Cognitive Subtyping in Schizophrenia: A Latent Profile Analysis

Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a “less-impaired” cognitive subtype, 2 subtypes with “intermediate cognitive impairment” differentiated by executive function performance, and a “globally impaired” cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.     

A comparison of cognitive structure in schizophrenia patients and healthy controls using confirmatory factor analysis

There is evidence that cognitive task performance breaks down into the same broad domains in schizophrenia as in healthy populations. However, this does not mean that the domains are independent of one another or that the interrelationships among domains are the same between groups. We used confirmatory factor analysis (CFA) to compare the latent structure of a broad neuropsychological battery in schizophrenia patients (n = 148) and healthy controls (n = 157). Main analyses examined the fit of a hierarchical six-factor model, in which associations among the factors were assumed to reflect their strong shared relationship to a general cognitive ability factor. The model incorporated the factors of verbal comprehension, perceptual organization, verbal memory, spatial memory, processing speed, and executive/working memory. The hierarchical model provided a good overall fit to data from both groups. However multiple groups CFA revealed significant differences in factor loadings between groups, reflecting a more generalized latent structure of cognitive ability in schizophrenia. This was also evident in higher bivariate correlations among cognitive domain composite scores calculated from the observed test data. Cognitive ability, as reflected in test performance, appears to be more unitary in schizophrenia than in healthy subjects. This finding may have measurement and treatment implications.     

Neural correlates of verbal and nonverbal working memory deficits in individuals with schizophrenia and their high-risk siblings

Impaired working memory and functional brain activation deficits within prefrontal cortex (PFC) may be associated with vulnerability to schizophrenia. This study compared working memory and PFC activation in individuals with schizophrenia, their unaffected siblings and healthy comparison participants. We administered a "2back" version of the "nback" task. Functional MRI (fMRI) was used to measure brain activity. Nineteen individuals with DSM-IV schizophrenia, 18 of their siblings, and 72 healthy comparison participants underwent fMRI scans while performing word and face "nback" working memory tasks. Repeated trials (items whose prior presentation was not in the correct nback position) allowed us to assess group differences in the ability to code the temporal order of items. Individuals with schizophrenia and their siblings performed worse than controls on repeated lure trials, suggesting an association between schizophrenia and impairments in the coding of temporal order within working memory. Both individuals with schizophrenia and their siblings also demonstrated abnormal brain activation in PFC, such that both groups had hyperactivation in response to word stimuli and hypoactivation in response to face stimuli. These results provide further evidence that individuals with schizophrenia and their siblings are impaired in their ability to encode the temporal order of items within working memory and that disturbances in working memory and PFC activation may be genetic markers of the vulnerability to schizophrenia.     

Shared intermediate phenotypes for schizophrenia and bipolar disorder: neuroanatomical features of subtypes distinguished by executive dysfunction

Background

Shared genetic vulnerability for schizophrenia and bipolar disorder may be associated with common neuroanatomical features. In view of the evidence for working memory dysfunction as a candidate intermediate phenotype for both disorders, we explored neuroanatomical distinctions between subtypes defined according to working memory (n-back task) performance.

Methods

We analyzed T₁-weighted MRI scans for patients with schizophrenia-spectrum disorder, bipolar-I disorder (BD-I) and healthy controls. The VBM8 toolbox was used to assess differences in grey and white matter volume across traditional diagnostic groups (schizophrenia v. BD-I). Subsequently, groups were defined as “executively spared” (ES) based on the achievement of greater than 50% accuracy in the 2-back task performance (comparable to performance in the control group) or “executively deficit” (ED) based on the achievement of less than 50% accuracy.

Results

Our study included 40 patients with schizophrenia-spectrum disorders, 30 patients with BD-I and 34 controls. Both the schizophrenia and BD-I groups showed grey matter volume reductions relative to the control group, but not relative to each other. The ED subtype (n = 32 [10 BD-I, 22 schizophrenia]) showed grey matter volume reductions in the bilateral superior and medial frontal gyri, right inferior opercular gyri and hippocampus relative to controls. The ES subtype (n = 38 [20 BD-I, 18 schizophrenia]) showed grey matter volume reductions in the right precuneus and left superior and medial orbital frontal gyri relative to controls. The ED subtype showed grey matter volume reduction in the right inferior frontal and precentral gyri relative to the ES subtype. There were no significant differences in white matter volume in any group comparisons.

Limitations

This analysis was limited by small sample sizes. Further, insufficient numbers were available to assess a control-deficit comparison group. We were unable to assess the effects of mood stabilizer dose on brain structure.

Conclusion

Neuroanatomical commonalities are evident among patients with schizophrenia-spectrum disorders and BD-I with working memory deficits. Reduced inferior frontal lobe volume may mediate cognitive deficits shared across the psychosis–mood spectrum.     

The Effect of Context Processing on Different Aspects of Social Cognition in Schizophrenia

Background: It is well known that individuals with schizophrenia have impaired social cognition. The construct of social cognition involves several components, including perception, interpretation, and the ability to integrate context (Adolphs R. The neurobiology of social cognition. Curr Opin Neurobiol. 2001;11:231–239; Brothers L. The social brain: a project for integrating primate behavior and neurophysiology in a new domain. Concepts Neurosci. 1990;1:27–61). Importantly, a number of studies have suggested that deficits in context processing underlie cognitive dysfunction in schizophrenia (Penn DL, Corrigan PW, Bentall RP, Racenstein JM, Newman L. Social cognition in schizophrenia. Psychol Bull. 1997;121(1):114–132; Green MF, Nuechterlein KH. Should schizophrenia be treated as a neurocognitive disorder? Schizophr Bull. 1999;25:309–319). Thus, the purpose of the current study was to investigate the relationship between context processing and different aspects of social cognition in schizophrenia. Method: Individuals with schizophrenia (n = 41) and the healthy controls (n = 32) participated in this study. The participants completed 2 sections of The Awareness of Social Inference Test: (1) social inference minimal (SI-M) and (2) social inference enriched (SI-E). They also completed face and voice emotion discrimination tasks. In addition, we used the AX-Continuous Performance Test (AX-CPT) to measure context processing and the n-back task to measure working memory more generally. Results: AX-CPT performance in schizophrenia was positively correlated with both SI-M and SI-E performance but not with either the face or the voice discrimination. Furthermore, the correlation between AX-CPT performance and SI-M/SI-E performance was significantly stronger in individuals with schizophrenia than in controls. Conclusion: These results suggest that impairments in context processing are related to inferential components of social cognition in schizophrenia but not to the ability to recognition facial or vocal emotion. As such, deficits in context processing may contribute to deficits in both “hot” and “cold” aspects of cognition in schizophrenia.     

A Meta-analysis of Cognitive Remediation for Schizophrenia: Efficacy and the Role of Participant and Treatment Factors

The number of randomized, controlled studies of cognitive remediation (CR) for schizophrenia, a therapeutic approach designed to improve cognitive skills and function, has grown substantially over the past 20 years. Active elements of CR treatment, however, remain unknown. The current meta-analysis investigated treatment, study, and participant factors in the size of observed treatment effects. Electronic databases were searched up to May 2020 using variants of the key words “cognitive remediation,” “clinical trials,” and “schizophrenia.” This search produced 73 unique, randomized, controlled trials. Data were independently extracted by 3 reviewers with excellent reliability. Random-effects models were used to assess primary cognitive and secondary symptom and functional outcomes. Moderator analyses investigated the role of a variety of treatment, study, and participant factors. The meta-analysis (4594 participants) revealed that CR produced significant small-to-moderate size improvements in all domains of cognition studied (Hedge’s gs = .19–.33). and a significant small improvement in function (Hedge’s g = .21). CR programs that included a discussion (“bridging”) group to help apply acquired cognitive skills to everyday life produced larger effects on global cognition and verbal memory. CR programs with strategy-coaching produced larger effects on episodic memory. Sample age, gender, positive, negative, and overall symptoms, and medication dose did not serve as barriers to treatment gains. CR produces small-to-moderate improvements in cognition and function in schizophrenia. Programs of CR that utilize bridging groups and strategy-coaching are more cognitively potent. Future research should focus on ways to modify CR to bolster generalization of cognitive improvements to function.     

Anatomical Distance Affects Functional Connectivity in Patients With Schizophrenia and Their Siblings

Background: The efficiency of human brain depends on the integrity of both long- and short-range connections, but the long-range connections need to be “penalized” to reduce overall wiring costs. This principle, termed as the anatomical distance function (ADF), refers to the presence of an inverse relationship between anatomical distance and connectivity. A crucial developmental feature that occurs in normal adolescence is the weakening of ADF, which is characterized by a selective strengthening of long-distance connections. Schizophrenia is associated with widespread dysconnectivity that is linked to aberrant cortical development. Methods: We studied the ADF in adults with schizophrenia (n = 28), their age-matched siblings (n = 28), and healthy controls (n = 60). We investigated the proportional abnormalities in the long-range connections involving interhemispheric, subcortical, frontal, and salience network regions and localized the connections showing most significant changes in schizophrenia. The groups were discriminated on the basis of short- and long-range connectivity using a machine-learning algorithm. Results: Both patients and their siblings showed abnormally pronounced ADF. This was associated with a disproportionate reduction in the number of long-range connections, affecting the subcortical, interhemispheric, and the salience network connections. The abnormalities in long-range connections had superior ability to accurately identify group membership. Conclusions: A crucial organizing principle of the brain architecture that becomes apparent during normal adolescence is disturbed in schizophrenia. While siblings show some evidence of compensating for this deficit, patients lack putative compensatory changes. Age-related shift in ADF provides an explanatory framework for the developmental emergence of widespread dysconnectivity that is influenced by genetic risk in schizophrenia.Key words: anatomical distance, schizophrenia, genetic risk, functional connectivity, wiring cost, salience network     

Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia

Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.     

Factor analysis of neurocognitive tests in a large sample of schizophrenic probands, their siblings, and healthy controls

Large batteries of neuropsychological tests are typically necessary to identify cognitive deficits in schizophrenia and routinely examine multiple cognitive processes, with many tests often yielding more than one measure of interest. This study investigates the feasibility of a partial solution to the problem of multiple comparisons: the use of factor analysis to reduce the number of phenotypic variables and to better understand the underlying cognitive architecture in schizophrenia. Using a principle components analysis followed by a varimax rotation, we identified factor structures for schizophrenic patients (n=99), their unaffected siblings (n=167), and control subjects (n=131), both separately and as a composite group. Exploratory factor analysis of the full sample yielded a 7-factor model that included verbal memory, working memory, visual memory, IQ/speed/fluency, executive function, attention and digit span. A confirmatory factor analysis (CFA) with maximum likelihood estimation revealed that the 7-factor model fit observed data from the three groups adequately. Since we identified a factor structure representative of all groups that reduced 24 original variables to 7 variables of interest, factor analysis was useful in reducing the complexity of large batteries of cognitive measures to more manageable numbers of phenotypic variables. Furthermore, these findings provide the first confirmation that cognitive structure is comparable in family members of schizophrenia patients, as well as in patients themselves and controls.     

Cognitive estimation and its assessment

Purpose. We evaluated the internal consistency and construct and criterion validity of a 10-item revision of the Cognitive Estimation Task (CET–R) developed by Shallice and Evans to assess problem-solving hypothesis generation. Method. The CET–R was administered to 216 healthy adults from the Aging, Brain Imaging, and Cognition study and 57 adult outpatients with schizophrenia. Results. Exploratory and confirmatory factor analysis (EFA and CFA) of the healthy sample revealed that seven of the 10 CET–R items constitute a more internally consistent scale (CET–R–7). Though EFA indicated that two CET–R–7 dimensions might be present (length and speed/time estimation, respectively), CFA confirmed that a single factor best represents the seven items. The CET–R–7 was modeled best by crystallized intelligence, adequately by fluid intelligence, and inadequately by visuospatial problem solving. Performance on the CET–R–7 correlated significantly with the neuropsychological domains of speed and fluency, but not memory or executive function. Finally, CET–R performance differed by diagnosis, sex, and education, but not age. Conclusions. This study identified an internally consistent set of items that measures the construct of cognitive estimation. This construct relates to several important dimensions of psychological functioning, including crystallized and fluid intelligence, generativity, and self-monitoring. It also is sensitive to cognitive dysfunction in adults with schizophrenia.     

Symptom structure and severity: A comparison of responses to the positive and negative syndrome scale (PANSS) between patients with PTSD or schizophrenia

Objectives

To describe and compare the structure and relative severity of symptoms in clinical trial patients diagnosed with Post Traumatic Stress Disorder (PTSD) or schizophrenia using the Positive and Negative Syndrome Scale (PANSS), developed originally to evaluate symptoms of schizophrenia.

Method

This secondary data analysis used baseline PANSS symptom ratings (n = 267) from a six-month multicenter randomized placebo-controlled trial of adjunctive risperidone in patients with chronic military-related PTSD. First, using a split-half design, Exploratory Factor Analysis (EFA) was employed to identify independent factors which were then compared to published factor structures for schizophrenia. Next, Confirmatory Factor Analysis (CFA) was applied to the second half of the sample to compare the results of the EFA and published factor structures. Finally, T-tests were used to compare the severity of factor scores between the PTSD sample and the baseline PANSS ratings from the Clinical Antipsychotic Trial for Intervention Effectiveness (CATIE) schizophrenia sample (n = 1460).

Results

EFA suggested five factors similar to those identified in a summary of 29 schizophrenia studies by Wallwork (Schizophrenia Research, 137:246–250). CFA showed that the five factor Wallwork model fit the data better than the EFA, although both had relatively high goodness of fit. T-tests showed that the PTSD sample had more severe symptoms on the Depressive factor, and the schizophrenia sample on the Positive, Negative, and Disorganized factors, with no significant difference on the Excited factor.

Conclusion

Veterans with PTSD had similar symptom structure to patients with schizophrenia on the PANSS, but were less symptomatic on psychosis-related factors and more symptomatic on depression. Dimensional symptom factors can be virtually the same across diagnoses.     

Neuroplasticity-Based Cognitive Training in Schizophrenia: An Interim Report on the Effects 6 Months Later

Background: New cognitive treatments for schizophrenia are needed that drive persistent gains in cognition and functioning. Using an innovative neuroplasticity-based cognitive training approach, we report our interim findings on the effects on cognition and functional outcome at 6 months after treatment. Methods: Thirty-two clinically stable schizophrenia subjects were randomly assigned to either targeted cognitive training (TCT, N = 22) or a computer games (CGs) control condition (N = 10). Twelve TCT subjects completed 50 hours of auditory based training; 10 TCT subjects completed an additional 50 hours of training targeting visual and cognitive control processes. Subjects were assessed on neurocognition and functional outcome after training and at 6-month follow-up. Results: Both TCT subject groups showed significant durable gains at 6 months on measures of verbal learning/memory and cognitive control. Only TCT subjects who completed 100 hours of training showed durable gains on processing speed and global cognition, with nonsignificant improvement in functional outcome. Improved cognition was significantly associated with improved functional outcome at 6 months for TCT subjects. Conclusions: A total of 50 hours of neuroplasticity-based computerized cognitive training appears sufficient to drive improvements in verbal learning/memory and cognitive control that endure 6 months beyond the intervention, but a higher “dose” and more “broad-spectrum” training may be necessary to drive enduring gains in processing speed and global cognition. Training-induced cognitive improvement is related to enhanced functioning at 6 months. These data suggest that (1) higher and “broader” doses of cognitive training may confer the most benefits for schizophrenia patients; (2) the posttraining period opens a critical window for aggressive adjunctive psychosocial rehabilitation.     

Hierarchical Pathways from Sensory Processing to Cognitive,Clinical, and Functional Impairments in Schizophrenia

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.     

Validated five-factor model of Positive and Negative Syndrome Scale for schizophrenia in Chinese population

The Positive and Negative Syndrome Scale (PANSS) is the most widely used instrument to assess the severity of symptoms of schizophrenia. Most studies have showed that PANSS measures five dimensions of symptomatology of schizophrenia. However, few studies have ever investigated the structure of PANSS in Chinese schizophrenia population. We recruited two large independent study samples including 903 and 942 Chinese schizophrenia patients and examined the underlying structure of PANSS. By building a confirmatory factor analysis (CFA) model based on the factor loadings of the exploratory factor analysis (EFA) and by testing the CFA model in an independent validation sample, we found that PANSS scores consisted of five factors, which were positive factor, negative factor, excitement factor, depression factor, and cognitive factor. The items loaded on these factors were similar to the consensus items published in previous studies except for PANSS items P2 conceptual disorganization, P5 grandiosity, N5 abstract thinking, and G11 poor attention. This difference might be due to the influence of culture on clinical presentation of schizophrenia. By elucidating the structure, symptoms of Chinese schizophrenia patients could possibly be deconstructed and investigated in future studies.     

Dimensions of executive functioning in schizophrenia and their relationship with processing speed

Context: The nature of executive dysfunction in schizophrenia is nebulous, due to inconsistencies in conceptualizing and operationalizing the construct, and the broader question of whether schizophrenia is best characterized in terms of specific vs generalized cognitive deficits. The current study aimed to determine whether executive functions represent unitary vs diverse constructs in schizophrenia.Methods: Participants included 145 community-dwelling individuals with schizophrenia. Executive functions were measured with the Delis-Kaplan Executive Functioning System (D-KEFS). We conducted an exploratory factor analysis (EFA) with principal axis factoring, as well as parallel analyses to examine the latent constructs underlying the D-KEFS tasks, a second EFA on weighted residuals of the D-KEFS tasks (after accounting for processing speed measured with the Digit Symbol task), and bivariate correlations to examine relationships between the D-KEFS components and relevant demographic and clinical variables, crystallized verbal knowledge, and functional capacity.Results: EFA of the D-KEFS tasks yielded 2 factors (cognitive flexibility/timed tests and abstraction). EFA of the processing speed-weighted D-KEFS residuals also yielded 2 factors (cognitive flexibility and abstraction). Cognitive flexibility was negatively correlated with psychopathology. Better abstraction was associated with higher education, shorter illness duration, and better functional capacity. Both factors were positively correlated with crystallized verbal knowledge.Conclusions: Executive functions in schizophrenia could be parsed into 2 partially related but separable subconstructs. Future efforts to elucidate functional outcomes as well as neurobiological underpinnings of schizophrenia may be facilitated by attending to the distinction between cognitive flexibility and abstraction.     

The Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia: A Meta-analysis of Existing Findings and New Data in a First-Episode Sample

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP − CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of “neurocognitively less impaired” patients, who only developed psychosis after a relatively early initiation into cannabis use.     

Normal Birth Weight Variation Is Related to Cortical Morphology Across the Psychosis Spectrum

Background:

Normal birth weight variation affects schizophrenia risk and cognitive performance in schizophrenia patients and healthy controls. Brain cortical anatomy is altered in psychotic disorders and in low birth weight subjects, but if birth weight variation relates to cortical morphology across the psychosis spectrum is not known.

Methods:

Magnetic Resonance Imaging brain scans and clinical-, neurocognitive-, and medical birth registry data were collected from 359 adults including patients with a DSM-IV diagnosis of schizophrenia (n = 90, mean age 29.4±10.2 [95% CI], 62% male), bipolar disorder (n = 79, age 29.4±11.8, 39% male) or other psychosis (n = 40, age 26.3±10.0, 56% male), and healthy controls (n = 140, age 30.8±12.0,53% male). We explored the relationship between whole-range birth weight variation and cortical surface area and thickness and their possible associations to cognitive performance.

Results:

Across all groups, lower birth weight was associated with smaller total surface area (t = 3.87, P = .0001), within specific regions of the temporal, parietal, and frontal cortex bilaterally. There were no associations between birth weight and cortical thickness, and no diagnosis by birth weight interaction effects on cortical thickness or surface area. Smaller cortical area (t = 2.50, P = .013) and lower birth weight (t = 2.53, P = .012) were significantly related to poorer working memory performance in all diagnostic groups except schizophrenia.

Conclusion:

Birth weight relates to adult cortical surface area, but not cortical thickness, in patients across the psychosis spectrum and in healthy controls. Cortical area appears to be a diagnosis-independent general marker of early neurodevelopment, with a dose-response association to normal birth weight variation.Key words: Magnetic Resonance Imaging, cortical area, neurodevelopment, schizophrenia, IQ, working memory     

Factors mediating cognitive deficits and psychopathology among siblings of individuals with schizophrenia

Schizotypal traits and cognitive disturbances are known to be present in first-degree relatives of people with schizophrenia. However, there is little understanding of how these endophenotypes are related to each other. We explored the nature of this relationship in individuals with schizophrenia, their full siblings, community controls, and their siblings. All participants were assessed in the domains of working memory, attention, episodic memory, and executive function, as well as in their level of positive, negative, and disorganization symptoms. Schizophrenia probands were significantly impaired on all cognitive domains, as compared with the other 3 groups, and displayed the highest levels of positive, negative, and disorganization symptoms. Proband siblings performed significantly worse than controls on tasks of working memory, episodic memory, and executive function, and they displayed significantly more positive and negative symptoms as compared with controls. Poorer task performance across all 4 cognitive domains was most strongly correlated with increased negative symptoms. Mediation analyses revealed that working memory, episodic memory, and executive function deficits partially mediated increases in negative symptoms among proband siblings. Negative symptoms fully mediated deficits in working memory and episodic memory but only partially mediated deficits in executive function. Results suggest that there is a complex relationship between cognitive and clinical factors in this high-risk population.     

Disrupted Prefrontal Interhemispheric Structural Coupling in Schizophrenia Related to Working Memory Performance

Background: Prominent regional cortical thickness reductions have been shown in schizophrenia. In contrast, little is known regarding alterations of structural coupling between regions in schizophrenia and how these alterations may be related to cognitive impairments in this disorder. Methods: T1-weighted magnetic resonance images were acquired in 54 patients with schizophrenia and 68 healthy control subjects aged 18–55 years. Cortical thickness was compared between groups using a vertex-wise approach. To assess structural coupling, seeds were selected within regions of reduced thickness, and brain-wide cortical thickness correlations were compared between groups. The relationships between identified patterns of circuit structure disruption and cognitive task performance were then explored. Results: Prominent cortical thickness reductions were found in patients compared with controls at a 5% false discovery rate in a predominantly frontal and temporal pattern. Correlations of the left dorsolateral prefrontal cortex (DLPFC) with right prefrontal regions were significantly different in patients and controls. The difference remained significant in a subset of 20 first-episode patients. Participants with stronger frontal interhemispheric thickness correlations had poorer working memory performance. Conclusions: We identified structural impairment in a left-right DLPFC circuit in patients with schizophrenia independent of illness stage or medication exposure. The relationship between left-right DLPFC thickness correlations and working memory performance implicates prefrontal interhemispheric circuit impairment as a vulnerability pathway for poor working memory performance. Our findings could guide the development of novel therapeutic interventions aimed at improving working memory performance in patients with schizophrenia.Key words: dorsolateral prefrontal cortex, MRI, cortical thickness, structural coupling     

RGS4 Polymorphisms Associated With Variability of Cognitive Performance in a Family-Based Schizophrenia Sample

Polymorphisms of the gene encoding the regulator of G protein signaling, subtype 4 (RGS4), may be associated with schizophrenia. Among first-episode schizophrenia patients, they are also associated with dorsolateral prefrontal cortex (DLPFC) volume. The DLPFC is a key region that regulates heritable cognitive functions implicated in schizophrenia pathogenesis. To further understand the relationship of RGS4 variants to schizophrenia, we examined their associations with cognitive functions among schizophrenia patients and their relatives. We analyzed 31 multiplex, multigenerational Caucasian families with schizophrenia recruited on the basis of 2 affected first-degree relatives. All participants underwent a computerized neurocognitive battery that evaluates accuracy and speed (response time) of performance on abstraction/mental flexibility; attention; verbal, spatial, and face memory; and spatial ability. “Tag” single-nucleotide polymorphisms (SNPs) representing common polymorphisms were genotyped. Measured genotype analyses accounting for family relationships were performed using Sequential Oligogenic Linkage Analysis Routines. SNPs rs10917670 (“SNP1”) and rs951439 (“SNP7”) were associated with face memory speed (P = .0003) at a significance level that survived Bonferroni correction (P = .039). The same SNPs have earlier been reported to be associated with schizophrenia. There also were uncorrected associations with rs10917670 (“SNP1”) and rs951439 (“SNP7”) on face memory efficiency (P = .03) and verbal memory efficiency (P = 0.02), rs28757217 on abstraction/mental flexibility speed (P = .02) and verbal memory efficiency (P = .03), SNP18 (rs2661319) on spatial memory accuracy (P = 0.02) and face memory speed (P = .03). RGS4 polymorphisms are associated with variations in cognitive functions and contribute a small but statistically significant proportion of variance in a family-based sample.