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Schizophr Bull. 2007 January; 33(1): 49–68.
Published online 2006 November 13. doi:  10.1093/schbul/sbl055
PMCID: PMC2632287

The Consortium on the Genetics of Schizophrenia: Neurocognitive Endophenotypes


The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be “neurocognitive” and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease.

Keywords: neurogenetics, attention, memory, emotion


Schizophrenia is a complex, heritable brain disorder, and progress in understanding its pathophysiology mandates integration of genetic and neurobiological methods. Symptom-based genetic studies have applied linkage and association analyses in a case-control design, with some replicated findings.1,2 An alternative approach examines the genetics of schizophrenia from the neurobiological perspective with neurocognitive endophenotypic markers of putative brain function. Studies of brain-behavior relations provide converging data leading to inclusion of neurocognitive measures in characterization of the endophenotype of the disorder, thus advancing beyond the traditional study of its clinical phenotypic expression. While symptoms may represent compensatory behavior and accordingly vary over the course of illness and treatment, the underlying brain dysfunction is likely a more stable trait marker that can be examined genetically. This approach is further motivated by the need to elucidate pathophysiology even after candidate alleles are established.

Disordered cognitive functioning is a hallmark of schizophrenia (eg, Bleuler3) that is associated with impaired quality of life and poor outcome (eg, Green et al4). Convergence of findings from neurocognitive, electrophysiological, structural, and functional imaging methodologies and postmortem work indicate that schizophrenia is characterized by aberrations in brain function affecting frontotemporal circuitry. Dysfunction of such circuitries would reflect the combined effect of genetic liability and environmental factors implicated in schizophrenia, and by their examination in families, it should be possible to establish the interplay of these factors. We anticipate that the quantitative, continuously distributed phenotypes related to brain function will serve as reliable risk factors and indicators of schizophrenia liability. We postulate that the endophenotypes that we proposed to genetically characterize are more proximal functions of gene action than is the diagnostic assignment of schizophrenia itself. Therefore, it should be simpler to localize the genetic loci contributing to the endophenotypes than to localize those for schizophrenia. With this strategy in mind, we selected neurocognitive measures that meet recommended criteria as endophenotypic markers and can be applied in the Consortium on the Genetics of Schizophrenia (COGS) multisite collaborative study.5 Here we review the rationale for selecting the COGS measures and the relevant literature. The COGS data will be presented in empirical articles.

Overview of Criteria for Evaluating and Selecting Candidate Endophenotypes

Criteria for applying endophenotypic measures have been formulated with the recommendation that the endophenotype be associated with the illness, be heritable, be primarily state independent, and cosegregate within families.6 The selection of the neurocognitive measures for COGS was guided by the following criteria: (1) Association with illness—moderate to large effect sizes between schizophrenia patients and community controls. (2) State independent: (a) adequate test-retest stability; (b) adequate between-site reliability; (c) evidence that impairments in patients are not due to medications, including direct comparisons between medicated vs unmedicated patients, medication-naive vs medicated patients, and correlations between performance and medications; (d) evidence that impairments are observed regardless of the illness state, including that first-episode, chronic, and remitted patients exhibit similar patterns of impairments. (3) Heritability: (a) in healthy populations and (b) in schizophrenia families. (4) Found in unaffected relatives at a higher rate than in the general population so that small to moderate effect sizes between biological relatives of schizophrenia patients and community controls are observed. In addition, the COGS selected measures that have a known neurobiological substrate relevant to schizophrenia and whose initial results support using them to test genetic hypotheses. Moreover, we considered the practicality of task administration in a large multisite protocol.

Several reviews have evaluated neurocognitive endophenotypes in schizophrenia (eg, Aleman et al,7 Snitz et al8). However, to our knowledge none have fully examined the extent to which candidate endophenotypes fulfill each of the above criteria. Here we review the endophenotypic candidacy of selected neurocognitive measures highly implicated in schizophrenia and chosen for the COGS project. These include attention, verbal memory, and working memory (WM). In addition, we present new candidates for consideration in future studies: face recognition memory and emotion processing.


Deficits in attention have long been considered to be central features of the clinical presentation of schizophrenia3,9 and have been a consistent focus of the experimental psychopathology of schizophrenia.1014 Attention is apparently dysfunctional in schizophrenia in several ways, including sustained focused attention,15,16 selective attention,17 and cognitive control of attention.18 While cognitive control of attention and selective attention have strong conceptual relationships to WM,19 a recent integration of factor analytic studies of cognition in schizophrenia indicates that sustained focused attention is separable from other neurocognitive factors.20 Furthermore, it is the deficit in sustained focused attention that has garnered the most support as an attention endophenotype for schizophrenia.2123

Continuous Performance Tests (CPTs) have become the most widely used measures of deficits in sustained focused attention and among the most frequently applied indices of neurocognitive deficits in schizophrenia.10,15,16 CPT refers to a type of rapidly paced vigilance task that was originally designed to examine sustained focused attention in individuals with suspected neurological damage24 and that has been adapted for research on schizophrenia,25,26 attention-deficit hyperactivity disorder,27 and other disorders.28 All versions evaluate the ability to maintain a focused readiness to detect and respond to selected target stimuli over a prolonged time period. CPTs typically involve a quickly paced series of stimuli (eg, one stimulus per second), brief stimulus durations (usually 30–100 milliseconds), and relatively short periods of vigilance (5–15 minutes).16 The individual stimuli are usually single visual letters or digits, but visual numbers with several digits and visual shapes25 and auditory stimuli29 have been used as well.

The subject's task in a CPT is to monitor the continuous series of stimuli and to respond each time that a target stimulus appears. The target can be one that can be discriminated within either a single stimulus presentation (eg, the letter “X” or the digit “0”) or a stimulus sequence (an “A” followed by an “X,” a “3” followed by a “7,” or 2 identical numbers in a row; see figure 1). Performance can be evaluated using correct target detections (hits) and incorrect responses to nontargets (false alarms), as well as through separation of signal/noise discrimination (d′ or A′) and response criterion dimensions by signal detection theory indices.30 The signal/noise discrimination index has become the most common primary score in recent studies. To increase the sensitivity to detect subtle abnormalities such as those characterizing vulnerability to schizophrenia, CPT stimuli have been blurred (degraded) to increase perceptual discrimination load26,31 or a high WM load has been added by defining the target as identical sequential stimuli rather than a fixed stimulus.25,32 Key evidence supporting an association between CPT performance and schizophrenia is presented in table 1.

Table 1
Summary Table of Key Evidence Supporting Each Candidate Endophenotype's Association With Schizophrenia and Occurrence in Relatives
Fig. 1
Examples of the stimuli in the computerized Degraded Stimulus Continuous Performance Test. The “0” is the target stimulus. Printed with permission of Keith H. Nuechterlein.

State Independence

Performance on both the CPT version involving blurred digits (Degraded Stimulus Continuous Performance Test [DS-CPT])31 and the CPT version involving successive identical sets of digits (Continuous Performance Test, Identical Pairs Version [CPT-IP])25 has shown substantial stability over time. The stability of DS-CPT d′ over 1 year was found to be 0.65 for schizophrenia patients and 0.72 for healthy subjects.62 For CPT-IP d′, stability over 2 years ranged from 0.56 to 0.73.25

For the computerized DS-CPT developed by Nuechterlein and Asarnow,63 signal/noise discrimination levels are highly consistent across sites for healthy subjects (eg, A′ of 0.94 ± 0.04, 0.95 ± 0.05, and 0.94 ± 0.05 in Los Angeles, Germany, and Japan, respectively) and for schizophrenia patients (A′ of 0.89, 0.88, and 0.88 in Los Angeles, Germany, and Japan, respectively).34,64,65 Similar reliability across sites characterizes the CPT-IP.25,50 The availability of standardized PC versions of these CPTs likely aids the repeatability of findings across sites.

CPT impairments have been documented even in medication-naive and medication-withdrawn schizophrenia patients.51,66 It was evident from initial studies of CPT performance that antipsychotic medications do not contribute to CPT deficits; rather, deficits within easier early CPT versions in schizophrenia patients were improved by first-generation antipsychotic medications.67,68 It appears from initial studies that second-generation antipsychotic medications have the ability to improve CPT performance, although not to normal levels, even for the more demanding DS-CPT69 and CPT-IP,70 although another study found stable DS-CPT performance from drug-free baseline to treatment with a second-generation antipsychotic medication.71 Thus, CPT deficits in schizophrenia are not due to antipsychotic medication, but their severity may be attenuated by antipsychotics.

Both cross-sectional66,72 and longitudinal studies39 indicate that CPT impairments are present in schizophrenia even in a clinically remitted state, so it is clear that these attentional impairments are not secondary to active symptoms. Whether a CPT deficit shows significant change with clinical state may vary by CPT version. The magnitude of DS-CPT d′ deficit has been shown to be stable across psychotic and remitted states when medications were unchanged, while d′ in a memory-load CPT type (3–7 CPT) clearly improved in clinical remission in the same sample.39 CPT signal/noise discrimination was also found to be stable despite introduction of medication and clinical improvement in a 1–9 CPT with flanker-distracting stimuli.51 Thus, while some types of CPT deficits improve with symptomatic amelioration, others are stable from psychotic to fully remitted clinical states. The CPT parameters that control whether performance deficits vary with symptomatic improvement are not wholly clear at this point and could benefit from more systematic study.

Occurrence in Unaffected Relatives and Heritability

CPTs with high perceptual discrimination loads or WM loads have been used successfully for detection of neurocognitive deficits among biological relatives of schizophrenia patients (see table 1). Simple CPT versions with low perceptual discrimination and low WM loads26,44,52 often fail to detect deficits in first-degree relatives, so the processing load appears to be relevant to successful use of CPT deficit as an endophenotype.12 Formal heritability estimates for CPT performance are beginning to be available, based on sib-sib or parent-child correlations. For the CPT-IP d′, heritability based on 30 healthy families was estimated as 0.39 for the verbal and 0.49 for the spatial condition.25 Among relatives of schizophrenia probands, Chen et al 45 reported estimated CPT d′ heritability ranging from 0.48 to 0.62. For a CPT-DS condition that comes closest to the DS-CPT used in the COGS project, heritability was estimated as 0.57 based on 10 families with data on 2 parents and 0.51 based on 18 families with data on 1 parent. An earlier study of siblings of schizophrenia patients estimated heritability for DS-CPT d′ at 0.79.46 Thus, larger studies are definitely needed, and these initial estimates of heritability need to be viewed cautiously due to small sample sizes. However, initial evidence suggests at least moderate heritability for CPT performance in healthy families and families with schizophrenia probands.

Cosegregation of Endophenotype and Illness Within Families

While the issue of cosegregation of schizophrenia and CPT deficits within families has not been formally addressed at this point, the issue of whether schizotypal personality features and CPT deficits are correlated within families of schizophrenia probands has received some attention. Initial data suggested that low DS-CPT d′ within siblings of schizophrenia probands might be associated with more social-interpersonal schizotypal features and with physical anhedonia.46 Subsequent research by Chen et al45 also found associations within families between degraded and undegraded CPT d′ and the interpersonal aspects of schizotypy but not the cognitive/perceptual aspects (illusions and odd ideas). The latter study also found significant associations between degraded and undegraded CPT d′ and the disorganization dimension of schizotypy. Generally consistent with the latter result is the finding from Nuechterlein et al,73 using a factor analytic approach, that DS-CPT d′ deficits in relatives of schizophrenia patients fell on the same Cognitive Disorganization factor as Trail Making B and Span of Apprehension performance and odd or eccentric behavior, although in this case other schizotypal features of disorganization were not associated with CPT deficits. Paralleling the Chen et al results, Nuechterlein et al found that the cognitive/perceptual schizotypal dimension (positive schizotypy) was not related to the cognitive performance deficits. Performance on the CPT-IP has also been associated with interpersonal difficulties in relatives of schizophrenia patients, at least in the sense that early CPT-IP d′ deficits in children of schizophrenia patients predicted later emergence of social withdrawal in adulthood.74 In contrast, 2 French studies of relatives of schizophrenia patients did not find significant associations between social or physical anhedonia and either DS-CPT d′ or CPT-IP d′.53,75 Thus, these associations between CPT deficits and schizotypal features among relatives need further examination, but initial indications suggest potential relationships to the social-interpersonal and disorganization dimensions of schizotypy. Within-family analyses are needed to examine cosegregation of CPT deficits and schizophrenia itself.

Neurobiological Substrates and Schizophrenia

The neurobiological substrate of CPT performance has not been extensively studied, but functional neuroimaging has provided some meaningful patterns. Using positron-emission tomography in healthy participants, the DS-CPT was found to activate right prefrontal and temporal regions.76 Signal/noise discrimination level (d′) correlated positively with relative glucose metabolic rates in medial superior frontal gyrus and right inferior temporal gyrus.77 Schizophrenia patients showed abnormally low relative glucose metabolic rate in right and left frontal cortex and right temporal cortex during DS-CPT activation.76 Later analyses of more differentiated regions indicated that patients have decreased activation during the DS-CPT in medial frontal cortex, cingulate gyrus, medial temporal lobe, and ventral caudate, supporting the role of cortical-striatal-thalamic pathways.78

Seidman et al29 developed an auditory CPT with and without WM demands. In a functional magnetic resonance imaging (fMRI) study of healthy men, compared with the vigilance task, performance of the WM task produced significant activation in the lateral and medial prefrontal cortex; precentral cortex; temporal lobe, including insula and hippocampus; parietal-occipital cortex; cingulate; thalamus; and superior colliculus. This paradigm was then applied to adult nonpsychotic relatives of persons with schizophrenia.79 Compared with controls, relatives showed greater task-elicited activation in the dorsolateral prefrontal cortex and the anterior and dorsomedial thalamus. When the effects of between-group performance differences were controlled, relatives showed significantly greater activation in the anterior cingulate. Results support the hypothesis that subtle abnormalities of brain function, in the anterior attentional network, are found in relatives of persons with schizophrenia, in the absence of psychosis.

Sponheim et al80 have demonstrated that relatives of schizophrenia patients show decreased late-positive amplitudes (P300) over parietal areas and increased early posterior (P1) and right frontal (anterior N1) event-related potentials (ERPs) during target detection. Thus, a pattern of augmented early potentials and diminished late potentials during sustained attention may be associated with genetic susceptibility to schizophrenia. Additional studies using neuroimaging with better temporal resolution (eg, ERP, fMRI), coupled with parametric manipulations of CPT dimensions, are needed to more clearly isolate the relevant neural pathways.

Utility in Tests of Genetic Hypotheses

While the data reviewed thus far are certainly encouraging regarding the value of CPT deficits as an endophenotype for schizophrenia, it has been argued that a recurrence risk ratio greater than that of schizophrenia itself is needed for an endophenotype to be clearly useful.81 The recurrence risk of schizophrenia is about 10. An analysis with a low memory-load CPT indicated that the recurrence risk ratio for CPT deficits in siblings of schizophrenia probands was elevated but was in the 3–5 range.40 However, a more recent study using a more demanding CPT version that involves degraded stimuli and a memory load found that the recurrence risk ratio using a cutoff of demographically adjusted z scores for d′ in the -2.5 to -3.0 range was much higher, ranging from 12 to 103 for parents and from 9 to 72 for siblings.47 While the extremely high recurrence risk ratios for the most d′-stringent cutoffs are unstable because the number of subjects at those extremes is small, the general magnitude of these ratios is very encouraging.

Specific genes related to CPT deficits are beginning to be examined. Deficits in CPT d′ are evident in schizophrenia patients with 22q11 deletion (velocardiofacial syndrome), so that location is a potential genetic contributor.82 DS-CPT d′ and CPT-IP d′ deficits were found to be among the contributors to a subtype of schizophrenia with pervasive neurocognitive deficit that explains linkage of schizophrenia to chromosome 6p24.83 While studies of normal genetic variation and attention have generally not employed CPT variants, one might also expect from studies of other attentional measures that the dopaminergic genes catechol-O-methyltransferase (COMT) on chromosome 22 and dopamine receptor D4 on chromosome 11 may influence sustained focused attention, with the former showing more relevance to schizophrenia at this point.84 Indications that P50 suppression deficits in schizophrenia are linked to an alpha-7 nicotinic acetylcholine receptor gene85 suggest that this gene may also play a role in sustained attention because P50 suppression deficits are correlated with sustained attention deficits.86

Practicality for Multisite Protocols

The COGS project selected the DS-CPT26,31 and the CPT-IP25,32 to represent the attentional endophenotype due to both the promising literature using these versions and the ease with which the computerized versions of these tasks can be administered within multisite protocols. To maintain maximal independence of the WM endophenotype and the CPT phenotype, the perceptual-load DS-CPT rather than the memory-load CPT-IP is used as the primary attention measure, while the other is included as a useful supplementary measure.

The computer program for the DS-CPT allows this task to be administered using a PC and 15-in cathode-ray tube monitor.63 Single digits 0–9 are presented in quasirandom order at a rate of 1/second with 29-millisecond exposures. A random 40% of the pixels in each digit and in the background are changed from black to white, or vice versa, to create a highly blurred image. The participant's task is to monitor the rapid series of digits and to respond as quickly as possible with a button press to each blurred 0 that appears. After a practice period to train subjects in basic discrimination of the blurred digits, an 8-minute vigilance period with 480 stimuli follows. The entire measure takes about 15 minutes, including initial instructions. The computer program automatically provides several indices of performance, including the d′ summary score.

Administration of the PC version of the CPT-IP25 is also straightforward. The conditions being used involve sustained attention in situations demanding substantial verbal WM. Subjects are asked to respond each time that the same stimulus occurs twice in a row in a quasirandom sequence within a 3-digit and a 4-digit condition. Each condition involves presentation of 300 stimuli in a rapid, continuous sequence (1/second) with stimulus durations of 50 milliseconds. The d′ value for the 4-digit number condition is being used as the principal measure of performance because it has been used successfully to examine the predictive role of the CPT-IP in a longitudinal study of the offspring of schizophrenic patients.43 Testing time is 15 minutes, including instructions. The extent to which the CPT-IP version identifies the same endophenotype as the DS-CPT is as yet unclear, so inclusion of both versions will allow this issue to be examined.

Verbal Declarative Memory

Deficits in verbal declarative memory (VDM) are among the most prominent cognitive difficulties observed in schizophrenia,7,87 in less severe spectrum conditions,88 and in close biological relatives who do not meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria for a schizophrenia-related psychiatric disorder.8,55,57,89 A review of more than 110 studies showed that they are among the most robust deficits in schizophrenia55 (see table 1). The dysfunction takes several forms, including deficits in acquisition/encoding, memory storage (ie, abnormal forgetting), and retrieval.90,91 Less commonly, significantly abnormal rates of forgetting may occur,55,92 at least in a subgroup of patients.93 Most participants with schizophrenia show rates of forgetting that are only subtly impaired relative to controls, however, and are more like patients with subtle, material-specific memory disorders like temporal lobe epilepsy94,95 than they are like patients with Alzheimer's disease (AD).96 Patients do show prominent deficits in retrieval of information using free-recall paradigms, and/or difficulties encoding new information, but better performance on cued or recognition conditions.55,92,93,97,98

State Independence

Widely used measures of VDM, such as the Wechsler Memory Scale, Third Edition (WMS-III), test of story recall (Logical Memory [LM]99) and the California Verbal Learning Test, Second Edition (CVLT-II), test of list learning,100 report adequate levels of test-retest reliability in normal standardization samples. For example, WMS-III LM reliability coefficients for the immediate (I) and delayed (II) free-recall conditions are 0.74 and 0.76, respectively, for 16- to 54-year-old participants, with 2- to 12-week test-retest intervals. Test-retest coefficients for the CVLT-II, obtained with median 3-week test-retest intervals in 16- to 88-year-old subjects, ranged from 0.79 to 0.88 for trial 1–5 total correct responses, short-delay free-recall correct, long-delay free-recall correct, and recognition hits.

Few studies have assessed the stability of deficits in VDM in schizophrenia. In one, Harvey et al101 reported moderate test-retest coefficients after 8 weeks for total learning and for delayed recall (0.64 and 0.62, respectively) on the word list learning test102 in middle-aged and elderly patients with schizophrenia or schizoaffective disorder. The stability of VDM deficits was also confirmed in a 4-year follow-up study of adult nonpsychotic, first-degree biological relatives of patients with schizophrenia.81,103 Deficits in VDM (assessed by the WMS Revised version LM test) were among the most robust indicators of cognitive impairment in the relatives' sample.

Many large studies of schizophrenia, such as clinical trials, assess VDM across multiple sites (eg, Keefe et al70 collected data in 14 sites), although reliability across sites is often not reported. Good indications of strong between-site reliability, however, come from meta-analyses. The Global Verbal Memory construct of Heinrich and Zakzanis,33 which showed the most robust deficit in the battery of neurocognitive tests they examined in schizophrenia patients (d = 1.41), was based on 31 studies, mostly from different laboratories. Similarly, moderate LM I deficits in relatives of subjects with schizophrenia (d = 0.42) reported by Snitz et al8 came from 5 separate studies, although there is up to 0.5 standard deviations variability across sites.57

Two issues especially relevant to state independence involve medication effects. The first is whether medications for schizophrenia contribute to deficits in VDM. Although the issue is significant (eg, anticholinergic effects that characterize many antipsychotic medications to varying degrees have long been associated with impaired declarative learning and memory),104 medication effects themselves do not account for the extent of performance deficits observed in tests of verbal learning and memory.104 Moreover, deficits observed in the absence of medication, such as those occurring before or near the first psychotic episode, reflect their intrinsic nature.105,106

The second issue pertaining to state independence of memory deficits relates to whether they persist following treatment with antipsychotic medications. A majority of studies do demonstrate improvement in long-term memory following administration of second-generation antipsychotics (eg, 17 of 23 studies in a recent meta-analysis) and only slightly less positive effects for first-generation antipsychotic drugs (the difference in effect size was 0.17).70,107 Nevertheless, the magnitude of improvement is modest, usually reflecting effect sizes less than 0.5, which is substantially smaller than the usual deficit of 1.0–1.5 in this domain.33,82,108 Taken together, this literature shows that deficits in VDM in schizophrenia occur largely independently of positive or negative effects of antipsychotic medications.

Deficits in VDM are evident throughout the course of the illness, including the periods before psychosis, near the first psychotic episode, and after remission from psychotic symptoms.55,105 Deficits in VDM appear to be most related (though mildly so) to negative symptoms.55

Occurrence in Unaffected Relatives and Heritability

Like their relatives with schizophrenia, adult and adolescent nonpsychotic biological relatives of patients with schizophrenia also perform worse on encoding (but less so on the rate of forgetting) than controls on tests of VDM55,81,89,103,109111 (see table 1). These findings further support the view that impairments in learning and memory reflect intrinsic features of the disorder rather than epiphenomena related to effects of medication, psychosis, or other cognitive dysfunctions.98

Several studies examined the heritability of VDM in healthy people or in participants with schizophrenia. Typical of many studies that examined the heritability of particular mental abilities, Bouchard112 reported heritability estimates in the moderate range (about 0.50) for memory. Similarly, Finkel et al,113 using a twin sample, assessed recall on the WMS LM test. Heritability estimates for delayed recall were 0.47 for healthy young participants, 0.63 for middle-aged adults, and 0.61 for older adults. Lee et al114 examined performance on Buschke Selective Reminding Test in subjects from families with AD. Heritability estimates in unaffected family members (ie, without AD) were lower than those reported by Lee et al, using the LM test, but still remained in the moderate range (total recall = 0.32, delayed recall = 0.39, delayed recognition = 0.31).

Few studies have quantified the heritability of cognitive deficits in schizophrenia.115 In one, Tuulio-Henrikssen et al116 reported heritability estimates for several cognitive abilities in patients with schizophrenia and their first-degree biological relatives. Although verbal ability showed moderate heritability (0.62), recall on trials 1–5 of the CVLT, a verbal test of learning and memory, showed a small effect size (0.21). By contrast, recognition memory was higher (0.49). More studies will be necessary before conclusions about the heritability of deficits in verbal learning and memory can be drawn for schizophrenia.

Cosegregation of Endophenotype and Illness Within Families

Formal cosegregation investigations involving VDM are needed, although a few studies are relevant to the issue. In one, Johnson et al117 showed that deficits in cognitive functioning, including WMS LM I and II and CVLT recall on trials 1–5, occurred in unaffected cotwins of patients with schizophrenia, in association with symptoms of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, schizotypal personality disorder. Individuals with schizotypal symptoms who did not demonstrate a family history of schizophrenia also did not manifest these cognitive deficits. Faraone et al110 showed that greater degrees of “genetic loading” for schizophrenia (defined as having 2 first-degree relatives with schizophrenia rather than 1) were associated with greater deficits in VDM (ie, LM). Although Cannon et al118 found in one study that several cognitive deficits (eg, divided attention) covaried with the degree of genetic relationship in twins discordant for schizophrenia more strongly than did VDM, it is likely that deficits in VDM increase in families in association with increases in the density of schizophrenia and schizophrenia spectrum–related symptoms.

Neurobiological Substrates and Schizophrenia

Deficits in VDM most likely reflect an endophenotype that is related to the underlying neurobiological substrates in the medial temporal and the frontal lobes. Both of these brain regions mediate VDM, and both are impaired in schizophrenia.119122 Consistent with this view, Seidman et al123 reported that deficits in VDM (ie, LM) were correlated with smaller left hippocampi (a medial temporal lobe structure) in adult nonpsychotic, first-degree biological relatives of patients with schizophrenia. The moderate heritability estimate for deficits in recognition memory on the CVLT reported by Tuulio-Henrikssen et al116 implicates frontal lobe mechanisms of retrieval.

Utility in Tests of Genetic Hypotheses

Measures from the CVLT-II were selected as VDM endophenotypes for use in the COGS project. Measures from the WMS-III LM test were added recently to help assess the differential sensitivity of these 2 commonly used measures. Although these measures of VDM are likely to be informative in genetic analyses, currently the identification of possible genotypes related to VDM in schizophrenia is in its early stages. Cannon et al,124 eg, showed overrepresentation of disrupted-in schizophrenia 1 (DISC1) and translin-associated factor X genes (1q42) in patients with schizophrenia, which were associated with neurobiological and cognitive abnormalities that included VDM. The same group also reported evidence for a locus related to VDM in schizophrenia at 4q21.125

Practicality for Multisite Protocols

COGS training and ongoing quality assurance measures are designed to minimize procedural differences across the 7 sites in the Consortium. Thus far, they have been successful with respect to CVLT-II administration, which also benefits from relatively well-described, straightforward administration and training procedures.

Working Memory

WM deficits have been described as core cognitive features of schizophrenia126 and are particularly strong candidate endophenotypes (see table 1). WM is often defined as a limited-capacity storage system used for the temporary maintenance and manipulation of information, although a variety of conceptual models and methodological approaches have been used to investigate the cognitive functions that comprise WM (see Miyake and Shah,127 Repovs and Bresjanac128). For example, the influential, multicomponent model of WM proposed by Baddeley129,130 includes 3 limited-capacity storage buffers—the phonological loop, the visuospatial sketch pad, and the episodic buffer—and a central executive control system that guides the manipulation of information held within the subsidiary storage buffers. Other investigators emphasize distinctions between transient, online maintenance or manipulation functions of the WM system.131,132 The cognitive architecture and neurophysiological bases of WM processes have been extensively investigated in human and nonhuman primates,133137 and this rich body of basic research has facilitated investigations of WM processes that are associated with vulnerability to schizophrenia.

Within the schizophrenia research literature, investigators have used a variety of paradigms derived from cognitive neuroscience and clinical neuropsychology to assess WM functions. These diverse paradigms have been described as falling into 2 broad classes of WM functions.138 The first type of paradigm assesses transient, online maintenance functions that do not involve manipulation of the stored information. These tasks assess functions that in many ways map onto those ascribed to the storage buffers described in Baddeley's WM model (eg, rehearsal). Examples include spatial delayed response tasks and digit or spatial span forward repetition tasks. In the spatial domain, this aspect of WM is very amenable to animal model research exploring its neurobiological underpinnings.139 The second class of paradigms involves maintenance plus manipulation of information or “executive functioning WM.” Central executive or control functions are required when stored information needs to be transformed in some way, updated, temporally coded or sequenced, or protected from interference or decay. Examples include N-back tasks and digit or spatial span backward repetition tasks. A newer, more challenging verbal span task, the Letter-Number Span task140 and its adaptation for the WMS, Version III, called the Letter-Number Sequencing task (LNS99), requires subjects to both categorize alternating letters and numbers into separate classes and reorder the stimuli within each class (see figure 2).

Fig. 2
The Letter-Number Sequencing Test comprises 2 conditions. In the Letter-Number Sequencing task (LNS)–forward condition, the tester verbally presents different sets of increasingly longer sequences of intermixed letters and numbers at a rate of ...

Performance deficits shown by schizophrenia patients often appear to be more severe on WM tasks that involve maintenance plus complex manipulation functions than those observed in maintenance-only tasks.141,142 For example, in the verbal domain, patients and controls show an average separation of about of 0.71–0.82 standard deviations on digit span forward and backward tasks,7 whereas effect sizes for the more challenging LNS have exceeded 1.4 standard deviations (eg, Perry et al,138 Gold et al,140 Conklin et al143). WM deficits do not appear to be artifacts of any particular task parameter, such as duration of delay interval, and the magnitude of performance differences between patients and nonpatient controls is comparable across verbal, spatial, and object WM tasks.59 The WM deficits of schizophrenia patients show associations with clinically important features of the disorder. For example, impairments on WM tasks show substantial relationships with measures of more complex cognitive processes such as problem solving, language comprehension, and planning.140,144 WM impairments also show consistent relationships with various aspects of poor functional outcome, including poor social and vocational functioning and less benefit from rehabilitation interventions (eg, Green et al,4 Kopelowicz et al,145 Smith et al146). Thus, WM impairments are robust and clinically significant features of schizophrenia.

State Independence

WM deficits appear to reflect traitlike features of schizophrenia that are not attributable to potential confounds. As noted above, WM impairments show minimal cross-sectional correlations with severity of delusions and hallucinations. In addition, WM deficits are detectable in clinically stable outpatients and demonstrate considerable constancy across both time and fluctuations in clinical status, suggesting that they are not merely secondary manifestations of psychotic symptoms.147151 Although WM task performance is typically not associated with acute psychotic symptoms such as delusions and hallucinations, moderate associations with severity of negative symptoms and formal thought disorder are often found.152154 WM deficits do not reflect side effects of antipsychotic medications as they are present in neuroleptic-free and neuroleptic-naive patients (eg, Barch et al,155 Carter et al156), and atypical antipsychotics may actually improve WM to some degree.157 WM impairments are also not secondary to factors associated with chronicity, such as illness progression or prolonged exposure to antipsychotic medications, because comparably severe deficits are also detectable during the immediate postonset period.144,158 WM impairments thus appear to reflect fundamental features of schizophrenia that are stable throughout the course of illness.

Occurrence in Unaffected Relatives and Heritability

Several studies indicate that similar, though attenuated, WM disturbances are also present in clinically unaffected biological relatives of schizophrenia patients, compared with the general population (see table 1). As in patients, WM impairments among their relatives may be more severe on tasks that require demanding executive functions. A recent report by Conklin et al143 found this pattern across multiple verbal and spatial WM tasks, with the largest effect size in the verbal domain obtained for the more demanding LNS (d = 0.66).

Research in both nonclinical and schizophrenia patient samples indicates that genes substantially influence WM abilities. Heritability estimates for verbal and spatial WM storage and executive functions in nonclinical samples are moderately high (0.43–0.49159,160). Comparable heritability estimates have been reported for visual and verbal WM in schizophrenia (0.36–0.42116,161). These findings suggest that WM deficits are partially under genetic control in both healthy individuals and in the families of individuals with schizophrenia.

Cosegregation of Endophenotype and Illness Within Families

We are unaware of any true cosegregation studies examining WM within families of schizophrenia probands. However, some studies do report significant relationships between severity of WM impairment and level of genetic loading for schizophrenia among unaffected relatives. Severity of WM impairments relate to genetic loading among singleton vs multiplex families116,161 and in discordant dizygotic vs monozygotic twin pairs.118,162 The COGS design will allow us to directly evaluate whether WM impairments cosegregate within the families of schizophrenia probands.

Neurobiological Substrates and Schizophrenia

The functional neuroanatomy of WM has been fairly well characterized and abnormalities in the key neural systems that are involved in WM have been extensively documented in schizophrenia. A wealth of animal and human studies indicate that the prefrontal cortex, particularly the dorsolateral prefrontal cortex, and the dopaminergic system, in conjunction with posterior brain regions such as the posterior parietal cortex, are critical for intact WM.163 The precise roles of these cortical regions and dopamine in the component processes of WM continue to be actively investigated (eg, Braver and Barch,164 Jonides et al,165 Owen et al166).

Disruptions of the dopaminergic system as well as gross morphological, cytoarchitectonic, and functional abnormalities of prefrontal cortex have been well established in schizophrenia and figure prominently in etiological theories of this disorder.167172 Furthermore, individuals with schizophrenia, as well as their unaffected biological relatives, demonstrate altered physiological activity in the prefrontal cortex while performing WM tasks.173177 Thus, the neurobiological systems that are essential for WM are strongly implicated in the pathophysiology of schizophrenia.

Utility in Tests of Genetic Hypotheses

Evidence that WM deficits are heritable and dependent on neurobiological substrates that are disrupted in schizophrenia strongly implicates genes that regulate these neural systems as candidate susceptibility genes. There have already been several efforts to identify polymorphisms in specific genes that modulate WM performance in both the normal population and individuals with schizophrenia (see Greenwood and Parasuraman84). Most reports have focused on the val158met polymorphism of the COMT gene on chromosome 22, which plays a key role in cortical dopamine metabolism. Several groups have reported association between this polymorphism and performance on, as wells as prefrontal physiological activation during, measures of WM and executive control in schizophrenia patients, their family members, and healthy controls (see Bruder et al,178 Goldberg and Weinberger179). However, these findings have not been uniformly replicated.180,181

Initial reports also indicate that alleles in the DISC1 gene on chromosome 2 show association with WM task performance, as well as prefrontal physiological abnormalities, in schizophrenia patients and their unaffected twins.175,182,183 In healthy subjects, associations between the G-to-A polymorphism of the dopamine beta-hydrosylase gene have recently been found to specifically modulate WM,184 though this association has not yet been examined in schizophrenia. Thus, emerging research supports the feasibility of detecting associations between specific genes and WM performance in schizophrenia patients and their biological relatives.

Practicality for Multisite Protocols

The COGS project has selected the LNS to assess WM. The LNS is simple to administer in a standardized manner,99 relatively brief, and includes both forward (intermixed letter-number strings repeated verbatim) and reordered conditions (intermixed letter-number strings repeated with numbers first in ascending order and then letters in alphabetical order) to assay both maintenance-only and executive control functions of the WM system. The LNS and related verbal span tasks have been successfully implemented in large, multicenter studies of schizophrenia patients (eg, Keefe et al,185 McGurk et al186). The LNS-reordered condition also has the advantage of showing larger separations in performance for schizophrenia patients and their biological relatives as compared with healthy controls than conventional span tasks, presumably due to its heavier demands on central executive functions.

Penn Computerized Neurocognitive Battery: Candidate Endophenotypes

The Penn computerized neurocognitive battery (CNB) was validated in healthy people187 and patients with schizophrenia.188 These studies demonstrated test-retest reliability, sensitivity to diagnosis, age effects, and sex differences. The CNB was robust to repeated measures with minimal practice effects, limited to speed. Except for modest improvement in spatial memory, scores were not affected by treatment with olanzapine.189 The battery was designed for large-scale studies and is administered on a portable computer, in the laboratory or in the field, in a fixed order using clickable icons. It was included in the COGS to characterize the neurocognitive functioning of participants in multiple cognitive domains and to provide additional potential endophenotypes. To reduce redundancy with core COGS neurocognitive endophenotypes described above, tasks were selected to assess 7 domains (examples in figure 3): abstraction and mental flexibility (Penn Conditional Exclusion Test190), attention and WM (Letter-n-Back191), face memory (Penn Face Memory Test [PFMT]192), spatial memory (Visual Object Learning Test [VOLT]193), spatial processing (Computerized Judgment of Line Orientation187), sensorimotor dexterity (Computerized Finger-Tapping Task and Motor Praxis test), and emotion processing (Penn Emotion Recognition Test [PERT]—40194).

Fig. 3
Examples of stimuli from the Penn computerized neurocognitive battery.

For each domain, 3 performance functions are calculated: (1) accuracy, which reflects the number of correct responses; (2) processing speed, reflected by the median response time for correct responses; and (3) efficiency, which reflects both accuracy and processing speed [accuracy/log(speed)]. Thus, the computerized battery has the advantage of providing separate measures of facets of performance typically inaccessible to traditional paper-and-pencil measures. The administration time of the COGS version of the Penn battery is approximately 60 minutes, including brief standardized rest periods.

The neurocognitive domains of the Penn battery reflect a range of abilities, only some of which have been implicated as candidate endophenotypes. The current review focuses on 2 related domains involving facial processing abilities, which are assessed in the COGS and have been associated with schizophrenia but heretofore have not been widely regarded as candidate endophenotypes of the disorder: face recognition memory and emotion processing. We discuss the research that has been conducted on these abilities supporting their potential as endophenotypes, with the goal of fostering further research evaluating their candidacy.

The processing of facial information, including the ability to recognize and remember faces in order to distinguish the familiar from the unfamiliar, and the ability to evaluate emotions displayed in social situations are critical to effective social functioning and communication. The PFMT192 assesses face recognition memory through the presentation of 20 digitized faces, with neutral facial expressions, which are subsequently intermixed with 20 foils equated for age, gender, and ethnicity. Participants indicate whether or not they recognize each face, both immediately and after a 20-minute delay. Schizophrenia patients have frequently been reported to exhibit difficulty recognizing faces previously seen (eg, Gur et al,188 Conklin et al,195 Hellewell et al196). The PFMT has been used in several studies, employing different samples, reporting this effect.188,197199 It has been debated whether the impairment is specific to faces or instead is reflective of a more generalized memory or object memory dysfunction. Some work suggests that the face memory deficit is not accounted for by other memory and spatial deficits.195

Emotion tasks from the Penn battery were developed to address methodological drawbacks of extant emotion recognition tasks.200,201 Identification of facial affect is tested with an abbreviated (40 item) version of the Penn Emotion Recognition Test,202 which includes facial stimuli, balanced for gender, age, and ethnicity, depicting happiness, sadness, anger, fear, and neutral facial expressions (8 each; ER40). Long considered a core fundamental disturbance in schizophrenia, identification of facial affect has been reported to be impaired in schizophrenia patients across cultures (for reviews, see Kohler et al,203 Mandal et al204), including the United States (eg, Heimberg et al205), Germany,199,206 India (eg, Habel et al206), and Israel.207 Increased intensity of emotion does not appear to improve facial emotion recognition in schizophrenia patients as much as in healthy participants.194

A primary deficit in emotion recognition in schizophrenia is potentially consistent with observed social-interpersonal disturbances and clinical symptoms such as referential delusions. Errors reported include misidentification of neutral faces as emotional and negatively valenced, consistent with the potential relevance for clinical symptoms such as delusions of persecution, in which innocuous stimuli or people are interpreted as malevolent.194 There is some suggestion that particular difficulties in recognition of fear and disgust are superimposed on an overall impairment in affect recognition.194 However, a lingering question remains as to whether schizophrenia patients have a specific differential deficit in emotion recognition against the backdrop of a generalized impairment in facial processing (for reviews, see Kohler et al,203 Edwards et al208). Most studies have failed to support a specific deficit in emotion recognition when compared with nonemotional facial recognition abilities, such as age discrimination and face recognition (eg, Sachs et al,199 Kohler et al202), but studies have also varied considerably in the difficulty of comparison tasks.209 Recent work employing the same set of stimuli across emotion recognition, age discrimination, and face recognition memory tasks suggests a differential impairment in emotion recognition.209

State Independence

There is limited knowledge on the state independence of face recognition memory deficits in schizophrenia. In patients treated with olanzapine, Gur et al189 reported no significant difference in PFMT accuracy between 2 testings over a 4.5-month period, suggesting that face recognition memory accuracy is stable over time, despite clinical improvement. Face memory speed, however, improved, possibly related to practice effects.189 Gruzelier et al210 evaluated the longitudinal face memory performance (Warrington Recognition Memory Test) of schizophrenia patients tested initially when psychotic and retested when in symptomatic remission. Improvement in face memory was reported in patients classified according to symptom and behavioral data as “active” but not in patients classified as “withdrawn,” suggesting that stability of face memory deficits may be moderated by clinical subtype or symptoms.

Emotion recognition deficits have been reported in both first-episode (eg, Edwards et al,211 Wolwer et al212) and remitted (eg, Wolwer et al,212 Bediou et al213) patients, suggesting the deficit is apparent throughout the course of illness. However, there is some evidence that acutely ill patients are more impaired than remitted patients,214 that chronic patients are more impaired than recent onset patients,215 and that increased impairment is associated with higher levels of negative symptoms in clinically stable patients194 and with greater severity of both positive and negative symptoms in acute patients.202 The cumulated results suggest that emotion recognition is associated with symptom status and illness duration and that symptom improvement may reduce the appearance of emotion recognition impairment but does not fully ameliorate it.

Could treatment with psychotropic medications contribute to the observed deficit? Gaebel and Wolwer216 reported stable emotion recognition deficits in schizophrenia patients who were initially tested off medication and retested subsequent to treatment with either perazine or haloperidol. In a longitudinal comparison of facial emotion identification (Facial Emotion Identification Test) in schizophrenia patients receiving risperidone compared with those receiving haloperidol, reduced impairment in patients receiving risperidone, but not haloperidol, was reported.217 However, this study did not include a healthy comparison group, so risperidone treatment may not have improved face recognition performance to normal levels. Overall, the limited available evidence thus far suggests that although particular medications or symptom relief might enhance emotion recognition in schizophrenia patients, the observed impairments do not appear to be attributable to the effects of medication or acute symptomatology. However, more data are needed to address this question.

Occurrence in Unaffected Relatives and Heritability

Despite the long history of research on face memory and emotion recognition impairments in schizophrenia and notwithstanding considerable evidence for a genetic influence on many aspects of cognitive functioning (eg, McGue and Bouchard218), few studies have been conducted on the occurrence of impairments in schizophrenia families or the heritability of face memory and emotion recognition. Perhaps this lack of data reflects the traditional emphasis on understanding the neurobiological or clinical relevance of observed deficits, rather than their genetic underpinnings. However, the field is progressing toward more integrated, interdisciplinary approaches to understanding psychopathology (eg, Plomin and McGuffin219). Indeed, recent results support the potential endophenotype candidacy of face recognition memory and emotion recognition. In a multisite investigation of 349 individuals from 35 multiplex, multigenerational families, heritability of PFMT accuracy was 33% and speed was 25%.198 Heritability of an emotion intensity discrimination test220 was also high and significant (37.3%).198 These results suggest that both face recognition memory and emotion recognition are heritable characteristics in schizophrenia families reflecting genetic influences shared among family members.

Face recognition memory impairment in the relatives of schizophrenia patients was first reported by Conklin et al,195 using the WMS (WMS-III) Faces subtest. Calkins et al197 replicated and extended this finding, using the PFMT, the VOLT as a nonfacial object memory comparison task, and a larger sample. Significant immediate and delayed face memory deficits were observed in relatives. Although patients were more impaired in visual object memory than comparison subjects, relatives were not, suggesting that the face memory deficits are not secondary to generalized object memory deficits. Finally Gur et al.198 reported significantly reduced PFMT accuracy and speed in first-degree relatives from multigenerational families with multiple schizophrenia probands. Thus, the few studies conducted to date are in strong support that face recognition memory deficits can be observed in unaffected relatives. Moreover, in light of the limited available data on the state independence of face recognition impairments in schizophrenia patients, it is important to note that impairments in healthy relatives support the trait status in probands because relatives are not affected by potentially confounding variables associated with chronic illness, including medications.

To our knowledge, only a handful of investigations have examined emotion recognition in relatives. Toomey et al221 found no differences on tests of affect recognition between a small sample of first-degree relatives of schizophrenia patients (n = 21) and controls (n = 19). Bolte and Poustke222 reported a nonsignificant trend for schizophrenia patients' parents (n = 35) to score lower on a test of facial affect recognition than controls (n = 22) but no differences between their siblings (n = 11) and controls. Two other investigations reported evidence for subtle facial affect recognition in relatives (parents,223 siblings224). In contrast, we have recently found evidence of significant impairment in the accurate discrimination of emotion intensity among relatives (n = 291) of multiplex, multigenerational families.198 There are several possible explanations for the relative success of the latter investigation, including the larger sample size, the presumably greater genetic loading of the schizophrenia families, or the sensitivity of the emotion-processing tasks (eg, Erwin et al200). Regardless, coupled with the observed significant heritability, the results strongly support further examination of emotion-processing abilities in relatives.

Cosegregation of Endophenotype and Illness Within Families

No studies to our knowledge have addressed the coaggregation of face memory and emotion recognition in schizophrenia families. However, the data from the multiplex families in our collaborative investigations can be used to test the hypothesis that multiply affected individuals from the same families share deficits in these abilities.

Neurobiological Substrates and Schizophrenia

Lesion, imaging, and nonhuman primate studies have implicated the right fusiform gyrus, located in the occipitotemporal cortex, in face-processing tasks requiring perception of faces and objects (for discussions, see Conklin et al,143 Gur et al226). The observed face recognition memory impairment in schizophrenia families is thus consistent with a frontotemporal impairment dysfunction associated with the genetic liability for schizophrenia.

Much evidence suggests that emotional behavior is regulated by the limbic system, especially amygdala, hypothalamus, mesocorticolimbic dopaminergic systems, and cortical regions (orbitofrontal, dorsolateral prefrontal, temporal, and parietal),226 and several studies have reported amygdala or amygdala–hippocampal complex abnormalities in schizophrenia patients and their relatives (for review, see van Rijn et al227). Using fMRI and facial stimuli employed in the PERT, Gur et al226 found increased limbic response, especially the amygdala but also the hippocampus and other circumscribed limbic regions, during emotion discrimination, but not age discrimination, in healthy participants. A subsequent investigation in schizophrenia patients228 examined emotional valence discrimination and found decreased activation of the left amygdala and bilateral hippocampus in schizophrenia patients compared with controls. These results are consistent with several lines of evidence implicating emotion-processing deficits in schizophrenia (for review, see Phillips et al229). Thus, there is evidence that neurobiological substrates relevant to schizophrenia regulate performance on face recognition memory and emotion recognition measures.

Utility in Tests of Genetic Hypotheses

There is a growing body of literature examining emotion processing and the role of limbic dysfunction in schizophrenia.227 Family studies support the candidacy of face and emotion processing as endophenotypes, although there are no informative genetic studies in schizophrenia that have linked such deficits with genetic variability. Studies in healthy people have reported that serotonin transporter genetic variation is related to amygdalar reactivity. For example, 5-hydroxytryptamine transporter gene linked polymorphic region short-allele genotype was associated with greater amygdala activity in an fMRI study of a threat-related task.230 Furthermore, carriers of the short allele had reduced gray matter volume in limbic regions in an anatomic magnetic resonance imaging study and altered activity in the amygdala-cingulate circuit in an fMRI study.231 Future studies can examine mechanisms underlying emotion regulation deficits in schizophrenia.

Practicality for Multisite Protocols

The computerized format of the PFMT and the ER40 are particularly well suited for multicenter studies, because they are briefer and far less vulnerable to variations in administration, scoring, and data entry than traditional measures.187 They are currently being used in 12 academic centers in the context of 3 multisite investigations of the genetics of schizophrenia.5,198,232 Data from these investigations will be used to assess the cross-site reliability of the tasks.

Summary and Conclusions

The application of neurobehavioral measures as endophenotypes in genetic studies in schizophrenia has gained momentum. We have selected several measures that tap important neurocognitive domains—attention, verbal memory, and WM—implicated in the pathophysiology of schizophrenia. These measures not only meet established criteria for endophenotypes but also are linked to neurobiology and can elucidate mechanisms underlying their impairment in schizophrenia. In addition, we propose the inclusion of facial processing measures as promising new endophenotypes that can advance the understanding of affective deficits in schizophrenia.

We are mindful that the application of endophenotypic measures in genetic studies presents feasibility and methodology challenges. The COGS has met the feasibility challenge by demonstrating that high-quality neurocognitive data can be collected in multisite genetically informative samples.5 However, because large-scale studies are underway, there are little convincing data yet that the genetic architecture of the endophenotypes is substantially simpler than that of the schizophrenia phenotype. Furthermore, studies to date have examined individual domains when the underlying neurocognitive systems are inherently complex and interrelated. The interrelationship of neurocognitive endophenotypes among biological relatives of schizophrenia probands has received little empirical attention in the past. Indeed, examination of these interrelationships is one of the goals of the COGS. In schizophrenia patients, an integration of the evidence regarding separable neurocognitive dimensions, primarily based on factor analytic studies, suggested that 7 dimensions could be identified.20 These dimensions may be somewhat correlated rather than independent of each other.233,234 In relatives of schizophrenia probands, it is possible that combinations of several neurocognitive measures may be useful to identify a dimension of cognitive disorganization73 or a homogeneous familial subtype that is characterized by pervasive neurocognitive deficit.83 The large sample being assessed in the COGS should allow more thorough examination of these issues than prior studies. It will be necessary to move to efficient multidimensional methods of integrating data within and across modalities and levels of analysis.

Notwithstanding these challenges, by providing rigorous measures related to brain function, the quantitative endophenotype approach provides a rich source of information beyond linkage of specific phenotypes to gene action. The biometric nature of these endophenotypes should permit better parcellation of genetic and nongenetic contributions to major domains of human behavior. Such information will be pivotal for clinical applications to emanate from this line of work.


This research was supported by the following grants. University of Pennsylvania: RO1-MH65578; University of California Los Angeles: RO1-MH65707; Harvard University: RO1-MH065562, MH43518; Commonwealth Research Center of the Massachusetts Department of Mental Health. For general inquiries regarding the COGS contact David L. Braff, MD, Director of COGS, e-mail: ude.dscu@ffarbD


1. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68. [PubMed]
2. Owen MJ, Craddock N, O'Donovan MC. Schizophrenia: genes at last? Trends Genet. 2005;21:518–525. [PubMed]
3. Bleuler E. Dementia Praecox or the Group of Schizophrenias. New York, NY: International Universities Press; 1950.
4. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull. 2000;26:119–136. [PubMed]
5. Calkins ME, Dorcas DJ, Cadenhead KS, et al. Schizophr Bull. The Consortium on the Genetics of Endophenotypes in Schizophrenia (COGS): “model” recruitment, assessment, and endophenotyping methods for a multi-site collaboration. [PMC free article] [PubMed]
6. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–645. [PubMed]
7. Aleman A, Hijman R, de Haan EHF, Kahn RS. Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry. 1999;156:1358–1366. [PubMed]
8. Snitz BE, Macdonald AW, III, Carter CS. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull. 2006;32:179–194. [PMC free article] [PubMed]
9. Kraepelin E. Dementia Praecox and Paraphrenia. Edinburgh, Scotland: E. & S. Livingston; 1919.
10. Braff DL. Information processing and attention dysfunctions in schizophrenia. Schizophr Bull. 1993;19:233–259. [PubMed]
11. Nuechterlein KH. Reaction time and attention in schizophrenia: a critical evaluation of the data and theories. Schizophr Bull. 1977;3:373–428. [PubMed]
12. Nuechterlein KH, Dawson ME. Information processing and attentional functioning in the developmental course of schizophrenia disorders. Schizophr Bull. 1984;10:160–203. [PubMed]
13. Shakow D. Segmental set: a theory of the formal psychological deficit in schizophrenia. Arch Gen Psychiatry. 1962;6:1–17. [PubMed]
14. Seidman LJ. Schizophrenia and brain dysfunction: an integration of recent neurodiagnostic findings. Psychol Bull. 1983;94:195–238. [PubMed]
15. Cornblatt BA, Keilp JG. Impaired attention, genetics, and the pathophysiology of schizophrenia. Schizophr Bull. 1994;20:31–46. [PubMed]
16. Nuechterlein KH. Vigilance in schizophrenia and related disorders. In: Steinhauer SR, Gruzelier JH, Zubin J, editors. Handbook of Schizophrenia, Neuropsychology, Psychophysiology and Information Processing. Amsterdam, The Netherlands: Elsevier Science Publishers; 1991. pp. 397–433.
17. Nestor PG, Han SD, Niznikiewicz M, et al. Semantic disturbance in schizophrenia and its relationship to the cognitive neuroscience of attention. Biol Psychol. 2001;57:23–46. [PMC free article] [PubMed]
18. Cohen JD, Braver TS, O'Reilly RC. A computational approach to prefrontal cortex, cognitive control and schizophrenia: recent developments and current challenges. Philos Trans R Soc Lond B Biol Sci. 1996;351:1515–1527. [PubMed]
19. Cohen JD, Barch DM, Carter C, Servan-Schreiber D. Context-processing deficits in schizophrenia: Converging evidence from three theoretically motivated cognitive tasks. J Abnorm Psychol. 1999;108:120–133. [PubMed]
20. Nuechterlein KH, Barch DM, Gold JM, et al. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004;72:29–39. [PubMed]
21. Chen WJ, Faraone SV. Sustained attention deficits as markers of genetic susceptibility to schizophrenia. Am J Med Genet. 2000;97:52–57. [PubMed]
22. Cornblatt BA, Malhotra AK. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Am J Med Genet. 2001;105:11–15. [PubMed]
23. Nuechterlein KH, Asarnow RF, Subotnik KL, et al. Neurocognitive vulnerability factors for schizophrenia: convergence across genetic risk studies and longitudinal trait/state studies. In: Dworkin R, editor. Origins and Development of Schizophrenia: Advances in Experimental Psychopathology. Washington, DC: American Psychological Association; 1998. pp. 299–327.
24. Rosvold HE, Mirsky AF, Sarason I, Bransome ED, Jr, Beck LH. A continuous performance test of brain damage. J Consult Psychol. 1956;20:343–350. [PubMed]
25. Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-Kimling L. The Continuous Performance Test, Identical Pairs Version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Res. 1988;26:223–238. [PubMed]
26. Nuechterlein KH. Signal detection in vigilance tasks and behavioral attributes among offspring of schizophrenic mothers and among hyperactive children. J Abnorm Psychol. 1983;92:4–28. [PubMed]
27. Riccio CA, Reynolds CR, Lowe P, Moore JJ. The continuous performance test: a window on the neural substrates for attention? Arch Clin Neuropsychol. 2002;17:235–272. [PubMed]
28. Mirsky AF, Anthony BJ, Duncan CC, Ahearn MB, Kellam SG. Analysis of the elements of attention: a neuropsychological approach. Neuropsychol Rev. 1991;2:109–145. [PubMed]
29. Seidman LJ, Breiter HC, Goodman JM, et al. A functional magnetic resonance imaging study of auditory vigilance with low and high information processing demands. Neuropsychology. 1998;12:505–518. [PubMed]
30. Green DM, Swets JA. Signal Detection Theory and Psychophysics. New York, NY: Wiley; 1966.
31. Nuechterlein KH, Parasuraman R, Jiang Q. Visual sustained attention: image degradation produces rapid sensitivity decrement over time. Science. 1983;220:327–329. [PubMed]
32. Cornblatt BA, Lenzenweger MF, Erlenmeyer-Kimling L. The continuous performance test, identical pairs version: II. Contrasting attentional profiles in schizophrenic and depressed patients. Psychiatry Res. 1989;29:65–85. [PubMed]
33. Heinrichs RW, Zakzanis KK. Neurocognitive deficits in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12:426–445. [PubMed]
34. Ito M, Kanno M, Mori Y, Niwa S. Attention deficits assessed by Continuous Performance Test and Span of Apprehension Test in Japanese schizophrenic patients. Schizophr Res. 1997;23:205–211. [PubMed]
35. Bowen L, Wallace CJ, Glynn SM, et al. Schizophrenic individuals' cognitive functioning and performance in interpersonal interactions and skills training procedures. J Psychiatr Res. 1994;28:289–301. [PubMed]
36. Orzack MH, Kornetsky C. Attention dysfunction in chronic schizophrenia. Arch Gen Psychiatry. 1966;14:323–326. [PubMed]
37. Seidman LJ, Van Manen KJ, Turner WM, et al. The effects of increasing resource demand on vigilance performance in adults with schizophrenia or developmental attentional/learning disorders: a preliminary study. Schizophr Res. 1998;34:101–112. [PubMed]
38. Walker E. Attentional and neuromotor functions of schizophrenics, schizoaffectives, and patients with other affective disorders. Arch Gen Psychiatry. 1981;38:1355–1358. [PubMed]
39. Nuechterlein KH, Dawson ME, Gitlin M, et al. Developmental processes in schizophrenic disorders: longitudinal studies of vulnerability and stress. Schizophr Bull. 1992;18:387–425. [PubMed]
40. Egan MF, Goldberg TE, Gscheidle T, et al. Relative risk of attention deficits in siblings of patients with schizophrenia. Am J Psychiatry. 2000;157:1309–1316. [PubMed]
41. Braff DL, Freedman R. The importance of endophenotypes in studies of the genetics of schizophrenia. In: Davis K, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress: An Official Publication of the American College of Neuropsychopharmacology. Philadelphia, Pa: Lippincott/Williams & Wilkins; 2002. pp. 703–716.
42. Rutschmann J, Cornblatt B, Erlenmeyer-Kimling L. Sustained attention in children at risk for schizophrenia. Arch Gen Psychiatry. 1977;34:571–575. [PubMed]
43. Cornblatt B, Obuchowski M, Roberts S, Pollack S, Erlenmeyer-Kimling L. Cognitive and behavioral precursors of schizophrenia. Dev Psychopathol. 1999;11:487–508. [PubMed]
44. Maier W, Franke P, Hain C, Kopp B, Rist F. Neuropsychological indicators of the vulnerability to schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 1992;16:703–715. [PubMed]
45. Chen WJ, Liu SK, Chang CJ, et al. Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry. 1998;155:1214–1220. [PubMed]
46. Grove WM, Lebow BS, Clementz BA, et al. Familial prevalence and coaggregation of schizotypy indicators: a multitrait family study. J Abnorm Psychol. 1991;100:115–121. [PubMed]
47. Chen WJ, Chang CH, Liu SK, Hwang TJ, Hwu HG. Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis. Biol Psychiatry. 2004;55:995–1000. [PubMed]
48. Asarnow RF, Nuechterlein KH, Subotnik KL, et al. Neurocognitive impairments in non-psychotic parents of children with schizophrenia and attention deficit hyperactivity disorder: the UCLA Family Study. Arch Gen Psychiatry. 2002;59:1053–1060. [PubMed]
49. Saoud M, d'Amato T, Gutknecht C, et al. Neuropsychological deficit in siblings discordant for schizophrenia. Schizophr Bull. 2000;26:893–902. [PubMed]
50. Franke P, Maier W, Hardt J, Hain C, Cornblatt BA. Attentional abilities and measures of schizotypy: their variation and covariation in schizophrenic patients, their siblings, and normal control subjects. Psychiatry Res. 1994;54:259–272. [PubMed]
51. Finkelstein JRJ, Cannon TD, Gur RE, Gur RC, Moberg P. Attentional dysfunctions in neuroleptic-naive and neuroleptic-withdrawn schizophrenic patients and their siblings. J Abnorm Psychol. 1997;106:203–212. [PubMed]
52. Mirsky AF, Lochhead SJ, Jones BP, et al. On familial factors in the attentional deficit in schizophrenia: a review and report of two new subject samples. J Psychiatr Res. 1992;26:383–403. [PubMed]
53. Laurent A, Saoud M, Bougerol T, et al. Attentional deficits in patients with schizophrenia and in their non-psychotic first-degree relatives. Psychiatry Res. 1999;89:147–159. [PubMed]
54. Appels MC, Sitskoorn MM, Westers P, Lems E, Kahn RS. Cognitive dysfunctions in parents of schizophrenic patients parallel the deficits found in patients. Schizophr Res. 2003;63:285–293. [PubMed]
55. Cirillo M, Seidman LJ. A review of verbal declarative memory function in schizophrenia: from clinical assessment to genetics and brain mechanisms. Neuropsychol Rev. 2003;13:43–77. [PubMed]
56. Gold JM. Cognitive deficits as treatment targets in schizophrenia. Schizophr Res. 2004;72:21–28. [PubMed]
57. Sitskoorn MM, Aleman A, Ebisch SJ, Appels MC, Kahn RS. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr Res. 2004;71:285–295. [PubMed]
58. Trandafir A, Méarya A, Schürhoffa F, Leboyera M, Szöke A. Memory tests in first-degree adult relatives of schizophrenic patients: a meta-analysis. Schizophr Res. 2006;81:217–226. [PMC free article] [PubMed]
59. Lee J, Park S. Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol. 2005;114:599–611. [PubMed]
60. Erlenmeyer-Kimling L, Rock D, Roberts SA, et al. Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York high-risk project. Am J Psychiatry. 2000;157:1416–1422. [PubMed]
61. Jones LA, Cardno AG, Sanders RD, Owen MJ, Williams J. Sustained and selective attention as measures of genetic liability to schizophrenia. Schizophr Res. 2001;48:263–272. [PubMed]
62. Nuechterlein KH, Dawson ME, Ventura J, Yee-Bradbury C. Longitudinal stability of vigilance and span of apprehension deficits in the early phase of schizophrenia. Sixth Annual Meeting of the Society for Research in Psychopathology; 1991; Cambridge, MA.
63. Nuechterlein KH, Asarnow RF. Degraded Stimulus Continuous Performance Test (DS-CPT) Program for IBM-Compatible Microcomputers, Version 8.12. Los Angeles, CA: Nuechterlein KH and Asarnow RF; 1999.
64. Nuechterlein KH, Green MF, Subotnik KL, et al. Cognitive factors are highly predictive of work outcome in the early course of schizophrenia. Mt. Sinai Conference on Cognition in Schizophrenia; 1999; Santa Fe, NM.
65. Suslow T, Arolt V. Paranoid schizophrenia: non-specificity of neuropsychological vulnerability markers. Psychiatry Res. 1997;72:103–114. [PubMed]
66. Wohlberg GW, Kornetsky C. Sustained attention in remitted schizophrenics. Arch Gen Psychiatry. 1973;28:533–537. [PubMed]
67. Orzack MH, Kornetsky C, Freeman H. The effects of daily administration of carphenazine on attention in the schizophrenic patient. Psychopharmacologia. 1967;11:31–38. [PubMed]
68. Spohn HE, Lacoursiere RB, Thompson K, Coyne L. Phenothiazine effects on psychological and psychophysiological dysfunction in chronic schizophrenics. Arch Gen Psychiatry. 1977;34:633–644. [PubMed]
69. Sax KW, Strakowski SM, Keck PE., Jr Attentional improvement following quetiapine fumarate treatment in schizophrenia. Schizophr Res. 1998;33:151–155. [PubMed]
70. Keefe RS, Seidman LJ, Christensen BK, et al. Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biol Psychiatry. 2006;59:97–105. [PubMed]
71. Liu SK, Chen WJ, Chang CJ, Lin HN. Effects of atypical neuroleptics on sustained attention deficits in schizophrenia: a trial of risperidone versus haloperidol. Neuropsychopharmacology. 2000;22:311–319. [PubMed]
72. Asarnow RF, MacCrimmon DJ. Residual performance deficit in clinically remitted schizophrenics: a marker of schizophrenia? J Abnorm Psychol. 1978;87:597–608. [PubMed]
73. Nuechterlein KH, Asarnow RF, Subotnik KL, et al. The structure of schizotypy: relationships between neurocognitive and personality disorder features in relatives of schizophrenic patients in the UCLA Family Study. Schizophr Res. 2002;54:121–130. [PubMed]
74. Cornblatt B, Lenzenweger MF, Dworkin R, Erlenmeyer-Kimling L. Childhood attentional dysfunction predicts social deficits in unaffected adults at risk for schizophrenia. Br J Psychiatry. 1992;161:59–64. [PubMed]
75. Laurent A, Biloa-Tang M, Bougerol T, et al. Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives. Schizophr Res. 2000;46:269–283. [PubMed]
76. Buchsbaum MS, Nuechterlein KH, Haier RJ, et al. Glucose metabolic rate in normals and schizophrenics during the Continuous Performance Test assessed by positron emission tomography. Br J Psychiatry. 1990;156:216–227. [PubMed]
77. Siegel BV, Nuechterlein KH, Abel L, Wu JC, Buchsbaum MS. Glucose metabolic correlates of continuous performance test performance in adults with a history of infantile autism, schizophrenics, and controls. Schizophr Res. 1995;17:85–94. [PubMed]
78. Siegel BV, Jr, Buchsbaum MS, Bunney WE,, Jr, et al. Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients. Am J Psychiatry. 1993;150:1325–1336. [PubMed]
79. Thermenos HW, Seidman LJ, Breiter H, et al. Functional MRI during auditory verbal working memory in non-psychotic relatives of persons with schizophrenia: a pilot study. Biol Psychiatry. 2004;55:490–500. [PubMed]
80. Sponheim SR, McGuire KA, Stanwyck JJ. Neural anomalies during sustained attention in first-degree biological relatives of schizophrenia patients. Biol Psychiatry. 2006;60:642–652. [PubMed]
81. Faraone SV, Seidman LJ, Kremen WS, et al. Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J Abnorm Psychol. 1995;104:286–304. [PubMed]
82. van Amelsvoort T, Henry J, Morris R, et al. Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophr Res. 2004;70:223–232. [PubMed]
83. Hallmayer JF, Kalaydjieva L, Badcock J, et al. Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet. 2005;77:468–476. [PubMed]
84. Greenwood PM, Parasuraman R. Normal genetic variation, cognition, and aging. Behav Cogn Neurosci Rev. 2003;2:278–306. [PMC free article] [PubMed]
85. Freedman R, Coon H, Myles-Worsley M, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA. 1997;94:587–592. [PubMed]
86. Cullum CM, Harris JG, Waldo MC, et al. Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia. Schizophr Res. 1993;10:131–141. [PubMed]
87. Saykin AJ, Gur RC, Gur RE, et al. Neuropsychological function in schizophrenia. Selective impairment in memory and learning. Arch Gen Psychiatry. 1991;48:618–624. [PubMed]
88. Siever L, Davis K. The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry. 2004;161:398–413. [PubMed]
89. Kremen WS, Hoff AL. Neurocognitive deficits in the biological relatives of individuals with schizophrenia. In: Stone W, Faraone S, Tsuang M, editors. Early Clinical Intervention and Prevention with Schizophrenia. Totowa, NJ: Humana Press; 2004. pp. 133–158.
90. Beatty WW, Jocic Z, Monson N, Staton D. Memory and frontal lobe dysfunction in schizophrenia and schizoaffective disorder. J Nerv Ment Dis. 1993;181:448–453. [PubMed]
91. Gold J, Randolph C, Carpenter C, Goldberg T, Weinberger D. Forms of memory failure in schizophrenia. J Abnorm Psychol. 1992;101:487–494. [PubMed]
92. Seidman L, Cassens G, Kremen W, Pepple J. Neuropsychology of schizophrenia. In: White R, editor. Clinical Syndromes in Adult Neuropsychology: The Practitioner's Handbook. Amsterdam, The Netherlands: Elsevier Science Publishers; 1992. pp. 381–449.
93. Paulsen JS, Heaton RK, Sadek JR, et al. The nature of learning and memory impairments in schizophrenia. J Int Neuropsychol Soc. 1995;1:88–99. [PubMed]
94. Gold J, Blaxton T, Hermann B, et al. Memory and intelligence in lateralized temporal lobe epilepsy and schizophrenia. Schizophr Res. 1995:59–65. [PubMed]
95. Seidman LJ, Stone WS, Jones R, Harrison RH, Mirsky AF. Effects of schizophrenia and complex partial epilepsy on memory. J Int Neuropsychol Soc. 1998;4:342–352. [PubMed]
96. Heaton R, Paulsen J, LA M, et al. Neuropsychological deficits in schizophrenics. Relationship to age, chronicity, and dementia. Arch Gen Psychiatry. 1994;51:469–476. [PubMed]
97. Brebion G, Amador X, Smith MJ, Gorman JM. Mechanisms underlying memory impairment in schizophrenia. Psychol Med. 1997;27:383–393. [PubMed]
98. Weiss A, Heckers S. Neuroimaging of declarative memory in schizophrenia. Scand J Psychol. 2001;42:239–250. [PubMed]
99. Wechsler D. Wechsler Memory Scale—Third Edition. San Antonio, Tex: The Psychological Corporation, Harcourt Brace & Company; 1997.
100. Delis D, Kramer J, Kaplan E, Ober B. California Verbal Learning Test: Second Edition. Adult Version. Manual. New York, NY: The Psychological Corporation; 2000.
101. Harvey PD, Palmer BW, Heaton RK, et al. Stability of cognitive performance in older patients with schizophrenia: an 8-week test-retest study. Am J Psychiatry. 2005;162:110–117. [PubMed]
102. Ferris SH, Mackell JA, Mohs R, et al. A multicenter evaluation of new treatment efficacy instruments for Alzheimer's disease clinical trials: overview and general results: the Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S1–S12. [PubMed]
103. Faraone SV, Seidman LJ, Kremen WS, et al. Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a 4-year follow-up study. J Abnorm Psychol. 1999;108:176–181. [PubMed]
104. Brebion G, Bressan RA, Amador X, Malaspina D, Gorman JM. Medications and verbal memory impairment in schizophrenia: the role of antipsychotic drugs. Psychol Med. 2004;34:369–374. [PubMed]
105. Joyce E. Origins of cognitive dysfunction in schizophrenia: clues from age at onset. Br J Psychiatry. 2005;186:93–95. [PubMed]
106. Saykin AJ, Shtasel DL, Gur RE, et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51:124–131. [PubMed]
107. Thornton AE, Van Snellenberg JX, Sepehry AA, Honer W. The impact of antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol. 2006;20:335–346. [PubMed]
108. Heinrichs R. The primacy of cognition in schizophrenia. Am Psychol. 2005;60:229–242. [PubMed]
109. Cannon TD, Zorrilla LE, Shtasel DL, et al. Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers. Arch Gen Psychiatry. 1994;51:651–661. [PubMed]
110. Faraone SV, Seidman LF, Kremen WS, et al. Neuropsychological functioning among the nonpsychotic relatives of schizophrenia patients: the effect of genetic loading. Biol Psychiatry. 2000;48:120–126. [PubMed]
111. Seidman LJ, Giuliano AJ, Smith CW. Neuropsychological functioning in adolescents and young adults at genetic risk for schizophrenia and affective psychoses: results from the Harvard and Hillside adolescent high risk studies. Schizophr Bull. 2006;20:507–524. [PMC free article] [PubMed]
112. Bouchard T., Jr Genetic and environmental influences on adult intelligence and special mental abilities. Hum Biol. 1988;70:257–279. [PubMed]
113. Finkel D, Pedersen NL, McGue M, McClearn GE. Heritability of cognitive abilities in adult twins: comparison of Minnesota and Swedish data. Behav Genet. 1995;25:421–431. [PubMed]
114. Lee JH, Flaquer A, Stern Y, Tycko B, Mayeux R. Genetic influences on memory performance in familial Alzheimer disease. Neurology. 2004;62:414–421. [PubMed]
115. Weickert TW, Goldberg TE, Gold JM, et al. Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry. 2000;57:907–913. [PubMed]
116. Tuulio-Henriksson A, Haukka J, Partonen T, et al. Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. Am J Med Genet. 2002;114:483–490. [PubMed]
117. Johnson JK, Tuulio-Henriksson A, Pirkolac T, et al. Do schizotypal symptoms mediate the relationship between genetic risk for schizophrenia and impaired neuropsychological performance in co-twins of schizophrenic patients? Biol Psychiatry. 2003;54:1200–1204. [PubMed]
118. Cannon TD, Huttunen MO, Lonnqvist J, et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet. 2000;67:369–382. [PubMed]
119. Broadbent NJ, Clark RE, Zola S, Squire LR. The medial temporal lobe and memory. In: Squire LR, Schacter DL, editors. Neuropsychology of Memory. New York, NY: The Guilford Press; 2002. pp. 3–23.
120. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology. 2004;174:151–162. [PubMed]
121. Wagner AD. Cognitive control and episodic memory: contributions from prefrontal cortex. In: Squire LR, Schacter DL, editors. Neuropsychology of Memory. New York, NY: The Guilford Press; 2002. pp. 174–192.
122. Weinberger DR. Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry. 1999;45:395–402. [PubMed]
123. Seidman LJ, Faraone SV, Goldstein JM, et al. Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry. 2002;59:839–849. [PubMed]
124. Cannon TD, Hennah W, van Erp TG, et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005;62:1205–1213. [PubMed]
125. Paunio T, Tuulio-Henriksson A, Hiekkalinna T, et al. Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. Hum Mol Genet. 2004;13:1693–1702. [PubMed]
126. Goldman-Rakic PS. Working memory dysfunction in schizophrenia. In: Salloway SP, Malloy PF, Duffy JD, editors. The Frontal Lobes and Neuropsychiatric Illness. Washington, DC: American Psychiatric Publishing, Inc.; 2001. pp. 71–82.
127. Miyake A, Shah P. Models of Working Memory: Mechanisms of Active Maintenance and Executive Control. New York, NY: Cambridge University Press; 1999.
128. Repovs G, Bresjanac M. Cognitive neuroscience of working memory: a prologue [Introduction to special issue on working memory] Neuroscience. 2006;139:1–3.
129. Baddeley AD. Working Memory. New York, NY: Oxford University Press; 1986.
130. Baddeley AD. The episodic buffer: a new component of working memory? Trends Cogn Sci. 2000;4:417–423. [PubMed]
131. Petrides M. Mapping prefrontal cortical systems for the control of cognition. In: Toga AW, Mazziotta JC, editors. Brain Mapping: The Systems. San Diego, Calif: Academic Press; 2000. pp. 159–176.
132. Goldman-Rakic PS. The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. In: Roberts AC, Robbins TW, Weiskrantz L, editors. The Prefrontal Cortex: Executive and Cognitive Functions. Oxford University Press; 1998. pp. 87–102. [PubMed]
133. Collette F, van der Linden M. Brain imaging of the central executive component of working memory. Neurosci Biobehav Rev. 2002;26:105–125. [PubMed]
134. Constantinidis C, Procyk E. The primate working memory networks. Cogn Affect Behav Neurosci. 2004;4:444–465. [PMC free article] [PubMed]
135. D'Esposito M, Postle BR. The Organization of Working Memory Function in Lateral Prefrontal Cortex: Evidence from Event-related Functional MRI. New York, NY: Oxford University Press; 2002.
136. Sawaguchi T, Goldman-Rakic PS. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science. 1991;251:947–950. [PubMed]
137. Smith EE, Jonides J. Storage and executive processes in the frontal lobes. Science. 1999;283:1657–1661. [PubMed]
138. Perry W, Heaton RK, Potterat E, et al. Working memory in schizophrenia: transient “online” storage versus executive functioning. Schizophr Bull. 2001;27:157–176. [PubMed]
139. Castner SA, Goldman-Rakic PS, Williams GV. Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology. 2004;174:111–125. [PubMed]
140. Gold JM, Carpenter C, Randolph C, Goldberg TE, Weinberger DR. Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry. 1997;54:159–165. [PubMed]
141. Barch DM. The cognitive neuroscience of schizophrenia. Annu Rev Clin Psychol. 2005;1:321–353. [PubMed]
142. Kim J, Glahn DC, Nuechterlein KH, Cannon TD. Maintenance and manipulation of information in schizophrenia: further evidence for impairment in the central executive component of working memory. Schizophr Res. 2004;68:173–187. [PubMed]
143. Conklin HM, Curtis CE, Calkins ME, Iacono WG. Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology. Neuropsychologia. 2005;43:930–942. [PubMed]
144. Hutton SB, Puri BK, Duncan LJ, et al. Executive function in first-episode schizophrenia. Psychol Med. 1998;28:463–473. [PubMed]
145. Kopelowicz A, Liberman RP, Ventura J, Zarate R. Mintz J. Neurocognitive correlates of recovery from schizophrenia. Psychol Med. 2005;35:1165–1173. [PubMed]
146. Smith TE, Hull JW, Huppert JD. Silverstein SM. Recovery from psychosis in schizophrenia and schizoaffective disorder: symptoms and neurocognitive rate-limiters for the development of social behavior skills. Schizophr Res. 2002;55:229–237. [PubMed]
147. Heaton RK, Gladsjo JA, Palmer BW, et al. Stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry. 2001;58:24–32. [PubMed]
148. Hill SK, Schuepbach D, Herbener ES, Keshavan MS, Sweeney JA. Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia. Schizophr Res. 2004;68:49–63. [PubMed]
149. Park S, Püschel J, Sauter BH, Rentsch M, Hell D. Spatial working memory deficits and clinical symptoms in schizophrenia: a 4-month follow-up study. Biol Psychiatry. 1999;46:392–400. [PubMed]
150. Park S, Püschel J, Sauter BH, Rentsch M, Hell D. Spatial selective attention and inhibition in schizophrenia patients during acute psychosis and at 4-month follow-up. Biol Psychiatry. 2002;51:498–506. [PubMed]
151. Tyson PJ, Laws KR, Roberts KH, Mortimer AM. A longitudinal analysis of memory in patients with schizophrenia. J Clin Exp Neuropsychol. 2005;27:718–734. [PubMed]
152. Daban C, Amado I, Baylé F, et al. Disorganization syndrome is correlated to working memory deficits in unmedicated schizophrenic patients with recent onset schizophrenia. Schizophr Res. 2003;61:323–324. [PubMed]
153. Pantelis C, Harvey CA, Plant G, et al. Relationship of behavioural and symptomatic syndromes in schizophrenia to spatial working memory and attentional set-shifting ability. Psychol Med. 2004;34:693–703. [PubMed]
154. Silver H, Feldman P, Bilker W, Gur RC. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am J Psychiatry. 2003;160:1809–1816. [PubMed]
155. Barch DM, Carter CS, Braver TS, et al. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry. 2001;58:280–288. [PubMed]
156. Carter C, Robertson L, Nordahl T, Chaderjian M. Spatial working memory deficits and their relationship to negative symptoms in unmedicated schizophrenia patients. Biol Psychiatry. 1996;40:930–932. [PubMed]
157. Green MF, Marshall BD,, Jr, Wirshing WC, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry. 1997;154:799–804. [PubMed]
158. Lussier I, Stip E. Memory and attention deficits in drug naive patients with schizophrenia. Schizophr Res. 2001;48:45–55. [PubMed]
159. Ando J, Ono Y, Wright MJ. Genetic structure of spatial and verbal working memory. Behav Genet. 2001;31:615–624. [PubMed]
160. Hansell NK, Wright MJ, Luciano M, et al. Genetic covariation between event-related potential (ERP) and behavioral non-ERP measures of working-memory, processing speed, and IQ. Behav Genet. 2005;35:695–706. [PubMed]
161. Tuulio-Henriksson A, Arajarvi R, Partonen T, et al. Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients. Biol Psychiatry. 2003;54:623–628. [PubMed]
162. Glahn DC, Therman S, Manninen M, et al. Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry. 2003;53:624–626. [PubMed]
163. Wager TD, Smith EE. Neuroimaging studies of working memory: a meta-analysis. Cogn Affect Behav Neurosci. 2003;3:255–274. [PubMed]
164. Braver TS, Barch DM. A theory of cognitive control, aging cognition, and neuromodulation. Neurosci Biobehav Rev. 2002;26:809–817. [PubMed]
165. Jonides J, Lacey SC, Nee DE. Processes of working memory in mind and brain. Curr Dir Psychol Sci. 2005;14:2–5.
166. Owen AM, McMillan KM, Laird AR, Bullmore E. N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp. 2005;25:46–59. [PubMed]
167. Bunney BG, Bunney WE, Stein R, Potkin SG. Cortical pathology in schizophrenia: a review of data from the dorsolateral prefrontal cortex. Curr Opin Psychiatry. 2003;16:S9–S14.
168. Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res Neuroimaging. 2003;122:69–87. [PubMed]
169. Grace AA. Developmental dysregulation of the dopamine system and the pathophysiology of schizophrenia. In: Keshavan MS, Kennedy JL, Murray RM, editors. Neurodevelopment and Schizophrenia. New York, NY: Cambridge University Press; 2004. pp. 273–294.
170. Selemon LD, Kleinman JE, Herman MM, Goldman-Rakic PS. Smaller frontal gray matter volume in postmortem schizophrenic brains. Am J Psychiatry. 2002;59:1983–1991. [PubMed]
171. Selemon LD, Mrzljak J, Kleinman JE, Herman MM, Goldman-Rakic PS. Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9. Arch Gen Psychiatry. 2003;60:69–77. [PubMed]
172. Steen RG, Hamer RM, Lieberman JA. Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis. Neuropsychopharmacology. 2005;30:1949–1962. [PubMed]
173. Callicott JH, Bertolino A, Mattay VS, et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex. 2000;10:1078–1092. [PubMed]
174. Callicott JH, Egan MF, Mattay VS, et al. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am J Psychiatry. 2003;160:709–719. [PubMed]
175. Cannon TD, Glahn DC, Kim J, et al. Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia. Arch Gen Psychiatry. 2005;62:1071–1080. [PubMed]
176. Carter CS, Perlstein W, Ganguli R, et al. Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry. 1998;155:1285–1287. [PubMed]
177. Glahn DC, Ragland JD, Abramoff A, et al. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005;25:60–69. [PubMed]
178. Bruder GE, Keilp JG, Xu H, et al. Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry. 2005;58:901–907. [PubMed]
179. Goldberg TE, Weinberger DR. Genes and the parsing of cognitive processes. Trends Cogn Sci. 2004;8:325–335. [PubMed]
180. Ho BC, Wassink TH, O'Leary DS, Sheffield VC, Andreasen NC. Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry. 2005;10:229, 287–298. [PubMed]
181. Stefanis NC, van Os J, Avramopoulos D, et al. Variation in catechol-O-methyltransferase val158met genotype associated with schizotypy but not cognition: a population study in 543 young men. Biol Psychiatry. 2004;56:510–515. [PubMed]
182. Burdick KE, Hodgkinson CA, Szeszko PR, et al. DISC1 and neurocognitive function in schizophrenia. Neuroreport. 2005;16:1399–1402. [PubMed]
183. Gasperoni TL, Ekelund J, Huttunen M, et al. Genetic linkage and association between chromosome 1q and working memory function in schizophrenia. Am J Hum Genet. 2003;116B:8–16. [PubMed]
184. Parasuraman R, Greenwood PM, Kumar R, Fossella J. Beyond heritability: neurotransmitter genes differentially modulate visuospatial attention and working memory. Psychol Science. 2005;16:200–207. [PMC free article] [PubMed]
185. Keefe RSE, Seidman LJ, Christensen BK, et al. Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry. 2004;161:985–995. [PubMed]
186. McGurk SR, Carter C, Goldman R, et al. The effects of clozapine and risperidone on spatial working memory in schizophrenia. Am J Psychiatry. 2005;162:1013–1016. [PubMed]
187. Gur RC, Ragland JD, Moberg PJ, et al. Computerized neurocognitive scanning: I. Methodology and validation in healthy people. Neuropsychopharmacology. 2001;25:766–788. [PubMed]
188. Gur RC, Ragland JD, Moberg PJ, et al. Computerized neurocognitive scanning: II. The profile of schizophrenia. Neuropsychopharmacology. 2001;25:777–788. [PubMed]
189. Gur RE, Kohler C, Ragland JD, et al. Neurocognitive performance and clinical changes in olanzapine-treated patients with schizophrenia. Neuropsychopharmacology. 2003;28:2029–2036. [PubMed]
190. Kurtz MM, Ragland JD, Moberg PJ, Gur RC. The Penn Conditional Exclusion Test: a new measure of executive-function with alternate forms for repeat administration. Arch Clin Neuropsychol. 2004;19:191–201. [PubMed]
191. Ragland JD, Turetsky BI, Gur RC, et al. Working memory for complex figures: an fMRI comparison of letter and fractal N-back tasks. Neuropsychology. 2002;16:370–379. [PubMed]
192. Gur RC, Jaggi JL, Ragland JD, et al. Effects of memory processing on regional brain activation: cerebral blood flow in normal subjects. Int J Neurosci. 1993;72:31–44. [PubMed]
193. Glahn DC, Gur RC, Ragland JD, Gur RE. Reliability, performance characteristics, and construct validity and initial application of the visual object learning test (VOLT) Neuropsychology. 1997;11:602–612. [PubMed]
194. Kohler CG, Turner TH, Bilker WB, et al. Facial emotion recognition in schizophrenia: intensity effects and error pattern. Am J Psychiatry. 2003;160:1768–1774. [PubMed]
195. Conklin HM, Calkins ME, Anderson CW, III, Dinzeo TJ, Iacono WG. Recognition memory for faces in schizophrenia patients and their first-degree relatives. Neuropsychologia. 2002;40:2314–2324. [PubMed]
196. Hellewell JS, Connell J, Deakin JF. Affect judgement and facial recognition memory in schizophrenia. Psychopathology. 1994;27:255–261. [PubMed]
197. Calkins ME, Gur RC, Ragland JD, Gur RE. Face recognition memory deficits and visual object memory performance in patients with schizophrenia and their relatives. Am J Psychiatry. 2005;162:1963–1966. [PubMed]
198. Gur RE, Nimgaonkar VL, Almasy L, et al. Am J Psychiatry. Neurocognitive endophenotypes in a multiplex multigenerational family study of schizophrenia. [PubMed]
199. Sachs G, Steger-Wuchse D, Kryspin-Exner I, Gur RC, Katschnig H. Facial recognition deficits and cognition in schizophrenia. Schizophr Res. 2004;68:27–35. [PubMed]
200. Erwin RJ, Gur RC, Gur RE, et al. Facial emotion discrimination: I. Task construction and behavioral findings in normal subjects. Psychiatry Res. 1992;42:231–240. [PubMed]
201. Schneider F, Gur RC, Gur RE, Shtasel DL. Emotional processing in schizophrenia: neurobehavioral probes in relation to psychopathology. Schizophr Res. 1995;17:67. [PubMed]
202. Kohler CG, Bilker W, Hagendoorn M, Gur RE, Gur RC. Emotion recognition deficit in schizophrenia: association with symptomatology and cognition. Biol Psychiatry. 2000;48:127–136. [PubMed]
203. Kohler CG, Turner TH, Gur RE, Gur RC. Recognition of facial emotions in neuropsychiatric disorders. CNS Spectr. 2004;9:267–274. [PubMed]
204. Mandal MK, Pandey R, Prasad AB. Facial expressions of emotions and schizophrenia: a review. Schizophr Bull. 1998;24:399–412. [PubMed]
205. Heimberg C, Gur RE, Erwin RJ, Shtasel DL, Gur RC. Facial emotion discrimination: III. Behavioral findings in schizophrenia. Psychiatry Res. 1992;42:253–265. [PubMed]
206. Habel U, Gur RC, Mandal MK, et al. Emotional processing in schizophrenia across cultures: standardized measures of discrimination and experience. Schizophr Res. 2000;42:57–66. [PubMed]
207. Silver H, Shlomo N, Turner T, Gur RC. Perception of happy and sad facial expressions in chronic schizophrenia: evidence for two evaluative systems. Schizophr Res. 2002;55:171. [PubMed]
208. Edwards J, Jackson HJ, Pattison PE. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clin Psychol Rev. 2002;22:789–832. [PubMed]
209. Schneider F, Gur RC, Koch K, et al. Impairment in the specificity of emotion processing in schizophrenia. Am J Psychiatry. 2006;163:442–447. [PubMed]
210. Gruzelier J, Wilson L, Richardson A. Cognitive asymmetry patterns in schizophrenia: retest reliability and modification with recovery. Int J Psychophysiol. 1999;34:323–331. [PubMed]
211. Edwards J, Pattison PE, Jackson HJ, Wales RJ. Facial affect and affective prosody recognition in first-episode schizophrenia. Schizophr Res. 2001;48:235–253. [PubMed]
212. Wolwer W, Streit M, Polzer U, Gaebel W. Facial affect recognition in the course of schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1996;246:165–170. [PubMed]
213. Bediou B, Franck N, Saoud M, et al. Effects of emotion and identity on facial affect processing in schizophrenia. Psychiatry Res. 2005;133:149–157. [PubMed]
214. Cutting J. Judgement of emotional expression in schizophrenics. Br J Psychiatry. 1981;139:1–6. [PubMed]
215. Kucharska-Pietura K, David AS, Masiak M, Phillips ML. Perception of facial and vocal affect by people with schizophrenia in early and late stages of illness. Br J Psychiatry. 2005;187:523–528. [PubMed]
216. Gaebel W, Wolwer W. Facial expression and emotional face recognition in schizophrenia and depression. Eur Arch Psychiatry Clin Neurosci. 1992;242:46–52. [PubMed]
217. Kee KS, Kern RS, Marshall BD,, Jr, Green MF. Risperidone versus haloperidol for perception of emotion in treatment-resistant schizophrenia: preliminary findings. Schizophr Res. 1998;31:159–165. [PubMed]
218. McGue M, Bouchard TJ., Jr Genetic and environmental influences on human behavioral differences. Ann Rev Neurosci. 1998;21:1–24. [PubMed]
219. Plomin R, McGuffin P. Psychopathology in the postgenomic era. Ann Rev Psychol. 2003;54:205–228. [PubMed]
220. Gur RE, Kohler CG, Ragland JD, et al. Flat affect in schizophrenia: relation to emotion processing and neurocognitive measures. Schizophr Bull. 2006;32:279–287. [PMC free article] [PubMed]
221. Toomey R, Seidman LJ, Lyons MJ, Faraone SV, Tsuang MT. Poor perception of nonverbal social-emotional cues in relatives of schizophrenic patients. Schizophr Res. 1999;40:121–130. [PubMed]
222. Bolte S, Poustka F. The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives. Psychol Med. 2003;33:907–915. [PubMed]
223. McCown W, Johnson J, Austin S, Shefsky M. Deficits in ability to decode facial affects in families of schizophrenics. Psychother Priv Pract. 1988;6:93–101.
224. Kee KS, Horan WP, Mintz J, Green MF. Do the siblings of schizophrenia patients demonstrate affect perception deficits? Schizophr Res. 2004;67:87–94. [PubMed]
225. Yoo SS, Choi BG, Juh RH, et al. Working memory processing of facial images in schizophrenia: fMRI investigation. Int J Neurosci. 2005;115:351–366. [PubMed]
226. Gur RC, Schroeder L, Turner T, et al. Brain activation during facial emotion processing. Neuroimage. 2002;16:651. [PubMed]
227. van Rijn S, Aleman A, Swaab H, Kahn RS. Neurobiology of emotion and high risk for schizophrenia: role of the amygdala and the X-chromosome. Neurosci Biobehav Rev. 2005;29:385–397. [PubMed]
228. Gur RE, McGrath C, Chan RM, et al. An fMRI study of facial emotion processing in patients with schizophrenia. Am J Psychiatry. 2002;159:1992–1999. [PubMed]
229. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry. 2003;54:515–528. [PubMed]
230. Hariri AR, Drabant EM, Munoz KE, et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry. 2005;62:146–152. [PubMed]
231. Pezawas L, Meyer-Lindenberg A, Drabant EM, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005;8:828–834. [PubMed]
232. Aliyu MH, Calkins ME, Swanson CL. Project among African Americans to explore risks for schizophrenia: assessment and recruitment methods. Schizophr Res. 2006;87:32–44. [PubMed]
233. Gladsjo JA, McAdams LA, Palmer BW, et al. A six-factor model of cognition in schizophrenia and related psychotic disorders: relationships with clinical symptoms and functional capacity. Schizophr Bull. 2004;30:739–754. [PubMed]
234. Dickinson D, Ragland JD, Calkins ME, Gold JM, Gur RC. A comparison of cognitive structure in schizophrenia patients and healthy controls using confirmatory factor analysis. Schizophr Res. 2006;85:20–29. [PubMed]

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