provides an additional opportunity to identify develop-

mental differences present before the typical age of onset ofschizophrenia that may aid in predicting psychosis.

Neurocognitive dysfunctions are well documented in studies ofadult nonpsychotic relatives (ages 30–70) (Gur et al., 2007; Kre-men et al., 1994; Sitskoorn, Aleman, Ebisch, Appels & Kahn,2004; Snitz, McDonald & Carter, 2005; Szöke et al., 2005; Tran-dafir, Meary, Schurhoff, Leboyer & Szoke, 2006). In brief, meta-analyses document that adult relatives manifest deficits on tasks ofsustained attention, declarative and working memory, perceptual-motor speed, verbal fluency, and executive functions (EFs), usuallyintermediate between persons with schizophrenia and controls (Sits-koorn, Aleman, Ebisch, Appels & Kahn, 2004; Snitz, McDonald &Carter, 2005; Szöke et al., 2005; Trandafir et al., 2006). Thedeficits in executive control processes and memory dysfunctionsare stable over time in adulthood (Faraone et al., 1999) and areassociated with degree of genetic loading (Faraone et al., 2000).Overall, this literature suggests a common difficulty in high-loadexecutive control processing across tasks during adulthood (Corn-blatt & Keilp, 1994; Nuechterlein & Dawson, 1984).

A substantial literature examines cognitive measures amongyounger relatives, usually offspring # age 31 years. There are atleast 30 FHR studies indicating results comparable with that ob-served in older relatives in similar cognitive domains (reviewed inAgnew-Blais & Seidman, in press; Keshavan et al., 2010; Niemi,Suvisaari, Tuulio-Henriksson & Lonnqvist, 2003; Seidman et al.,2006). Relevant to the current study, vigilance or sustained atten-tion on high-load visual information processing tasks remainsconsistently impaired throughout late childhood and adolescencein those who go on to develop schizophrenia (Cornblatt, Winters &Erlenmeyer-Kimling, 1989). High loads of information and/orspeed of processing demands are common to tests that have thelargest effect sizes (ESs) in patients and relatives, such as digitsymbol/coding or story memory free recall (Dickinson, Ramsey, &Gold, 2007; Heinrichs & Zakzanis, 1998; Mesholam-Gately et al.,2009).

Comparing neuropsychological deficits among adolescents ver-sus older relatives is an important strategy for a number of reasons.First, samples of young relatives who have not passed through thepeak age of risk for psychosis (# age 31) may contain some futurecases, whereas those $ age 30 have significantly lower risk ofdeveloping schizophrenia. Thus, cognitive impairments may begreater compared with controls in younger relatives. Second, the

289AUDITORY WORKING MEMORY IN SCHIZOPHRENIA

efficient processing of certain high load tasks such as workingmemory tends to peak in the 20’s in the normal population (Luna,Padmanabhan, & O’Hearn, 2010). Therefore, it is important todetermine whether those at FHR show a similar developmentaltrend or whether development of this function may be disrupteddifferentially in youth at FHR compared with older relatives.Finally, studying premorbid differences may identify predictors ofillness and inform targets for prevention or early intervention.

Development of Novel Auditory ContinuousPerformance Tasks (CPTs) to Identify Key

Neurocognitive Vulnerabilities for Schizophrenia

Vigilance

Problems in vigilance and sustained attention have long beenconsidered key impairments in schizophrenia (Cornblatt, Risch,Friedman & Erlenmeyer-Kimling, 1988; Mirsky, Anthony, Dun-can, Ahern, & Kellam, 1991; Nuechterlein & Dawson, 1984;Seidman, 1983). Vigilance is a “state of readiness to detect andrespond to certain small changes occurring at random time inter-vals” (Mackworth, 1948). Vigilance tasks require subjects to sus-tain their attention to subtle sensory signals, to minimize distract-ibility to irrelevant stimuli, and to maintain alertness over time.

Vigilance tasks vary according to stimulus sensory modality,complexity, rate of presentation, signal probability, response type,sensory clarity, and memory load (Parasuraman & Davies, 1977).These task parameters can be systematically varied to tax thelimited processing capacity of attention (Kahneman, 1973; Nor-man & Bobrow, 1975). Overload of information (i.e., that whichrequires very “effortful” processing; Beatty, 1982) can be inducedby increasing working memory (WM) load, dividing attention(e.g., as in dichotic listening or shadowing tasks), increasinginterference, or decreasing stimulus clarity. For example, the orig-inal Continuous Performance Test (CPT; Rosvold, Mirsky, Sara-son, Bransome, & Beck, 1956), a widely used vigilance task, hasbeen made more demanding by degrading the sensory clarity of thestimulus (Nuechterlein, Parasuraman & Jiang, 1983; Seidman, VanManen et al., 1998) or by increasing memory load to burdenworking memory (WM) CPTs (Braver et al., 1997; Cohen et al.,1994; Cornblatt, Risch, Faris, Friedman & Erlenmeyer-Kimling,1988). Because several visual CPTs had already been developed,we developed an auditory CPT (ACPT) battery to complementthese tasks and that could be used in subsequent studies involvingdirect comparisons with visual CPTs (Makris et al., 2008) todetermine differential sensitivity. We were also motivated byaccumulating data pointing to deficits in auditory processing inschizophrenia, that is, that auditory processing areas of the tem-poral lobes (Heschls gyrus and the superior temporal gyrus) aredysfunctional in schizophrenia (Hirayasu et al., 2000), that deficitsin abnormal auditory event related potentials (ERPs) includingP300 are prominent (Jeon & Polich, 2003), and that auditorystimuli used in prepulse inhibition (Braff et al., 1978), P50 (Adleret al., 1982), and mismatch negativity (Michie, 2001) experimentsyield abnormal ERPs in individuals with schizophrenia and theirfirst-degree relatives.

Working Memory

WM refers to a set of processes involving temporary storage andmanipulation of information for use in various cognitive opera-tions (Baddeley, 1986; Baddeley & Hitch, 1994; Goldman-Rakic,1987). The information to be retrieved or manipulated must beretained in spite of interference from internal or external distrac-tions (Fuster, 1989; Gevins et al., 1996). WM tasks involve a“central executive” or “supervisory attentional system” that istapped by CPT tasks requiring manipulation and continuous cog-nitive updating (D’Esposito et al., 1995; Wager & Smith, 2003).

Several auditory-verbal WM tasks have previously been used instudies of patients with schizophrenia and relatives, such as theletter number-sequencing task (Gold, Carpenter, Randolph, Gold-berg & Weinberger, 1997; Horan et al., 2009) and dichotic listen-ing tasks (Faraone et al., 1995). However, these tasks involveshort-term storage, which is subserved by somewhat differentneural substrates than executive WM tasks that require continuouscognitive updating over several minutes (Wager & Smith, 2003).Auditory WM tasks that involve competing information, such asdichotic listening (Faraone et al., 1995) or dichotic shadowing(Spring, 1985), successfully discriminate the performance of rel-atives from controls. These findings encouraged us to developupdating tasks in which competing information (i.e., “interfer-ence”) increases task demands within a continuous cognitive up-dating (i.e., CPT) framework.

In developing effortful ACPTs, we chose to increase both WMload and interference control demands because, whereas personswith schizophrenia have global attention problems (Nuechterlein& Dawson, 1984; Seidman, 1983), their first-degree relativesexhibit impairment only on more demanding attention tasks (Corn-blatt & Keilp, 1994). Both patients and nonpsychotic relativesexhibit deficits in WM (Goldman-Rakic, 1991; Lee & Park, 2005;Park, Holzman & Rakic, 1995). Finally, tasks had to be difficultenough to be sensitive indicators of risk in unaffected relatives butnot too difficult for patients to perform. Thus, we created a seriesof information processing tasks along a continuum of difficulty tomaximize the potential for group differentiation.

Principles of Task Design

In addition to behavioral studies, these ACPTs were designedfor blocked design functional MRI (fMRI) applications that re-quire comparison of a “target experimental” task with a “baselinecontrol” task. Therefore, all task conditions were closely matchedon multiple parameters including the following: auditory sensorymodality, stimuli (letters), target response signal (the letter “A”),warning/cue signal (the letter “Q”), rate of presentation (one letter/second), and sensory clarity. The differences between task condi-tions were the parameters of interest: degree of WM and interfer-ence load. WM load was defined as the number of letters betweenthe warning/cue and the target. Level of interference was definedby the number of distracters (“Qs” and “As”) embedded betweenthe cue and the target. The initial paradigms were designed toevaluate block (time) effects by directly matching them as alter-nating epochs in one experimental presentation (see Figure 1a).The WM and interference tasks had additional requirements forparticipants to keep in mind both the identity and order of previ-ously presented letters and to continuously update the mentalrecord as the sequence of letters progressed.

290 SEIDMAN ET AL.

Procedures

For the initial study, we developed five versions of the ACPTnamed “A” and “QA” (vigilance), “Q3A-MEM” (high WMload/no interference), “Q1A-INT” (low WM load/low interferenceload), and “Q3A-INT” (high WM load/high interference load).Each task consisted of a baseline and target condition presented inan A-B-A-B format (see Figure 1a). In each condition, letters ofthe alphabet were presented monaurally at a rate of one per secondfor four blocks of 90 sec. Subjects were required to respond to alltarget stimuli by lifting their index finger. The simplest targetvigilance condition required subjects to respond to each “A” (i.e.,the A task). The next target vigilance condition required subjectsto respond to each A only if immediately preceded by a Q (i.e.,QA), a typical successive discrimination AX CPT (Cohen, Barch,Carter, & Servan-Schreiber, 1999; Rosvold, Mirsky, Sarason,Bransome, & Beck, 1956). Target probability and frequency of“lure” stimuli (individual “As” or “Qs” not constituting a QAcombination) are listed in Figure 1b. For interference tasks, thesestimuli were periodically inserted between warning Qs and targetAs interspersed with randomly selected letters of the alphabet.

In the target condition for the “Q1A-INT” task (AX CPT withinterference), subjects responded to each A when preceded by a Qseparated by one letter (e.g., Q R A), with some Q-A trialscontaining interspersed “Qs” or “As” (Figure 1b). There were twoversions of the increased memory load CPT in which the warning(Q) and target (A) stimuli were separated by three letters (“Q3A-MEM” and “Q3A-INT”). In the target condition for the “Q3A-MEM” task, subjects responded to each A when preceded by a Qseparated by three letters (e.g., Q R C T A), and there were neverQs or As between the Q (warning) and A (target) (i.e., no “inter-ference”). In “Q3A-INT,” like Q3A-MEM, randomly selectedletters of the alphabet were interspersed throughout the block,including freestanding Qs and As alone. To make the task moredifficult, combinations of the letters, Q, A, or QA were periodi-cally embedded in between the Q and the target A. For example,some of the embedded stimuli strings were like the following: “QQ c q A A b r.” In this example, capital Qs and As are cues andtargets, respectively, whereas the lower case “q” is a distracter.Trials with interspersed Q’s and interleaved series were designedto produce distraction, divide attention, and prevent counting be-

Figure 1. a: Experimental design and continuous performance task stimuli task design. b: ACPT task stimuli,instructions, response, and design for Study 1 and 2.


cause the subject was episodically required to maintain two sep-arate tracks simultaneously (e.g., constant updating of identifica-tion of stimuli from memory).

Previous Work

In initial fMRI studies, we demonstrated that two cohorts ofhealthy male volunteers performed significantly worse on theQ3A-INT task compared with a simple vigilance QA task (Seid-man et al., 1998). In and outside the scanner, the vigilance task wasperformed virtually without error, whereas the more demandingWM condition did not show ceiling effects, despite the higheducation and level of intelligence of the participants. In fMRIstudies, these two tasks were subsequently used, respectively, asbaseline (vigilance) and experimental (WM plus interference) teststo elicit group differences in fronto-subcortical circuitry betweennonpsychotic relatives of individuals with schizophrenia and con-trols (Seidman et al., 2007; Thermenos et al., 2004). In two smallsamples of approximately 10–15 subjects per group, relativesdemonstrated impaired performance during scanning on theWM % interference task (Q3A-INT). In this article, we present forthe first time a detailed analysis of performance on the entirebattery of ACPT tasks in persons with schizophrenia, first-degreerelatives, and healthy controls using two independent samples ofparticipants at substantially different ages to assess for age effects.

Study Goals

The auditory tests were designed to tap these putatively funda-mental cognitive deficits in schizophrenia (i.e., the effects ofWM % interference) to serve as potential endophenotypic markersfor the illness (Tsuang, Seidman & Faraone, 1999). These noveltasks could ultimately be used in future studies to track the prob-able increase in neurocognitive impairment from the premorbidthrough the prodromal period and the first episode of psychosisthat often characterizes schizophrenia (Seidman et al., 2010). Wealso designed these tasks to be effectively adapted for fMRIexperiments (Goldstein et al., 2005; Seidman et al., 1998; Seidmanet al., 2007; Thermenos et al., 2004).

To achieve these goals, we carried out two studies. First, weconducted a study in a sample of adult patients with schizophrenia,their nonpsychotic first-degree relatives, and matched healthy con-trols using five ACPT task conditions with varying levels ofdifficulty/load (Study 1). Next, we sought to replicate the Study 1findings with a younger, independent FHR sample. Because theWM plus interference tasks clearly discriminated patients andrelatives from controls in Study 1 and our aim was to developmeasures of risk for psychosis, in Study 2 we focused solely on thecomparison between relatives and controls and did not evaluate asecond sample of patients with schizophrenia. Based on the resultsof Study 1, in Study 2, we used a shorter version of the ACPTbattery consisting of three task conditions with an adolescentsample of nonpsychotic relatives and matched controls. Studies 1and 2 are complementary in terms of examining the influence ofage, as the relatives in Study 1 are largely older than 30 (M !41.0), whereas the relatives in Study 2 are all #26 years of age(M ! 19.4). We subsequently analyzed the combined data sets ofboth studies to assess the effects of age on condition and group,

and also to study the age by group interaction in our largest sampleof relatives #31 years of age.

Based on the literature indicating that high load tasks are mostsensitive in eliciting deficits in relatives of persons with schizo-phrenia, our overarching hypothesis was that the two interferenceWM tasks would be most sensitive to the presumed vulnerabilityto schizophrenia observed in first-degree relatives. Thus, we ex-pected to demonstrate task condition, group, and group by condi-tion interaction effects in which patients with schizophrenia wouldbe most impaired compared with controls, and relatives wouldshow milder deficits.

Study 1

Participants

Subjects were 20 patients with Diagnostic and Statistical Man-ual of Mental Disorders (DSM)–III–R diagnoses of schizophrenia,63 nonpsychotic, first-degree relatives of patients with DSM–III–Rdiagnoses of schizophrenia, and 56 healthy controls. All subjectsgave informed consent, and the study was approved by the Insti-tutional Review Boards at the Massachusetts Mental Health Center(MMHC), Brockton Department of Veterans Affairs Medical Cen-ter, Massachusetts General Hospital (MGH), and Harvard MedicalSchool (HMS). The subjects were part of previous studies (Fara-one et al., 2000; Seidman et al., 2002), but the ACPT data have notbeen previously published except for a subset of the tests (QA andQ3A-INT) in approximately 30% of the relatives and controlsparticipating in neuroimaging studies (Seidman et al., 2007; Ther-menos et al., 2004). Participants in this study were excluded if theyhad a diagnosis of substance abuse or dependence within the pastsix months, neurological disease, history of head injury or medicalillness with documented cognitive sequelae, sensory impairments,IQ less than 70, or fewer than eight years of formal education.Relatives and controls were included if they had no lifetimediagnosis of psychotic illness. As previously described (Faraone etal., 1995; Seidman et al., 2002), control participants were recruitedthrough advertisements in the same geographic catchment areas asthe hospitals from which the patients were recruited.

Procedures: Diagnostic and Personality Assessment

Patient diagnoses were derived from structured interviews usingthe Schedule for Affective Disorders and Schizophrenia (SADS,Spitzer & Endicott, 1978), review of the medical record, andclinician information. Two expert clinicians, unaware of the neu-ropsychological data, reviewed all available information to deter-mine consensus lifetime diagnoses. Relatives were interviewedwith the Structured Clinical Interview for DSM–III–R (SCID)(Spitzer et al., 1987) for Axis I disorders and the StructuredInterview for DSM–III Personality Disorders (SIDP) (Stangl &Zimmerman, 1983). The substance use section of the SADS wasused to screen for presence of substance abuse. Potential controlsunderwent a similar screening process as the relatives and patients,with the exception that they were assessed for current psychopa-thology using a short form of the Minnesota Multiphasic Person-ality Inventory (MMPI) (MMPI-168; Vincent et al., 1984) ratherthan a structured diagnostic interview. Controls were excluded ifthey reported a personal or family history of psychosis or psychi-

292 SEIDMAN ET AL.

atric hospitalization, or if any MMPI clinical or validity scale,except for Masculinity-Femininity, was above a T score of 70. Thereading subtest of the Wide Range Achievement Test–revised(WRAT-R; Jastak & Jastak, 1985) was used as an estimate ofintellectual ability (Kremen et al., 1996).

Data Analysis

Continuously distributed demographic variables such as age,education, WRAT-3 Reading, and parental education (the mean ofboth parents’ years of education or one parent’s years of educationwhen only one parent’s data were available) were comparedamong groups using analysis of variance (ANOVA). Sex andethnicity were compared using chi-square tests. The dependentmeasures reported are correct hit rates and signal detection indices(“d prime” or d&’). d& is a measure of efficiency that takes intoaccount both hit and false alarm rates (Green & Swets, 1966). Thecorrelations between hit rates and d& were high, ranging from .90to .98. Because age was expected to influence performance, agewas used as a covariate in all analyses except those assessing ageby group interactions. We assessed the relationship between ACPTperformance and sample characteristics using the Pearsonproduct–moment correlation to determine whether the use of ad-ditional covariates was warranted.

As stated previously, our a priori hypotheses were that therewould be directional effects of task Condition (WM interferencetasks would yield lower performance), Group effects (patientswould perform worst, followed by relatives, compared with con-trols), and a Group by Condition interaction (WM interferencetasks would produce the biggest impairments, especially in therelatives—controls comparison). For these a priori directionalcomparisons, we used p # .05 (one-tailed) as the significancelevel. We also studied the Time (block) effect in exploratoryanalyses, using p # .01 for these contrasts (two-tailed, as nospecific hypotheses were formulated, and multiple comparisonswere conducted). We examined the main effects of Group (schizo-phrenia, relatives, controls), Condition (five task conditions as inFigure 1a), and Time (i.e., whether performance changed acrossthe two blocks for each task condition), and the interactions usingANOVA and ANCOVA. Next, we conducted simple pairwiseANOVAs for each task Condition, collapsed across trials. Only thefirst two (of eight) QA blocks were analyzed to maintain compa-rability with the other conditions, each of which was administeredtwice (see Figures 1a). ESs were calculated for each pairwisecomparison with Cohen’s d (mean of the control group minus

mean of the case group divided by the pooled standard deviation,Cohen, 1988). Adjusted ESs were also calculated using age as acovariate.

Results

Sample Characteristics

Table 1 presents sample characteristics. Participants ranged inage from 20 to 75 years, and age did not differ across groups.There were significantly fewer males among the relatives than theschizophrenia and control groups. The sample was primarilyWhite, and the control group had a significantly higher proportionof White participants than the schizophrenia and relatives groups.Controls had significantly more years of education than the schizo-phrenia and relatives groups. However, the groups did not differ inparental education, which may be viewed as a proxy for SES.Controls exhibited higher WRAT-R Reading scores than the rel-atives. Age was not associated with performance on A or QA butwas negatively associated with Q3A-MEM (r ! '.27, p # .005)and Q3A-INT (r ! '.26, p # .005). Parental education wasassociated with Q1A-INT (r ! .19, p # .05) and Q3A-INT (r !.21, p # .05). Sex was not associated with ACPT performance.Non-White race was negatively associated with performance onQ1A-INT only (r ! '.18, p ! .038). Because race differed acrossgroups and was also associated with performance on the ACPT, itwas used as a covariate in addition to age.

Tests of a Priori Hypotheses

Task condition. Table 2 gives the results of the ANOVAsand ANCOVAs. There was a significant main effect of taskCondition, which remained significant after covarying age andrace. Post hoc contrasts for d& indicated that performance onQ3A-INT was lower than performance on all other conditions(ps # .001). Performance on Q1A-INT was lower than all otherconditions (ps # .001) except Q3A-INT. Performance on Q3A-MEM was lower than QA and A (ps # .001). Performance on QAdid not differ from A. This linear trend is apparent in all threegroups (see Figure 2 and Table 3).

Group. There was a main effect of Group that remainedsignificant after covarying age and race. The schizophrenia groupperformed worse than relatives (p # .001) and controls (p #.001). Relatives performed worse than controls (p ! .034).

Table 1Sample Characteristics for Study 1

Schizophrenia(n ! 20)M (SD)

Relatives(n ! 63)M (SD)

Normal control(n ! 56)M (SD)

Test statistic(p value)

Age 43.2 (8.3) 41.0 (11.2) 43.2 (12.8) F ! 0.62 (.540)Subject education 12.3 (2.1) 13.2 (2.6) 15.1 (2.2) F ! 15.25 (#.001)Parental educationa 12.1 (2.7) 11.6 (3.0) 11.5 (2.8) F ! 0.26 (.771)WRAT-3 reading 99.7 (17.5) 98.8 (13.0) 105.5 (12.4) F ! 3.79 (.025)Sex % male (n) 65.0 (13) 31.7 (20) 50.0 (28) (2 ! 8.24 (.016)Race % white (n) 75.0 (15) 81.0 (51) 92.9 (52) (2 ! 6.46 (.040)

a SZ (schizophrenia) n ! 16; Rel (Relatives) n ! 60; NC (normal controls) n ! 53.


Group ! Condition. The interaction between Group andCondition was significant. This interaction remained significantafter covarying age and race. ESs controlling for both age and raceare not shown because the results are very comparable with con-trolling for age alone. Simple pairwise comparisons and ESs bygroup and task condition are presented in Table 3.

Schizophrenia versus control. As expected, the schizophre-nia group performed significantly worse than controls on all taskconditions. Unadjusted ESs were large, ranging from 0.87 to 1.60.These effects remained significant with large effects across all taskconditions after controlling for age and race (ds from 1.11 to 1.87).

Schizophrenia versus relatives. The schizophrenia groupperformed significantly worse than the relatives on all task condi-

tions. Unadjusted ESs were large, ranging from 0.80 to 1.32. Theselarge effects remained significant across all conditions after con-trolling for age and race (ds from 0.83 to 1.74).

Relatives versus controls. The relatives did not differ fromcontrols on A or QA. On Q3A-MEM, relatives performed worseon d& after adjusting for age (d ! 0.35) but not on hit rate. Aspredicted, relatives performed significantly worse than controlson the two interference tasks. On Q1A-INT, d& (d ! 0.46) andhit rate (d ! 0.38) both remained significant after covarying ageand race. On Q3AINT, relatives performed worse than controls(d ! 0.36 for d&, d ! 0.43 for hit rate). This remained signif-icant after covarying age (d ! 0.51 hit rate, d ! 0.43for d&).

Table 2Results of Condition ) Group Analyses for the Auditory Continuous Performance Test forStudy 1

Conditiona

F(p)Groupa

F(p)Condition ) Groupa

F(p)

Correct hit % 301.37 (#.001) 30.57 (#.001) 3.90 (#.001)Correct hit % (adjusted for age) 13.04 (#.001) 32.51 (#.001) 4.24 (#.001)Correct hit % (adjusted for age and race) 2.29 (!.003) 30.32 (#.001) 3.36 (#001)d& ANOVA 338.02 (#.001) 33.37 (#.001) 2.55 (!.005)d* ANCOVA (adjusted for age) 16.10 (#.001) 35.12 (#.001) 2.86 (!.002)d* (adjusted for age and race) 4.71 (#.001) 32.75 (#.001) 2.24 (!.012)

Note. Results of three-way ANOVAs and ANCOVAs with two within-subjects variables (five task conditions,two trials per condition) and one between-subjects variable (three groups). Interactions with Time are not shownas they were not statistically significant. d& is a measure of efficiency that takes into account both hit and falsealarm rate.a Analyses evaluated at p # .05 (one-tailed).

Figure 2. Study 1: Hit rates for ACPT by group and task condition. The A and QA task conditions are vigilancetasks. Q3A-MEM is a working memory task. Q1A-INT combines low levels of working memory andinterference control. Q3A-INT combines working memory and a high level of interference control. NC !Normal Control; Rel ! Relatives; SZ ! Schizophrenia.

294 SEIDMAN ET AL.

Exploratory Analyses

None of the exploratory analyses examining hit rate or d&reached the significance level of p # .01 after controlling for ageand race. Of note, for the Time ) Group interactions, in whichthere was a marginal trend (overall analyses p # .024, two-tailed),the performance of the schizophrenia group did not differ acrosstrials, whereas the performance for both the relatives and controlsimproved from Trial 1 to 2 (both ps # .001).

Study 2

Participants

Study 2 data were collected as part of the Harvard AdolescentFamily High Risk Study between 1998 and 2007. This sampleand its ascertainment procedures were described previously(Seidman et al., 2006). In brief, participants for this study werethe biological children and siblings of schizophrenia probands(our FHR sample), and the biological children and siblings ofcommunity control probands. All participants were between theages of 13 and 25 at the time of their ACPT assessment. TheFHR group comprised 41 children and siblings of adult pro-bands (at least 18 years of age) diagnosed according to DSM–IVcriteria with either schizophrenia or schizoaffective disorder,depressed type, using the Diagnostic Interview for GeneticStudies (DIGS; Nurnberger et al., 2004) and the Family Inter-view for Genetic Studies (FIGS; Maxwell, 1996). The controlgroup comprised 55 children of parents diagnosed according toDSM–IV criteria with no mental illness (n ! 25), major depres-sive disorder (n ! 8), mood disorder attributable to a generalmedical condition (n ! 1), or cannabis abuse (n ! 1) using theDIGS and FIGS. The adult control probands were drawn fromrespondents to local newspaper advertisements and announce-ments posted in the sites from which FHR probands wererecruited (e.g., local hospital and clinics). The children andsiblings of probands were subsequently ascertained to deter-

mine their eligibility and willingness to participate as subjectsin the study.

Exclusion criteria were similar to Study 1. FHR participantswere excluded if they had any lifetime diagnosis of psychoticillness, substance dependence, or neurological disease, a history ofhead injury or medical illness with documented cognitive sequelae,sensory impairments, current psychotropic medication use, or afull-scale IQ estimate of less than 70 based on eight subtests of theWISC–III (Wechsler, 1991) or WAIS-III (Wechsler, 1997). Par-ticipants in the control group were screened with the same criteria,with an additional exclusion criterion of any first- or second-degree biological relatives with lifetime history of a psychoticdisorder. Offspring and siblings of control and schizophrenia pro-bands were screened for presence of psychosis with the Washing-ton University Kiddie SADS (KSADS; Geller, Zimmerman, Wil-liams & Frazier, 1994). The Psychosis, Substance Abuse andMood Disorders modules of the WASH-U-KSADS were admin-istered along with a Neurodevelopmental Questionnaire (Faraoneet al., 1995) to establish other inclusion and exclusion criteria. Thereading subtest of the Wide Range Achievement Test–third edition(WRAT-3; Wilkinson, 1993) was used as an estimate of intellec-tual ability.

Participants age 18 and older gave informed consent, whilesubjects younger than 18 years of age gave assent in conjunctionwith informed consent provided by a parent. Subjects received anhonorarium. The study was approved by the human researchcommittees of the MMHC, MGH, HMS, and other recruitmentsites.

Measures and Procedures

The ACPT task battery was modified slightly from Study 1 inthe following ways: Only the “QA,” “Q3A-MEM,” and “Q3A-INT” task conditions were administered to shorten the batterybased on data that “A” and “QA,” and “Q1AINT” and “Q3AINT,”respectively, had comparable discriminating utility in Study 1.Although the tasks contained the identical stimuli as in Study 1,

Table 3Task Performance and Effect Sizes by Group and Task Condition for the Auditory Continuous Performance Test for Study 1

Task conditionSchizophrenia

M (SD)RelativesM (SD)

Normal controlsM (SD)

Schizophrenia vs.Normal control

Schizophrenia vs.Relatives

Relatives vs.Normal control

da db da db da db

A correct hit % .87 (.16) .99 (.02) .98 (.05) 0.87!!d 1.11!!! 0.99!!d 1.42!!! 0.24 0.29QA correct hit % .83 (.19) .98 (.03) .98 (.03) 1.10!!!d 1.51!!! 1.09!!d 1.50!!! 0.03 0.03Q3A-MEM correct hit % .64 (.26)c .84 (.13) .87 (.13) 1.14!!! 1.39!!! 1.00!!! 1.21!!! 0.22 0.29Q1A-INT correct hit % .59 (.22)c .81 (.15) .87 (.13) 1.53!!! 1.81!!! 1.17!!! 1.28!!! 0.38! 0.41!

Q3A-INT correct hit % .39 (.21) .53 (.15) .60 (.18) 1.13!!! 1.21!!! 0.80!!! 0.83!! 0.43! 0.51!!

A d& 3.54 (.75) 4.19 (.24) 4.17 (.24) 1.13!!! 1.44!!! 1.16!!! 1.52!!! 0.07 0.07QA d& 3.35 (.85) 4.18 (.26) 4.24 (.23) 1.42!!! 1.87!!! 1.32!!! 1.74!!! 0.23 0.22Q3A-MEM d& 2.75 (.91)c 3.53 (.53) 3.68 (.48) 1.27!!! 1.55!!! 1.05!!! 1.24!!! 0.29 0.35!

Q1A-INT d& 2.49 (.79)c 3.32 (.64) 3.60 (.58) 1.60!!! 1.78!!! 1.14!!! 1.18!!! 0.46!! 0.50!!

Q3A-INT d& 1.79 (.70) 2.48 (.47) 2.67 (.56) 1.38!!! 1.56!!! 1.16!!! 1.28!!! 0.36! 0.43!

Note. Means and standard deviations are unadjusted. d ! Cohen’s d. d& is a measure of efficiency that takes into account both hit and false alarm rate.a p values based on planned contrasts (unadjusted). b p values based on ANCOVAs controlling for age. Cohen’s d based on least squared means. c n !18 because of missing data. d p values based on t test with unequal variance.! p # .05. !! p # .01. !!! p # .001 (one tailed).


one of the blocks of QA was eliminated (we had administeredeight blocks of QA task in Study 1), as data analysis by blockshowed no change over time on QA performance (See Figure 1a,Tasks 5A–8A). Otherwise, stimuli were the same and the admin-istration identical to Study 1.

Data analysis. Data analytic procedures were similar toStudy 1. Continuously distributed demographic variables (age,education, WRAT-3 Reading, parental SES as measured by theHollingshead (1975) four factor scale) were compared betweengroups using ANOVA, while sex and ethnicity were comparedusing chi-square tests. Age was used as a covariate in all analyses.The main dependent measures were hit rate and d&. The correla-tions between d& and raw hit rates ranged from .89 to .97.

We hypothesized that there would be directional Conditioneffects (WM interference tasks would be performed worst), Groupeffects (relatives would be impaired compared with controls), anda Group by Condition interaction (the Q3A-INT task would pro-duce the largest impairment in the relatives). For these compari-sons we used p # .05 (one-tailed) as the significance level. Wealso studied the Time effect in exploratory analyses, using p # .01for these contrasts (two-tailed as no specific hypotheses had beenformulated and multiple comparisons were conducted). We exam-ined the main effects of Group (relatives, controls), Condition(three task conditions), and Time (i.e., whether performancechanged across the two blocks for each task condition) and theinteractions using ANOVA and ANCOVA. Next, we conductedsimple pairwise ANOVAs for each task condition, collapsedacross trials. As in Study 1, only the first two QA trials wereanalyzed. Adjusted and unadjusted ESs were calculated for eachpairwise comparison, with age as a covariate.

Results

Sample Characteristics

Sample characteristics are presented in Table 4. Participantsranged in age from 13 to 25; the FHR relatives were significantlyolder than controls. The sample was evenly split in terms of sex,and the groups did not differ on race or years of education.Controls reported higher parental SES. There was a marginal trendfor normal controls having higher WRAT-3 Reading scores. Agewas associated with performance on Q3A-INT (r ! .22, p # .05).Parental SES was associated with performance on Q3A-MEM(r ! .35, p # .05) and Q3A-INT (r ! .41, p # .001).

Tests of a Priori Hypotheses

Task condition. The results of ANOVAs and ANCOVAs arepresented in Table 5. There was a significant main effect of taskCondition, which remained significant after covarying age. Posthoc contrasts conducted on d& indicated that performance onQ3A-INT was lower than performance on Q3A-MEM, which waslower than performance on QA (ps # .001). This linear trend isapparent in both groups (see Figure 3).

Group. There was a significant effect for both hit rate and d&.The relatives performed significantly more poorly than controlsafter adjusting for age.

Condition ! Group. There was a significant interactionbetween Condition and Group for hit rate and a nonsignificanttrend for d& (p ! .059). Simple pairwise comparisons and ESs bygroup and task condition are presented in Table 6. The relativesand controls did not differ on QA. On Q3A-MEM, relativesperformed worse than controls on hit rate and d& after covaryingage. On Q3A-INT, relatives performed significantly worse thancontrols after covarying age on both hit rate and d*, and the ES wasgreater after covarying age than before.

Exploratory analyses. None of the exploratory analyses(Time, Time ) Condition, Time ) Group, Time ) Group )Condition) reached the significance level of p # .01 for either hitrate or d& after age was controlled.

Ability of Task Conditions to Discriminate BetweenRelatives and Controls in the Combined Sample

Logistic regression examined the ability of the different taskconditions to differentiate between relatives and controls in thecombined sample (relatives n ! 104; controls n ! 111). Q3A-INThit rate was a significant predictor of group status (B ! 2.41, SE !0.83, p ! .004, 95% CI ! 2.18–56.82), correctly classifying58.6% of participants. Neither QA nor Q3A-MEM was a signifi-cant predictor of group membership, and adding them did notincrease the predictive validity of the model nor attenuate signif-icant results. To determine whether these findings were accountedfor by a generalized deficit in cognition, we examined whetherQ3A-INT would continue to be a significant predictor of groupmembership after covarying scores on WRAT-3 Reading.WRAT-3 Reading is a general measure of intellectual abilityshown to differentiate between relatives and healthy controls(Agnew-Blais & Seidman, in press), was significantly different inour combined sample, and was moderately associated with Q3A-INT

Table 4Sample Characteristics for Study 2

Relatives (n ! 41)M (SD)

Normal controls (n ! 55)M (SD) Test statistic (p)

Age 19.4 (3.8) 17.0 (3.6) F ! 10.31 (.002)Subject education 11.4 (2.7) 10.8 (3.3) F ! 1.15 (.287)WRAT-3 reading SS 102.5 (10.3) 106.6 (9.5) F ! 3.87 (.052)Hollingshead (SES) 38.8 (16.5)a 47.5 (15.6) F ! 6.62 (.012)Sex % male (n) 48.8% (20) 45.5% (25) (2 ! 0.10 (.747)Race % white (n) 58.5% (24) 60.7% (34) (2 ! 0.11 (.745)

a Relatives n ! 37.

296 SEIDMAN ET AL.

hit rate in the combined sample (r ! .31, p # .001). After covaryingWRAT-3 Reading, Q3A-INT hit rate remained a significant predictorof group membership (B ! 1.73, SE ! 0.88 p ! .049, 95% CI !1.01–31.69), with the model correctly classifying 63.5% of subjects.WRAT-3 Reading was also a significant predictor of group member-ship (p ! .006) after covarying Q3A-INT suggesting that both vari-ables uniquely predicted group membership.

To examine whether psychometric properties of the task condi-tions influenced their ability to discriminate between relatives andcontrols, we examined the correlations for hit rate between blocks1 and 2 for each condition as a measure of reliability. The intra-class correlations were as follows: QA r ! .33, Q3A-MEM r !.54, and Q3A-INT r ! .69. Restricted range (i.e., ceiling effects)likely contributed to the lower correlation for QA.

Age by Group Interactions in the Combined Sample

To more directly examine the effect of age on performance forQ3A-INT, two-way between-Groups ANOVAs with age andgroup as the independent variables were conducted on hit rate andd&. There was no interaction between group and age for hit rate,F ! 0.70, p ! .864, or d&, F ! 0.59, p ! .943, for the overallsample. However, for the combined sample under age 31 (relativesn ! 53; controls n ! 65), a statistically significant age by groupinteraction was found. Participants were separated into those age13–20 (relatives n ! 25; controls n ! 43) and age 21–30 (relativesn ! 28; controls n ! 22). There was a significant interactionbetween group and age for hit rate, F ! 4.93, p ! .028, and d&,F ! 5.24, p ! .024. These effects are presented in Figure 4 and

Figure 3. Study 2: Hit rates for ACPT by group and task condition. QA is a vigilance task. Q3A-MEM is aworking memory task. Q3A-INT combines working memory and high levels of interference control. NC !Normal Control; Rel ! Relatives.

Table 5Results of Condition ) Group Analyses for the Auditory Continuous Performance Test forStudy 2

Conditiona

F(p)Groupa

F(p)Condition ) Groupa

F(p)

Correct hit % 324.41 (#.001) 3.03 (.043) 1.65 (.098)Correct hit % (adjusted for age) 26.58 (#.001) 6.85 (.005) 2.95 (.028)d& 387.17 (#.001) 2.38 (.063) 1.05 (.176)d* (adjusted for age) 29.68 (#.001) 6.02 (.008) 2.16 (.059)

Note. Results of three-way ANOVAs and ANCOVAs (adjusted for age) with two within-subjects variables(three task conditions, two trials per condition) and one between-subjects variable (two groups). Exploratoryanalyses not shown as none were statistically significant. d& is a measure of efficiency that takes into accountboth hit and false alarm rate.a Analyses evaluated at p # .05 (one-tailed).


indicate that performance improved as a function of age to agreater extent among controls compared with relatives.

Discussion

We carried out two studies of auditory vigilance with tasksinvolving WM and interference to identify the information pro-cessing vulnerabilities in people with schizophrenia and two inde-pendent samples of nonpsychotic relatives of individuals withschizophrenia and control groups. Results are summarized below.

Summary of Study 1

In this study of adults up to age 75, the results supported thehypotheses. First, the interference tasks were more difficult thanthe other tasks, and the memory task was intermediate in difficulty,whereas the simple vigilance tasks were easiest for all groups.Second, relatives and controls performed comparably on both

vigilance tasks (A and QA), whereas QA was more difficult thanA only among patients. Third, there was a clearly observable trendfor schizophrenia patients to perform worse than relatives who, inturn, performed worse than controls. The differences betweenrelatives and controls were only significant on the WM tasks,especially the two interference tasks, and the effect magnitude wasmodest (d ! "0.40–0.50). For patients, the ESs were quite large,averaging approximately d ! 1.5 compared with controls, and theywere impaired on all five versions of the ACPT. Finally, as thetasks had been designed to allow for analysis of learning/practiceeffects, there was a nonsignificant trend for the overall Time )Group interaction, with improved performance in the second blockcompared with the first for the relatives and controls only (patientsdid not improve from the first to the second trial). The overallpattern of results was consistent with that of the patients having ageneral deficit compared with the comparison groups. Significantimpairment among the relatives emerged mainly when memory

Figure 4. The interaction of group and age on Q3A-INT hit rate in the Combined Sample of individuals 30 oryounger. Q3A-INT combines working memory and interference control. Error bars represent standard errors(Rel ! relatives; NC ! Normal Controls).

Table 6Task Performance and Effect Sizes by Group and ACPT Task Condition for Study 2

RelativesM (SD)

Normal controlsM (SD) d a d b

QA correct hit % .95 (.07) .96 (.07) 0.22 0.31Q3A-MEM correct hit % .83 (.12) .86 (.14) 0.20 0.35!

Q3A-INT correct hit % .53 (.17) .59 (.18) 0.38! 0.54!!

QA d& 4.03 (.34) 4.09 (.32) 0.17 0.27Q3A-MEM d& 3.47 (.57) 3.58 (.59) 0.21 0.36!

Q3A-INT d& 2.41 (.62) 2.62 (.58) 0.36! 0.57!!

Note. Means and standard deviations are unadjusted. d ! Cohen’s d. d& is a measure of efficiency that takesinto account both hit and false alarm rate.a ANOVAs and effect sizes based on unadjusted group means and standard deviations. b ANCOVAs control-ling for age; Cohen’s d based on least squared means.! p # .05. !! p # .01. !!! p # .001 (one tailed).

298 SEIDMAN ET AL.

and interference were combined at low (Q1A-INT) or high (Q3A-INT) levels of difficulty.

Summary of Study 2

In this study of youth ages 13–25, results supported the hypoth-eses and were comparable with Study 1. The interference task wasmore difficult than the memory task, which was more difficult thanthe vigilance task. The relatives and controls did not differ onvigilance. As in Study 1, group differences began to emerge on thememory task, with relatives performing worse than controls aftercovarying age. As in Study 1, the ESs on the interference task werelarger than on the memory task, with relatives performing signif-icantly worse than controls. The ESs were moderate and similarbut slightly larger in magnitude to those observed in Study 1.There was no significant effect of Time or Time ) Group inter-action. Overall, the results were consistent with the hypothesis thatthe task condition that combined memory and interference mostclearly differentiated relatives from controls. Given the relativelylarge combined samples of more than 100 relatives and 100controls, the data strongly support the idea that these novel audi-tory WM % interference tasks tap an important component of thevulnerability to schizophrenia across a wide age range.

General Discussion

Of interest, the simple vigilance CPT task was quite easy in thatalmost all nonpatients achieved perfect performance beginningwith the first block, and no significant improvement occurred as aresult of ceiling effects. This pattern is typical of traditional “X”and “AX” CPTs (Nuechterlein, 1991). In contrast, although a fewsubjects were able to perform perfectly, there were no ceilingeffects on the interference WM CPTs. Improvement was achievedover time within task (except in schizophrenia patients) but did notreach ceiling. Among controls, the pattern of results on the QAvigilance task and the Q3AINT WM tasks in these samples ofaverage intelligence are consistent with that observed in twoindependent cohorts of highly educated, healthy male controlsparticipating in fMRI studies (Seidman et al., 1998). Significantlypoorer performance on the WM than vigilance task is consistentwith that found by others who have shown that error rates increasewith memory load (Barch et al., 1997; Braver et al., 1997; Gevinset al., 1996). Of note, the reliability of the WM % INT task acrossblocks was the highest of the three task conditions used in bothstudies, probably contributing to their enhanced discriminatingpower.

The CPT tasks, especially the interference tasks, had an ES aslarge as the most discriminating tasks (such as digit symbol cod-ing) for schizophrenia (Dickinson, Ramsey & Gold, 2007;Mesholam-Gately, Giuliano, Faraone, Goff & Seidman, 2009),even though the mean IQ in this schizophrenia sample was about100, somewhat higher than is typical (Aylward, Walker & Bettes,1984; Woodberry, Giuliano & Seidman, 2008). Similarly, theeffect for the interference task in relatives, which was moderate(i.e., d "0 .40–0.50), was roughly equivalent to the largest ESs inmeta-analyses of neurocognitive impairment among nonpsychoticrelatives (e.g., Snitz, MacDonald & Carter, 2005). This suggeststhat the interference tasks are sensitive in terms of tapping into animportant component of vulnerability to schizophrenia.

Task performance on the memory and interference tasks was neg-atively correlated with age across the whole sample, consistent with alarge literature suggesting that aging is associated with decline incognitive function (Salthouse, 1994). However, there was no signif-icant group by age interaction across the entire sample, suggesting thegroup differences were largely comparable across age. We carriedout an exploratory analysis for the age range of 13–30 based onhypotheses that deficits may be largest in the period when theonset of schizophrenia peaks (late teens to late 20s). In that epoch,containing approximately half of the overall sample, there was asignificant age by group interaction; controls improved with agewhereas the relatives did not, suggesting a failure of developmen-tal maturation. The absence of improved performance in relativesmay reflect an increasing failure to respond to higher load taskdemands.

Future research should clarify how findings from these auditoryCPTs compare with those from other CPTs used in most endophe-notype studies. There are no published direct comparisons betweenthis set of tasks and other complex CPTs, however we can inferrelative sensitivity based on two comprehensive reviews of CPTs(Snitz, MacDonald & Carter, 2005; Gur et al., 2006). Indeed,differing conclusions as to whether FHR individuals show deficitsin vigilance may be attributable to an inability of simpler versionsof the CPT to identify subtle deficits. Several studies using simpleCPTs (Asarnow, Steffy, MacCrimmon & Cleghorn, 1977; Cohler,Grunebaum, Weiss, Gamer & Gallant, 1977) found no differencebetween FHR and controls. This is comparable with our observa-tion of no significant differences in relatives-control comparisonson the two auditory vigilance tasks (A and QA) used in the currentstudy. This pattern led investigators to focus on high-load, effortfulCPTs.

The two most frequently used high load CPTs in the FHRliterature are both visual, the degraded stimulus CPT (Nuechter-lein, Parasuraman, & Jiang, 1983) and the CPT-IP (Cornblatt,Risch, Friedman, & Erlenmeyer-Kimling, 1988). Overall, meta-analyses report moderate ESs for these two tasks; d " ! 0.43–0.54 for CPT d& in complex, high-load versions (Snitz, MacDonald& Carter, 2005; Gur et al., 2006). The CPT-IP is closer concep-tually to the auditory CPT battery because it manipulates WMload, whereas the degraded stimulus CPT burdens perceptual pro-cessing. Agnew-Blais and Seidman (in press) reported that themean ES across five studies of FHR youth below age 30 for theCPT-IP digits was '0.29 and for CPT-IP shapes was '0.26, bothsomewhat smaller than the ES for the WM % interference CPT inthe current Study 2, and smaller than the meta-analyses cited abovesuggest. Neither study of adolescents at FHR (Cosway et al.,2002;Seidman et al., 2006) found significant impairments in the CPT-IP,although some similar studies did successfully discriminate usingCPT-IP digits (Myles-Worsley et al., 2007) with moderate ESs(d ! '0.61). Moreover, in successive rounds of testing in SampleB of the New York HR Study, using the CPT-IP, FHR participantshad significantly poorer discriminability compared with controlsand with individuals at FHR for affective disorders, replicating theearlier finding in the double-digit Task B CPT (Erlenmeyer-Kimling & Cornblatt, 1992). Thus, because the variability offindings across studies makes it difficult to make definitive con-clusions, direct comparisons between CPT tasks are necessary toaddress the issue of comparative sensitivity and specificity.


Additional questions need to be addressed to help investigatorschoose among various tests for endophenotype studies. For exam-ple, (1) Do the tests identify the same subjects as impaired ornonimpaired? (2) For which populations are the tests appropriate?For example, the auditory Q3A-INT may be too difficult foryounger children. (3) How heritable are the different tests, and arethey associated with the same genetic processes or neural sub-strates? These questions are beyond the scope of this study, butthey highlight issues that need to be addressed to determine thedifferential utility of these tests.

Strengths and Limitations

This study has a number of strengths, including a novel batteryof auditory CPT tasks designed within a conceptual frameworkoriented to identifying core information processing deficits inschizophrenia. A large sample of relatives and controls was stud-ied. By studying two independent samples of relatives across awide age range, replication could be achieved, and impairmentsacross the wide age range from 13 to 75 were demonstrated. Therewere also some limitations. These include a fixed order of taskswithin each study. However, very similar results in two separatestudies of relatives, which had different task orders, argues againsta fatigue or order effect (see Figure 1a). Moreover, the fact thatboth relatives and controls showed comparable learning over timeargues against a substantial fatigue effect. In addition, the schizo-phrenia participants did not show a decline over time, consistentwith results reported by Lenzenweger, Cornblatt, and Putnick(1991) on the visual CPT-IP.

Another limitation of the study is the generalized deficit prob-lem (Chapman & Chapman, 1978). The current results appear tobe at least partially explained on the basis of a general deficit:patients # relatives # controls, with the deficit growing as taskdifficulty increases for all groups. That is, tasks with increasingdifficulty (and better reliability) had better discriminating power inpatients and relatives. Of note, however, the WM % INT taskcontinued to differentiate relatives from normal controls even afteraccounting for a general measure of intellectual ability and forsimple vigilance. The current study design does not allow us toprecisely pinpoint the mechanisms underlying the impairment onthe most sensitive tasks (i.e., WM % INT). One of the questionsgenerated by this study is whether WM alone or WM % interfer-ence are central to the cognitive vulnerability to schizophrenia.While our study design was not set up to optimally test fordifferential deficit, it is notable that whereas controls were equiv-alent in performance on Q3A-MEM and Q1A-INT in Study 1,relatives exhibited impairment only on the interference task. How-ever, the group by condition effect was not significant using thesetwo tasks with these two groups. If this initial finding of equivalentperformance among controls on these two tasks can be replicatedin a larger, independent sample, this would allow us to test fordifferential deficit in future studies. Moreover, comparison withother well-established cognitive vulnerability indicators (i.e., ver-bal declarative memory) on the same subjects would help identifywhether there are selective deficits in these cognitive processes.

Future Directions

Future work could evaluate the differential sensitivity of theseWM interference tasks compared with matched visual CPT tasks

and directly compare the differential sensitivity to other neurocog-nitive tasks that have been shown to be sensitive to genetic risk forschizophrenia (e.g., digit symbol coding, dichotic listening, storyrecall, etc.). Prospective, longitudinal studies could also examinewhether performance on these ACPTs enhances prediction ofconversion to psychosis among at-risk participants (e.g., Seidmanet al., 2010) or changes over time. It remains important to deter-mine the relationships among these tasks and functional outcome,symptoms, and other clinical features in relatives and patients withschizophrenia. Identifying whether these tasks are useful in dis-criminating other disorders (e.g., schizotypal personality disorder,attention-deficit/hyperactivity disorder) with presumed problemsin WM and effortful attention processing would be useful fordetermining the specificity of the deficits observed in these studies.Finally, such tasks could be tested in treatment studies and imagingstudies to determine the malleability or reversibility of the deficits(Barch & Smith, 2008).

References

Adler, L. E., Pachtman, E., Franks, R. D., Pecevich. M., Waldo, M. C., &Freedman, R. (1982). Neurophysiological evidence for a defect in neu-ronal mechanisms involved in sensory gating in schizophrenia. Biolog-ical Psychiatry, 17, 639–654.

Agnew-Blais, J., & Seidman, L. J. (In press). Neurocognition in youth andyoung adults under age 30 at familial risk for schizophrenia: A quanti-tative and qualitative review. Cognitive Neuropsychiatry, Special Issue:Cognitive Antecedents of Psychiatric Disorders, Edited by StevenWood, Alison Yung, & Christos Pantelis.

Asarnow, R. F., Steffy, R. A., MacCrimmon, D. J., & Cleghorn, J. M.(1977). An attentional assessment of foster children at risk for schizo-phrenia. Journal of Abnormal Psychology, 86, 267–275. doi:10.1037/0021-843X.86.3.267

Aylward, E., Walker, E., & Bettes, B. (1984). Intelligence in schizophre-nia: Meta-analysis of the research. Schizophrenia Bulletin, 10, 430–459.

Baddeley, A. D., & Hitch, G. J. (1994). Developments in the concept ofworking memory. Neuropsychology, 8, 485–493. doi:10.1037/0894-4105.8.4.485

Baddeley, A. D. (1986). Working memory. Oxford, England: Oxford Uni-versity Press.

Barch, D. M., Braver, T. S., Nystrom, L. E., Forman, S. D., Noll, D. C., &Cohen, J. D. (1997). Dissociating working memory from task difficultyin human prefrontal cortex. Neuropsychologia, 35, 1373–1380. doi:10.1016/S0028-3932(97)00072-9

Barch, D. M., & Smith, E. (2008). The cognitive neuroscience of workingmemory: Relevance to CNTRICS and schizophrenia. Biological Psychi-atry, 64, 11–17. doi:10.1016/j.biopsych.2008.03.003

Barch, D. M. (2005). The cognitive neuroscience of schizophrenia. In T.Cannon & S. Mineka (Eds.), Annual Review of Clinical Psychology (pp.321–353). Washington, DC: American Psychological Association.

Beatty, J. (1982). Task-evoked pupillary responses, processing load, andthe structure of processing resources. Psychological Bulletin, 91, 276–292. doi:10.1037/0033-2909.91.2.276

Bleuler, E. (1911). Dementia praecox or the group of schizophrenias. NewYork, NY: International Universities Press.

Braff, D., Stone, C., Callaway, E., Geyer, M., Glick, I., & Bali, L. (1978).Prestimulus effects on human startle reflex in normals and schizophren-ics. Psychophysiology, 15, 339 –343. doi:10.1111/j.1469-8986.1978.tb01390.x

Braver, T. S., Cohen, J. D., Nystrom, L. E., Jonides, J., Smith, E. E., &Noll, D. C. (1997). A parametric study of prefrontal cortex involvementin human working memory. Neuroimage, 5, 49 – 62. doi:10.1006/nimg.1996.0247

300 SEIDMAN ET AL.

Buchanan, R. W., Keefe, R. S. E., Lieberman, J. A., Barch, D. M.,Csernansky, J. G., Goff, D. C., . . . Marder, S. R. (2011). A randomizedclinical trial of MK-0777 for the treatment of cognitive impairments inpeople with schizophrenia. Biological Psychiatry, 69, 442–449. doi:10.1016/j.biopsych.2010.09.052

Chapman, L. J., & Chapman, J. P. (1978). The measurement of differentialdeficit. Journal of Psychiatric Research, 14, 303–311. doi:10.1016/0022-3956(78)90034-1

Cohen, J. (1988). Statistical power analysis for the behavioural sciences.Hillsdale, NJ: Erlbaum Associates.

Cohen, J. D., Barch, D. M., Carter, C., & Servan-Schreiber, D. (1999).Context-processing deficits in schizophrenia: Converging evidence fromthree theoretically motivated cognitive tasks. Journal of Abnormal Psy-chology, 108, 120–133. doi:10.1037/0021-843X.108.1.120

Cohen, J. D., Forman, S. D., Braver, T. S., Casey, B. J., Servan-Screiber,D., & Noll, D. C. (1994). Activation of prefrontal cortex in a non–spatialworking memory task with functional MRI. Human Brain Mapping, 1,293–304. doi:10.1002/hbm.460010407

Cohler, B. J., Grunebaum, H. U., Weiss, J. L., Gamer, E., & Gallant, D. H.(1977). Disturbance of attention among schizophrenic, depressed andwell mothers and their young children. Journal of Child Psychology andPsychiatry, 18, 115–135. doi:10.1111/j.1469-7610.1977.tb00424.x

Cornblatt, B., Winters, L., & Erlenmeyer-Kimling, L. (1989). Attentionalmarkers of schizophrenia: Evidence from the New York High-RiskStudy. In S. Schulz & C. Tamminga (Eds.), Schizophrenia: Scientificprogress (pp. 83–92). New York, NY: Oxford University Press.

Cornblatt, B. A., & Keilp, J. G. (1994). Impaired attention, genetics and thepathophysiology of schizophrenia. Schizophrenia Bulletin, 20, 31–46.

Cornblatt, B. A., Risch, N. J., Friedman, D., & Erlenmeyer-Kimling, L.(1988). The continuous performance test, Identical Pairs Version (CPT-IP): I. New findings about sustained attention in normal families. Psy-chiatry Research, 26, 223–238. doi:10.1016/0165-1781(88)90076-5

Cosway, R., Byrne, M., Clafferty, R., Hodges, E., Grant, J., Morris,J., . . . Johnstone, E. C. (2002). Sustained attention in young people athigh risk for schizophrenia. Psychological Medicine: A Journal of Re-search in Psychiatry and the Allied Sciences, 32, 277–286. doi:10.1017/S0033291701005050

D’Esposito, M., Detre, J. A., Alsop, D. C., Shin, R. K., Atlas, S., &Grossman, M. (1995). The neural basis of the central executive systemof working memory. Nature, 378, 279–281. doi:10.1038/378279a0

Dickinson, D., Ramsey, M. E., & Gold, J. M. (2007). Overlooking theobvious: A meta-analytic comparison of digit symbol coding tasks andother cognitive measures in schizophrenia. Archives of General Psychi-atry, 64, 532–542. doi:10.1001/archpsyc.64.5.532

Eack, S. M., Hogarty, G. E., Cho, R. S., Prasad, K. M. R., Greenwald,D. P., Hogarty, S. S., & Keshavan, M. S. (2010). Cognitive enhancementtherapy protects against gray matter loss in early schizophrenia: Resultsfrom a two-year randomized controlled trial. Archives of General Psy-chiatry, 67, 674–682. doi:10.1001/archgenpsychiatry.2010.63

Erlenmeyer-Kimling, L., & Cornblatt, B. A. (1992). Summary of atten-tional findings in the New York High-Risk Project. Journal of Psychi-atric Research, 26, 405–426. doi:10.1016/0022-3956(92)90043-N

Faraone, S. V., Green, A. I., Seidman, L. J., & Tsuang, M. T. (2001).“Schizotaxia”: clinical implications and new directions for research.Schizophrenia Bulletin, 27, 1–18. doi:10.1093/oxfordjournals.schbul.a006849

Faraone, S. V., Seidman, L. J., Kremen, W. S., Pepple, J. R., Lyons, M. J.,& Tsuang, M. T. (1995). Neuropsychological functioning among thenonpsychotic relatives of schizophrenic patients: A diagnostic efficiencyanalysis. Journal of Abnormal Psychology, 104, 286–304. doi:10.1037/0021-843X.104.2.286

Faraone, S. V., Seidman, L. J., Kremen, W. S., Toomey, R., Pepple, J. R.,& Tsuang, M. T. (1999). Neuropsychological functioning among thenonpsychotic relatives of schizophrenic patients: A four-year follow-up

study. Journal of Abnormal Psychology, 108, 176–181. doi:10.1037/0021-843X.108.1.176

Faraone, S. V., Seidman, L. J., Kremen, W. S., Toomey, R., Pepple, J. R.,& Tsuang, M. T. (2000). Neuropsychological functioning among thenonpsychotic relatives of schizophrenic patients: The effect of geneticloading. Biological Psychiatry, 48, 120 –126. doi:10.1016/S0006-3223(99)00263-2

Fuster, J. M. (1989). The prefrontal cortex: Anatomy, physiology andneuropsychology of the frontal lobe. New York, NY: Raven Press.

Geller, B., Zimmerman, B., Williams, M., & Frazier, J. (1994). WASH-U-KSADS: Washington University at St. Louis Kiddie and Young AdultSchedule for Affective Disorders and Schizophrenia—Lifetime and Pres-ent Episode Version for DSM-IV. St. Louis, MO: Washington UniversitySchool of Medicine.

Gevins, A., Smith, M. E., Le, J., Leong, H., Bennett, J., Martin,N., . . . Whitfield, S. (1996). High resolution evoked potential imagingof the cortical dynamics of human working memory. Electroencepha-lography & Clinical Neurophysiology, 98, 327–348. doi:10.1016/0013-4694(96)00288-X

Gold, J. M., Carpenter, C., Randolph, C., Goldberg, T. E., & Weinberger,D. R. (1997). Auditory working memory and Wisconsin Card SortingTest performance in schizophrenia. Archives of General Psychiatry, 54,159–165. doi:10.1001/archpsyc.1997.01830140071013

Goldman-Rakic, P. S. (1987). Circuitry of primate prefrontal cortex andregulation of representational memory. In V. B. Mountcastle (Ed.),Handbook of Physiology (pp. 373–417). Bethesda, MD: American Phys-iological Society.

Goldman-Rakic, P. S. (1991). Prefrontal cortical dysfunction in schizo-phrenia: The relevance of working memory. In B. J. Carroll & J. E.Barnett (Eds.), Psychopathology and the brain (pp. 1–23). New York,NY: Raven Press.

Goldstein, J. M., Jerram, M., Poldrack, R., Anagnoson, R., Breiter, H. C.,Makris, N., . . . Seidman, L. J. (2005). Sex differences in prefrontalcortical brain activity during fMRI of auditory verbal working memory.Neuropsychology, 19, 509–519. doi:10.1037/0894-4105.19.4.509

Gottesman, I., & Gould, T. (2003). The endophenotype concept in psychi-atry: Etymology and strategic intentions. The American Journal ofPsychiatry,160, 636–645. doi:10.1176/appi.ajp.160.4.636

Gottesman, I. (1991). Schizophrenia genesis: The origin of madness. NewYork, NY: Freeman.

Green, D. M., & Swets, J. A. (1966). Signal detection theory and psycho-physics. New York, NY: Wiley.

Green, M. F., Kern, R., Braff, D., & Mintz, J. (2000). Neurocognitivedeficits and functional outcome in schizophrenia: Are we measuring the“right stuff”? Schizophrenia Bulletin, 26, 119–136.

Green, M. F. (1996). What are the functional consequences of neurocog-nitive deficits in schizophrenia? The American Journal of Psychiatry,153, 321–330.

Gur, R. E., Calkins, M. E., Gur, R. C., Horan, W. P., Nuechterlein, K. H.,Seidman, L. J., & Stone, W. S. (2007). The consortium on the geneticsof schizophrenia: Neurocognitive endophenotypes. Schizophrenia Bul-letin, 33, 49–68. doi:10.1093/schbul/sbl055

Harvey, P. D., & Keefe, R. (2001). Studies of cognitive change in patientswith schizophrenia following novel antipsychotic treatment. The Amer-ican Journal of Psychiatry, 158, 176 –184. doi:10.1176/appi.ajp.158.2.176

Heinrichs, R. W., & Zakzanis, K. (1998). Neurocognitive deficit in schizo-phrenia: A quantitative review of the evidence. Neuropsychology, 12,426–445. doi:10.1037/0894-4105.12.3.426

Hirayasu, Y., McCarley, R. W., Salisbury, D. F., Tanaka, S., Kwon, J. S.,Frumin, M., . . . Shenton, M. E. (2000). Planum temporale and Heschl’sgyrus volume reduction in schizophrenia: An MRI study of first-episodepatients. Archives of General Psychiatry, 57, 692–699. doi:10.1001/archpsyc.57.7.692


Hollingshead, A. B. (1975). Four Factor Index of Social Status. NewHaven, CT: Yale University Department of Sociology.

Horan, W. P., Braff, D. L., Nuechterlein, K. H., Sugar, C. A., Cadenhead,K. S., Calkins, M. E., . . . Green, M. F. (2008). Verbal working memoryimpairments in individuals with schizophrenia and their first-degreerelatives: Findings from the Consortium on the Genetics of Schizophre-nia. Schizophrenia Research, 103, 218 –228. doi:10.1016/j.schres.2008.02.014

Jastak, S., & Jastak, G. S. (1985). Wide Range Achievement Test-Revised.Wilmington, DE: Jastak Associates.

Jeon, Y. W., & Polich, J. (2003). Meta-analysis of P300 and schizophrenia:Patients, paradigms, and practical limitations. Psychophysiology, 40,684–701. doi:10.1111/1469-8986.00070

Kahneman, D. (1973). Attention and effort. Englewood Cliffs, NJ: PrenticeHall.

Keefe, R. S. E., Beasley, C. E., & Poe, M. P. (2005). Defining a cognitivedecrement in schizophrenia. Biological Psychiatry, 57, 688–691. doi:10.1016/j.biopsych.2005.01.003

Keshavan, M. S., Kulkarni, S. R., Bhojraj, T., Francis, A., Diwadkar, V.,Montrose, D. M., . . . Sweeney, J. (2010). Premorbid cognitive deficitsin young relatives of schizophrenia patients. Frontiers in Human Neu-roscience, 3, 62.

Kraepelin, E. (1919). Dementia praecox and paraphrenia. Edinburgh,Scotland: E & S. Livingstone.

Kremen, W. S., Seidman, L. J., Faraone, S. V., Pepple, J. R., Lyons, M. J.,& Tsuang, M. T. (1996). The “3Rs” and neuropsychological function inschizophrenia: An empirical test of the matching fallacy. Neuropsychol-ogy, 10, 22–31. doi:10.1037/0894-4105.10.1.22

Kremen, W. S., Seidman, L. J., Faraone, S. V., Toomey, R., & Tsuang,M. T. (2000). The paradox of neuropsychologically normal schizophre-nia. Journal of Abnormal Psychology, 109, 743–752. doi:10.1037/0021-843X.109.4.743

Kremen, W. S., Seidman, L. J., Pepple, J., Lyons, M. J., Tsuang, M. T., &Faraone, S. V. (1994). Neuropsychological risk indicators for schizo-phrenia: A review of family studies. Schizophrenia Bulletin, 20, 103–119.

Lee, J., & Park, S. (2005). Working memory impairments in schizophrenia:A meta-analysis. Journal of Abnormal Psychology, 114, 599–611. doi:10.1037/0021-843X.114.4.599

Lenzenweger, M. F., Cornblatt, B., & Putnick, M. (1991). Schizotypy andsustained attention. Journal of Abnormal Psychology, 100, 84–89. doi:10.1037/0021-843X.100.1.84

Luna, B., Padmanabhan, A., & O’Hearn, K. (2010). What has fMRI told usabout the development of cognitive control through adolescence? Brainand Cognition, 72, 101–113. doi:10.1016/j.bandc.2009.08.005

Mackworth, N. H. (1948). The breakdown of vigilance during prolongedvisual search. The Quarterly Journal of Experimental Psychology, 1,6–21. doi:10.1080/17470214808416738

Makris, N., Gasic, G. P., Kennedy, D. K., Hodge, S. M., Kaiser, J. R., Lee,M. J., . . . Breiter, H. C. (2008). Cortical thickness abnormalities incocaine addiction – a reflection of both drug use and a pre-existingdisposition to drug abuse? Neuron, 60, 174 –188. doi:10.1016/j.neuron.2008.08.011

Maxwell, M. (1996). Family Instrument for Genetic Studies (FIGS). Clin-ical Neurogenetics Branch, Intramural Research Program, NIMH.

Mesholam-Gately, R. I., Giuliano, A. J., Faraone, S. V., Goff, K. P., &Seidman, L. J. (2009). Neurocognition in first-episode schizophrenia: Ameta-analytic review. Neuropsychology, 23, 315–336. doi:10.1037/a0014708

Michie, P. T. (2001). What has MMN revealed about the auditory systemin schizophrenia. International Journal of Psychophysiology, 42, 177–194. doi:10.1016/S0167-8760(01)00166-0

Mirsky, A. F., Anthony, B. J., Duncan, C. C., Ahern, M. B., & Kellam,S. G. (1991). Analysis of the elements of attention: A neuropsycholog-

ical approach. Neuropsychology Review, 2, 109 –145. doi:10.1007/BF01109051

Mishara, A. L., & Goldberg, T. A. (2004). Meta-analysis and criticalreview of the effects of conventional neuroleptic treatment on cognitionin schizophrenia: Opening a closed book. Biological Psychiatry, 55,1013–1022. doi:10.1016/j.biopsych.2004.01.027

Myles-Worsley, M., Ord, L. M., Ngiralmau, H., Weaver, S., Blailes, F., &Faraone, S. V. (2007). The Palau Early Psychosis Study: Neurocognitivefunctioning in high-risk adolescents. Schizophrenia Research, 89, 299–307. doi:10.1016/j.schres.2006.08.003

Niemi, L. T., Suvisaari, J., Tuulio-Henriksson, A., & Lonnqvist, J. (2003).Childhood developmental abnormalities in schizophrenia: Evidencefrom high-risk studies. Schizophrenia Research, 60, 239–258. doi:10.1016/S0920-9964(02)00234-7

Norman, D. A., & Bobrow, D. J. (1975). On data-limited and resource-limited processes. Cognitive Psychology, 7, 44–64. doi:10.1016/0010-0285(75)90004-3

Nuechterlein, K. H., & Dawson, M. E. (1984). Information processing andattentional functioning in the developmental course of schizophrenicdisorders. Schizophrenia Bulletin, 10, 160–203.

Nuechterlein, K. H., Parasuraman, R., & Jiang, Q. (1983). Visual sustainedattention: Image degradation produces rapid decrement over time. Sci-ence, 220, 327–329. doi:10.1126/science.6836276

Nuechterlein, K. H. (1991). Vigilance in schizophrenia and related disor-ders. In S. Steinhauer, J. Gruzelier, & J. Zubin (Eds.), Handbook ofschizophrenia, Volume 5 – Neuropsychology, psychophysiology andinformation processing (pp. 397–433). Amsterdam, The Netherlands:Elsevier.

Nurnberger, J. I., Blehar, M. C., Kaufmann, C. A., York-Cooler, C.,Simpson, S. G., Harkavy Friedman, J., . . . Kirch, D. (1994). Diagnosticinterview for genetic studies (DIGS): Rationale, unique features, andtraining. Archives of General Psychiatry, 51, 849–859. doi:10.1001/archpsyc.1994.03950110009002

Palmer, B. W., Heaton, R. K., Paulsen, J. S., Kuck, J., Braff, D., Harris,M. J., . . . Jeste, D. V. (1997). Is it possible to be schizophrenic yetneuropsychologically normal. Neuropsychology 11, 437– 446. doi:10.1037/0894-4105.11.3.437

Parasuraman, R., & Davies, D. R. (1977). A taxonomic analysis of vigi-lance. In Mackie, R. R. (Ed.), Vigilance: Theory, operational perfor-mance and physiological correlates (pp 559–574). New York, NY:Plenum.

Park, S., Holzman, P., & Goldman-Rakic, P. (1995). Spatial working memorydeficits in the relatives of schizophrenic patients. Archives of General Psychi-atry, 52, 821–828. doi:10.1001/archpsyc.1995.03950220031007

Rosvold, H. E., Mirsky, A. F., Sarason, I., Bransome, E. D., Jr., & Beck,L. H. (1956). A continuous performance test of brain damage. Journal ofConsulting Psychology, 20, 343–350. doi:10.1037/h0043220

Salthouse, T. A. (1994). The aging of working memory. Neuropsychology,8, 535–543. doi:10.1037/0894-4105.8.4.535

Seidman, L. J., Breiter, H., Goodman, J. M., Goldstein, J. M., Woodruff,P., O’Craven, K., . . . Rosen, B. R. (1998). A functional magnetic reso-nance imaging study of auditory vigilance with low and high informa-tion processing demands. Neuropsychology, 12, 505–518. doi:10.1037/0894-4105.12.4.505

Seidman, L. J., Giuliano, A. J., Meyer, E. C., Addington, J., Cadenhead,K. S., Cannon, T. D., . . . Cornblatt, B. (2010). Neuropsychology of theprodrome to psychosis in the NAPLS consortium: Relationship to familyhistory and conversion to psychosis. Archives of General Psychiatry, 67,578–588. doi:10.1001/archgenpsychiatry.2010.66

Seidman, L. J., Giuliano, A. J., Smith, C. W., Stone, W. S., Glatt, S. J.,Meyer, E. C., . . . Cornblatt, B. (2006). Neuropsychological functioningin adolescents and young adults at genetic risk for schizophrenia andaffective psychoses: Results from the Harvard and Hillside Adolescent

302 SEIDMAN ET AL.

High Risk Studies. Schizophrenia Bulletin, 32, 507–524. doi:10.1093/schbul/sbj078

Seidman, L. J., Kremen, W. S., Koren, D., Faraone, S. V., Goldstein, J. M.,& Tsuang, M. T. (2002). A comparative profile analysis of neuropsy-chological functioning in patients with schizophrenia and bipolar psy-choses. Schizophrenia Research, 53, 31– 44. doi:10.1016/S0920-9964(01)00162-1

Seidman, L. J., Thermenos, H. W., Koch, J. K., Ward, M., Breiter, H.,Goldstein, J. M., . . . Tsuang, M. T. (2007). Auditory verbal workingmemory load and thalamic activation in non-psychotic relatives ofpersons with schizophrenia: An FMRI replication. Neuropsychology, 21,599–610. doi:10.1037/0894-4105.21.5.599

Seidman, L. J., Van-Manen, K. J., Gamser, D. M., Turner, W. M., Faraone,S. V., Goldstein, J. M., & Tsuang, M. T. (1998). Effects of increasingprocessing load on vigilance in schizophrenia and in adults with atten-tional and learning disorders. Schizophrenia Research, 34, 101–112.doi:10.1016/S0920-9964(98)00097-8

Seidman, L. J. (1983). Schizophrenia and brain dysfunction. PsychologicalBulletin, 94, 195–238. doi:10.1037/0033-2909.94.2.195

Sitskoorn, M. M., Aleman, A., Ebisch, S., Appels, M., & Kahn, R. (2004).Cognitive deficits in relatives of patients with schizophrenia: A meta-analysis. Schizophrenia Research, 71, 285–295. doi:10.1016/j.schres.2004.03.007

Snitz, B. E., MacDonald, A., & Carter, C. (2005). Cognitive deficits inunaffected first-degree relatives of schizophrenia patients: A meta-analytic review of putative endophenotypes. Schizophrenia Bulletin, 32,179–194. doi:10.1093/schbul/sbi048

Spitzer, R., L., Williams, J., B., Gibbon, M., & First, M. B. (1987).Structured Clinical Interview for DSM-III-R. Washington, DC: Ameri-can Psychiatric Press.

Spitzer, R. L., & Endicott, J. (1978). Schedule for Affective Disorders andSchizophrenia (3rd ed.). New York, NY: Biometrics Research, NewYork State Psychiatric Institute.

Spring, B. (1985). Distractibility as a marker of vulnerability to schizo-phrenia. Psychopharmacology Bulletin, 21, 509–512.

Stangl, D., & Zimmerman, M. (1983). Structured Interview for DSM-IIIPersonality Disorders (2nd ed.). Iowa City, IA: University of Iowa.

Szöke, A., Schurhoff, F., Mathieu, F., Meary, A., Ionescu, S., & Leboyer,M. (2005). Tests of executive functions in first-degree relatives ofschizophrenic patients: A meta-analysis. Psychological Medicine, 35,771–782. doi:10.1017/S0033291704003460

Thermenos, H. W., Seidman, L. J., Breiter, H., Goldstein, J. M., Goodman,J. M., Poldrack, R., . . . Tsuang, M. T. (2004). Functional MRI duringauditory verbal working memory in non-psychotic relatives of personswith schizophrenia: A pilot study. Biological Psychiatry, 55, 490–500.doi:10.1016/j.biopsych.2003.11.014

Trandafir, A., Meary, A., Schurhoff, F., Leboyer, M., & Szöke, A. (2006).Memory tests in first degree adult relatives of schizophrenic patients: Ameta-analysis. Schizophrenia Research, 81, 217–226. doi:10.1016/j.schres.2005.09.005

Tsuang, M. T., Seidman, L. J., & Faraone, S. V. (1999). New approachesto the genetics of schizophrenia: Neuropsychological and neuroimagingstudies of nonpsychotic first degree relatives of people with schizophre-nia. In W. F. Gattaz and H. Hafner (Eds.), The fourth symposium on thesearch for the causes of schizophrenia (Vol. IV, pp. 191–207). Berlin,Germany: Springer.

Tsuang, M. T., Stone, W. S., & Faraone, S. V. (1999). Schizophrenia: Areview of genetic studies. Harvard Review of Psychiatry, 7, 185–207.

Vincent, K. R., Castillo, I. M., Hauser, R. I., Zapata, J. A., Stuart, H. J.,Cohn, C. K., & O’Shanick, G. J., 1984. MMPI-168 Codebook. Norwood,NJ: Ablex.

Wager, T. D., & Smith, E. E. (2003). Neuroimaging studies of workingmemory: A meta-analysis. Cognitive, Affective & Behavioral Neurosci-ence, 3, 255–274. doi:10.3758/CABN.3.4.255

Wechsler, D. (1991). Manual for the Wechsler Intelligence Scale forChildren-Third Edition. San Antonio, TX: The Psychological Corpora-tion.

Wechsler D. Wechsler Adult Intelligence Scale-Third Edition. (1997). SanAntonio, TX: The Psychological Corporation.

Wilk, C. M., Gold, J. M., McMahon, R. P., Humber, K., Iannone, V. N., &Buchanan, R. W. (2005). No, it is not possible to be schizophrenic andneuropsychologically normal. Neuropsychology, 19, 778 –786. doi:10.1037/0894-4105.19.6.778

Wilkinson, G. (1993). Wide Range Achievement Test, Administration Man-ual, 3rd ed. Wilmington, DE: Wide Range, Inc.

Woodberry, K. A., Giuliano, A. J., & Seidman, L. J. (2008). Premorbid IQin schizophrenia: A meta-analytic review. The American Journal ofPsychiatry, 165, 579–587. doi:10.1176/appi.ajp.2008.07081242

Received May 10, 2011Revision received January 9, 2012

Accepted February 16, 2012 !


288

Documents

harvard medical school

digit symbol coding

false alarm rate

continuous cognitive updating

human working memory

priori hypothesestask condition

randomly selected letters

nc normal control