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Cognitive impairment among children at-risk for schizophrenia
... Children with family history had first-or second-degree relatives with schizophrenia/schizoaffective disorder. A previous cross-sectional investigation of this sample (Dickson et al., 2014) identified impaired performance on a composite verbal memory index that included both verbal word-list learning and story memory. This impairment was specific to children with high familial loading (i.e., those with at least one first-or two second-degree affected relatives) relative to TD peers; it was not observed among children with lower familial loading (i.e., with a single second-degree affected relative only) or among ASz children. ...
... The lack of impairment observed previously on the composite verbal memory index among ASz children relative to their TD peers (Dickson et al., 2014) might also signify heterogeneity of risk within this group, related to the persistence versus transience of their symptoms into adolescence. Persistence of PLEs and internalising/externalising psychopathology during adolescence has been associated with increased risk for adverse mental health outcomes including psychosis (Colman et al., 2007;Dominguez et al., 2011;Kalman et al., 2019;Kim-Cohen et al., 2003). ...
... From 182 families invited to participate in the baseline research assessment (58 ASz, 43 FHx, 81 TD), 40.7% declined. The 108 participants who completed the verbal learning assessment comprised 45 TD, 16 ASz H , 16 ASz L , 16 1 Genetic liability scores, based on the degree of relatedness and the number of affected relatives (Campbell et al., 2010), differentiated children with and without first-degree affected relatives, with the exception of two children with two affected second-degree relatives whose liability scores were intermediate between those groups (Dickson et al., 2014). The FHx H group thus included 8 children with one first-degree affected relative only (6 of whom had relatives in the maternal line), 6 children with one first-and one second-degree relative (all in the maternal line), and 2 children with two second-degree relatives and multiple affected relatives of more distal relation (1 in the maternal line). ...
Poor verbal learning and memory function is well-documented among individuals with schizophrenia and those at clinical high-risk for psychosis. This study aimed to identify these impairments among children aged 9–12 years with different schizophrenia risk profiles (family history or antecedents of schizophrenia, each of higher[H] or lower[L] risk load) relative to typically developing peers. These three groups were recruited via community-screening, and differentiated for analysis into: typically developing children (TD = 45); children who had 1 first- or ≥2 second-degree affected relatives (FHxH = 16) or one second-degree relative (FHxL = 15); and children presenting multiple replicated antecedents of schizophrenia whose clinical symptoms persisted at 2- and/or 4-year follow-up (ASzH = 16) or remitted during follow-up (ASzL = 16). Verbal learning/memory measures assessed at baseline (age 9–12 years) included: (i) total recall; (ii) trial 1 recall; (iii) learning score; (iv) intrusions; (v) total words lost; and (vi) serial position patterns. Analyses of variance indicated that FHxH and ASzH youth demonstrated impaired total recall compared to TD and ASzL children and lost significantly more words between trials than TD and FHxL children. Learning score was impaired among both FHxH and FHxL relative to TD and ASzL children. Thus, among putatively at-risk children, total words recalled and lost distinguished those with higher risk load (by family history or persistent antecedent symptomology), whereas learning score indexed familial vulnerability. Follow-up of the sample is needed to determine the capacity of verbal learning deficits to predict later illness and provide a potential avenue for early remediation to improve clinical or functional outcomes.
... Premorbid cognitive impairment is one of the most consistent findings in schizophrenia (Aylward et al., 1984;Cannon et al., 2000;Dickson et al., 2014;Woodberry et al., 2008). In the British 1946 birth cohort, educational test scores at ages 8, 11 and 15 years were impaired among persons with schizophrenia (Jones et al., 1994). ...
... A military prospective study in Israel found that poorer verbal reasoning was associated with increased risk of schizophrenia (Reichenberg et al., 2006). Dickson et al. (2014) observed deficits in verbal comprehension and verbal working memory in children at-risk for psychosis. Although certain studies of premorbid cognitive functioning in psychiatric disorders do mention verbal deficits (Ang and Tan, 2004;Dickson, 2012), none has discovered any specific association to date between standardized achievement in mathematics and various psychiatric disorders (Wu et al., 2014). ...
... Previous studies have already confirmed the existence of premorbid cognitive deficits in schizophrenia (Dickson et al., 2014;Khandaker et al., 2011;Reichenberg et al., 2010). This study broadens the scope of research by describing the premorbid performance of persons with Table 2 Predictors of hospitalization with psychiatric disorders, compared with control group data (logistic regressions). ...
Population-based studies of premorbid cognitive functioning in schizophrenia have found verbal deficits and low IQ scores. It remains unclear, however, whether premorbid deficits are specific to schizophrenia, compared with other psychiatric disorders. Moreover, studies using school-based measures are few and their results inconsistent. This study assesses the eighth-grade (ages 13–14; n=11, 418) scholastic performance of adults with psychiatric disorders (n=194, 1.7, particularly with schizophrenia (n=86, 0.8%), comparing the results with those of their normative peers. The researchers examined report cards of eighth-graders at state secular schools in Jerusalem over a ten-year period (1978–1988), applying ANOVA and logistic regression models to evaluate associations between school performance and subsequent psychiatric hospitalization. The findings indicated that participants hospitalized with varied psychiatric disorders had lower grades in mathematics, gym, handcraft and academic core subjects, with significantly lower overall scores. Amended logistic regression models indicate that reduced performance (in mathematics, gym, handcraft and overall scores) was correlated with an increasing likelihood of hospitalization for the psychiatric disorders group and the subgroup with schizophrenia-related ailments. These results imply that eighth-grade school performance in core subjects is poorer among persons later hospitalized with psychiatric disorders than that of their classmates.
... In initial cross-sectional analyses conducted in ASz and TD groups only, we observed impairments in general intelligence, verbal memory, working memory, and executive function among ASz children aged 9-12 years [39] which were less pervasive and smaller in magnitude than those characterising adults with schizophrenia [40], but similar to those observed among CHR individuals [41,42]. In subsequent analyses performed on a larger, partially overlapping sample, ASz children performed at a level intermediate to FHx children with high familial loading (C1 first-degree or C2 seconddegree relatives) and FHx children with low familial loading (one affected second-degree relative only) across a range of neurocognitive subtests [43]. Preliminary analysis of longitudinal data collected across three biennial assessments spanning 9-16 years indicates different patterns of cognitive development through adolescence in ASz and FHx children relative to TD children. ...
... By age 11-14 years, FHx children (but not ASz children) showed a blunted CAR [43] that was not explained by experiences of psychosocial stressors and was more prominent among FHx children with a first-degree relative with schizophrenia than among FHx with an affected second-degree relative. In contrast to hypotheses, neither ASz nor FHx children were characterised by higher diurnal cortisol levels. ...
... In contrast to hypotheses, neither ASz nor FHx children were characterised by higher diurnal cortisol levels. Nonetheless, among both FHx and ASz children, abnormal cortisol levels (i.e. higher diurnal cortisol levels and greater blunting of the CAR) were associated with poorer memory and executive function, possibly reflecting underlying dysfunction in the brain regions which mediate both HPA axis function and these cognitive functions [43]. Neither ASz nor FHx children were characterised by pituitary volume enlargements [35], which contrasts with those identified among individuals with firstepisode psychosis [66][67][68][69] and in some (but not all) studies of older individuals at-risk for psychosis [69,70]. ...
Purpose:
The London Child Health and Development Study (CHADS) is a prospective, longitudinal investigation of children, sampled from the general community aged 9-11 years and assessed biennially, who present premorbid risk markers for schizophrenia. The study aims to characterise developmental trajectories of psychological, cognitive, and biological functioning in at-risk children and identify potential targets for early preventative intervention. This review summarises CHADS findings, discusses these in the context of recent theory regarding aetiology and prevention of schizophrenia, and highlights challenges to be addressed with future research.
Methods:
We review (1) epidemiological information on the prevalence and correlates of developmental antecedents of schizophrenia in the general child population, (2) evidence of psychosocial, cognitive, and biological dysfunctions in at-risk children presenting multiple antecedents of schizophrenia and at-risk children with a family history of schizophrenia, and (3) related findings from an associated sample of help-seeking children receiving intervention.
Results:
Community-based screening of 9-11-year olds identified ~9 % with a triad of antecedents of schizophrenia [including psychotic-like experiences (PLEs)] who are putatively at-risk of psychosis; these children reported greater exposure and responsivity to stressors, impairments in general intelligence and specific cognitive functions, brain structure and function abnormalities, and neuromotor dysfunction. Preliminary evidence suggests distressing PLEs are a viable target for cognitive-behavioural intervention in at-risk children.
Conclusions:
Intervention in early, premorbid phases of illness might alleviate current difficulties and avert future schizophrenia using benign treatments. The CHADS programme has identified several markers that may index early pathophysiology and constitute potential targets for preventative intervention.
... We have developed a novel community screening method for identifying children who may be at elevated risk for psychosis because they present with a triad of antecedents of schizophrenia (ASz), defined as (i) a speech and/or motor delay or abnormality, (ii) a social, emotional, and/or behavioural problem, and (iii) a psychotic-like experience (Laurens et al., 2007). We have previously demonstrated that, relative to their typically developing (TD) peers, ASz children, as well as children with a family history of schizophrenia (FHx), are more frequently exposed to psychosocial stressors and more distressed by these experiences , and that both groups show poorer neurocognitive function (Cullen et al., 2010;Dickson et al., 2014). The current study aimed to determine whether ASz and FHx children are also characterized by abnormal HPA axis function (elevated diurnal cortisol and/or a blunted CAR) relative to TD children. ...
... In line with our previous work examining neurocognitive function in ASz and FHx children at age 9-12 years (Cullen et al., 2010;Dickson et al., 2014), both ASz and FHx groups showed poorer performance on neurocognitive tests at age 11-14 years compared to the TD group (Table 1). Specifically, ASz children obtained significantly lower scores on the number-letter ( p = 0.009), verbal working memory ( p = 0.02), and verbal fluency -category switching subtests ( p = 0.004), whilst FHx children obtained lower scores on the verbal memory index ( p = 0.02) and the colour-word interference -inhibition subtest ( p = 0.009). ...
... Moderateto-large impairments across a range of neurocognitive domains have been observed consistently in patients with first episode psychosis relative to healthy controls (Mesholam-Gately et al., 2009), and prospective studies indicate that some of these impairments are present in children who go on to develop the disorder in later life (Dickson et al., 2012). The current study suggests that the deficits in memory and executive function that we have observed in ASz and FHx children (Cullen et al., 2010;Dickson et al., 2014), and which are also known to characterize UHR youth (Fusar-Poli et al., 2012), are associated with greater abnormality of HPA axis function. Specifically, a more blunted CAR was associated with poorer verbal memory and letter fluency among FHx and ASz children, respectively; moreover, in the FHx group only, higher diurnal cortisol was correlated with poorer performance on the number-letter subtest and towers test, and lower verbal memory index scores. ...
Abnormal hypothalamic-pituitary-adrenal (HPA) axis function, as indexed by elevated diurnal cortisol levels and/or a blunted cortisol awakening response (CAR), has been observed among patients with first episode psychosis and associated with neurocognitive deficits in this population. However, the extent to which these features precede illness onset is unclear. The current study aimed to determine whether children who are at putatively elevated risk for psychosis because they present multiple antecedents of schizophrenia (ASz), and high-risk children with a family history of illness (FHx), are characterised by abnormal cortisol levels when compared with their typically-developing (TD) peers. A further aim was to investigate the extent to which cortisol levels are associated with psychosocial stress and neurocognitive function. Thirty-three ASz children, 22 FHx children, and 40 TD children were identified at age 9-12 years using a novel community-based screening procedure or as relatives of individuals with schizophrenia. All participants were antipsychotic-naive and not currently seeking treatment for their symptoms. At age 11-14 years, participants provided salivary cortisol samples and completed psychosocial stress measures and tests of memory and executive function. Results indicated that FHx children, but not ASz children, were characterised by a blunted CAR relative to their TD peers (effect size = 0.73, p = 0.01) that was not explained by psychosocial stress exposure or by distress relating to these experiences. Neither FHx nor ASz children were characterised by elevated diurnal cortisol. Among both FHx and ASz children, more pronounced HPA axis function abnormalities (i.e., higher diurnal cortisol levels and greater blunting of the CAR) were associated with poorer performance on tests of verbal memory and executive function. These findings support the notion that at least some HPA axis abnormalities described in psychosis precede illness onset, rather than being a subsequent epiphenomenon. We speculate that the blunted CAR may constitute an early (potentially genetically-mediated) marker of psychosis vulnerability, whilst elevated diurnal cortisol levels may emerge only proximally to disease onset.
... Clinical studies have suggested that in the FHR individuals, neurocognitive deficits, especially in the verbal-and spatial-working memory domains, exist prior the presentation of positive and negative symptoms, and can be used as strong predictors of schizophrenia (Pukrop and Klosterkotter, 2010;Dickson et al., 2014;Scala et al., 2014;Bang et al., 2015;Hou et al., 2016). Among these studies, Bang et al. found that behavioral performance scores of the tests for verbaland spatial-working memory in the FHR subjects were intermediate between low risk controls and patients with first-episode schizophrenia (FES) (Bang et al., 2015). ...
... A Meta-analysis of 25 studies [published between January 1987 and February 2013, including clinical longitudinal data from 905 FES, 560 HR (including both clinical HR and FHR), and 405 healthy controls (HC)] suggested that verbal-memory deficits were already established in the HR subjects before the prodromal phase of psychosis, while no further decline occurred during followup assessments (Bora and Murray, 2014). In a new study, Dickson et al. also found verbal-and spatial memory deficits in the FHR subjects when compared to HC; whereas by adjusting statistical analyses for IQ, no significant between-group differences in any neurocognitive domains were remained (Dickson et al., 2014). The inconsistency among these existing neurobehavioral studies may be caused by the heterogeneity of the study samples, different tasks and assessment criteria being used, as well as other factors. ...
Background:
Working memory impairment (especially in verbal and spatial domains) is the core neurocognitive impairment in schizophrenia and the familial high-risk (FHR) population. Inconsistent results have been reported in clinical and neuroimaging studies examining the verbal- and spatial-memory deficits in the FHR subjects, due to sample differences and lack of understanding on interactions of the brain regions for processing verbal- and spatial-working memory.
Methods:
Functional MRI data acquired during a verbal- vs. spatial-memory task were included from 51 young adults [26 FHR and 25 controls]. Group comparisons were conducted in brain activation patterns responding to 1) verbal-memory condition (A), 2) spatial-memory condition (B), 3) verbal higher than spatial (A-B), 4) spatial higher than verbal (B-A), 5) conjunction of brain regions that were activated during both A and B (A∧B). Group difference of the laterality index (LI) in inferior frontal lobe for condition A was also assessed.
Results:
Compared to controls, the FHR group exhibited significantly decreased brain activity in left inferior frontal during A, and significantly stronger involvement of ACC, PCC, paracentral gyrus for the contrast of A-B. The LI showed a trend of reduced left-higher-than-right pattern for verbal-memory processing in the HR group.
Conclusions:
Our findings suggest that in the entire functional brain network for working-memory processing, verbal information processing associated brain pathways are significantly altered in people at familial high risk for developing schizophrenia. Future studies will need to examine whether these alterations may indicate vulnerability for predicting the onset of Schizophrenia.
... FHR-SZ studies usually recruit first-degree family members. When second-degree have been examined, either no differences with typical development (Hannah Dickson, Cullen, et al., 2014) or intermediate performance in cognitive measures between first-degree and healthy controls are found (Carpendale, Cullen, Dickson, & Laurens, 2022;Keshavan, Kulkarni, Bhojraj, Francis, Diwadkar, et al., 2010). Our whole sample was help-seeking, therefore, differences between two clinical groups may be smaller and, due to sample size, not detected. ...
AIM Neurodevelopmental and clinical problems in childhood often precede adult Schizophrenia Spectrum Disorders. We investigated if children attending a psychiatric clinic presented more cognitive and motor alterations if there was a family history of Schizophrenia Spectrum Disorder (FHR-SZ) diagnosis. We also searched if there was a relationship between clinical scores in CBCL Thought Problems and increased problems in motor and cognitive performance. METHODS Seventy-five children (aged 7 to 16; mean 12 y/o; 53% males) were recruited (45 reported FHR-SZ -seven of them first degree-). They completed the Wechsler Intelligence Scale for Children (WISC-V), Movement Assessment Battery for Children (MABC-2), social cognition from the Developmental NEuroPSYchological Assessment (NEPSY-II) and Conners Continuous Performance Test (CPT-3). Parents completed the Child Behaviour Checklist (CBCL) and Behaviour Rating Inventory of Executive Function (BRIEF-2). RESULTS A neurodevelopmental disorder was the primary diagnosis in 65% (mainly ADHD). Motor performance and emotion recognition were below expected by age, and IQ was average. No relevant differences in relation to family history were found. Patients with high scores in the CBCL Thought Problems subscale (n=38) were older, more often presented a diagnosis of combined ADHD, performed worse in Emotion Recognition, had Executive Function problems and clinical symptoms in subscales Anxious/Depressed, Withdrawal/Depressed and Attention problems. CONCLUSIONS In children attending a psychiatric clinic, CBCL Thought Problems subscale associates with more internalizing clinical problems, executive function, and social cognition difficulties. Larger samples and first-degree FHR-SZ probands are needed to delineate risk profiles.
... Participants also completed a computerized finger-tapping task, a well-established neuropsychological measure of motor deficits 7,59,[92][93][94][95][96][97][98] . This is an ideal task because it taps into broad motor network function, including motor timing, which is often affected in motor speech disorders, has been found to be sensitive to mechanisms driving psychosis, and is readily amenable to reliable and valid in-person and remote assessments 7,26,92,[99][100][101][102][103][104][105][106][107][108][109][110] . In this task, participants are instructed to press the spacebar with their index finger as quickly as possible for 10 s. ...
Background and hypothesis:
Motor abnormalities are predictive of psychosis onset in individuals at clinical high risk (CHR) for psychosis and are tied to its progression. We hypothesize that these motor abnormalities also disrupt their speech production (a highly complex motor behavior) and predict CHR individuals will produce more variable speech than healthy controls, and that this variability will relate to symptom severity, motor measures, and psychosis-risk calculator risk scores.
Study design:
We measure variability in speech production (variability in consonants, vowels, speech rate, and pausing/timing) in N = 58 CHR participants and N = 67 healthy controls. Three different tasks are used to elicit speech: diadochokinetic speech (rapidly-repeated syllables e.g., papapa…, pataka…), read speech, and spontaneously-generated speech.
Study results:
Individuals in the CHR group produced more variable consonants and exhibited greater speech rate variability than healthy controls in two of the three speech tasks (diadochokinetic and read speech). While there were no significant correlations between speech measures and remotely-obtained motor measures, symptom severity, or conversion risk scores, these comparisons may be under-powered (in part due to challenges of remote data collection during the COVID-19 pandemic).
Conclusion:
This study provides a thorough and theory-driven first look at how speech production is affected in this at-risk population and speaks to the promise and challenges facing this approach moving forward.
... A meta-analysis of 28 studies on young first-degree SCZ-RELs who had not reached the peak age illness risk (<age 30 years) demonstrated that SCZ-RELs presented deficits with a moderate level of severity compared with HC, with the largest average effect sizes for full-scale IQ, vocabulary, and single-word reading tests (often used as estimates of IQ) [37]. In addition to a lower full-scale IQ, young SCZ-RELs also exhibited significantly poorer scholastic achievement compared to typically developing children [38]. Interestingly, in a study that examined the association between a family history of psychosis, depression, mania, and alcohol or substance abuse and IQ in SCZ, siblings of SCZ and HCs reported a decrease in IQ in the sibling group compared to HCs, which was not influenced by family history [39]. ...
Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric disorders that share clinical features and several risk genes. Important information about their genetic underpinnings arises from intermediate phenotypes (IPs), quantifiable biological traits that are more prevalent in unaffected relatives (RELs) of patients compared to the general population and co-segregate with the disorders. Within IPs, neuropsychological functions and neuroimaging measures have the potential to provide useful insight into the pathophysiology of SCZ and BD. In this context, the present narrative review provides a comprehensive overview of the available evidence on deficits in neuropsychological functions and neuroimaging alterations in unaffected relatives of SCZ (SCZ-RELs) and BD (BD-RELs). Overall, deficits in cognitive functions including intelligence, memory, attention, executive functions, and social cognition could be considered IPs for SCZ. Although the picture for cognitive alterations in BD-RELs is less defined, BD-RELs seem to present worse performances compared to controls in executive functioning, including adaptable thinking, planning, self-monitoring, self-control, and working memory. Among neuroimaging markers, SCZ-RELs appear to be characterized by structural and functional alterations in the cortico–striatal–thalamic network, while BD risk seems to be associated with abnormalities in the prefrontal, temporal, thalamic, and limbic regions. In conclusion, SCZ-RELs and BD-RELs present a pattern of cognitive and neuroimaging alterations that lie between patients and healthy individuals. Similar abnormalities in SCZ-RELs and BD-RELs may be the phenotypic expression of the shared genetic mechanisms underlying both disorders, while the specificities in neuropsychological and neuroimaging profiles may be associated with the differential symptom expression in the two disorders.
... Those findings are consistent with verbal memory being associated with the genetic risk of psychosis, making it a potential endophenotype. Additionally, there is evidence that such deficits in verbal memory is already present in childhood and adolescence for those with increased genetic risk for psychosis [18,19]. Therefore, verbal memory impairment may reflect underlying neurodevelopmental abnormalities that convey the genetic risk of psychosis before its symptom onset or formal diagnosis. ...
Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay recall verbal memory. In particular, one locus (rs9896243) associated with long-delay recall was mapped to the NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) gene, indicating the role of membrane fusion in adolescent verbal memory. Based on the GWAS in the European subset, we estimated the SNP-heritability to be 15% to 29% for the three verbal memory traits. We found that verbal memory was genetically correlated with schizophrenia, providing further evidence supporting verbal memory as an endophenotype for psychosis.
... Post hoc analyses (detailed in the Supplemental Methods) were undertaken to determine whether variation between groups in general intelligence (IQ) might explain ERP differences, given the association of premorbid IQ deficits with MMN reductions in schizophrenia (42) and previously reported IQ differences between the ASz and FHx groups relative to TD (23,43,44 (relative to TD children) the developmental trajectories of ASz children who continued to present psychopathology and PLEs at the second and/or third assessments (ASz1, n = 19, 59%) and ASz children who did not (ASz2, n = 13), and of FHx children with at least 1 first-degree (FHx-1st, n = 12, 43%) or second-degree (FHx-2nd, n = 16) relative with schizophrenia/ schizoaffective disorder. Table 1 details participant and measurement characteristics for each group. ...
Background
Mismatch negativity (MMN) and P3a amplitude reductions are robust abnormalities of sensory information processing in schizophrenia, but are variably present in different profiles of risk (family history vs. clinical high-risk) for the disorder. This study aimed to determine whether these abnormalities characterize children presenting replicated risk factors for schizophrenia, using longitudinal assessment over ages 9-16 years in children with multiple replicated antecedents of schizophrenia (ASz), and with family history of schizophrenia (FHx), relative to typically developing (TD) peers.
Methods
105 children (52 female) sampled from the community were assessed aged 9-12 years and approximately 2 and 4 years later. Linear mixed models were fit to MMN and P3a peak amplitudes and latencies, with intercept and slope estimates from 32 ASz and 28 FHx children compared to those of 45 TD peers.
Results
In ASz relative to TD children, MMN amplitude initially increased and then prominently decreased during adolescence. Both ASz and FHx children had greater P3a amplitude than TD children at 11 years which reduced with age, in contrast to P3a amplitude increases during adolescence in TD youth. MMN abnormalities were specific to ASz children who continued to present symptoms during follow-up.
Conclusions
Age-dependent MMN and P3a abnormalities demarcate adolescent development of ASz and FHx from TD children, with auditory change detection abnormalities specific to ASz children with continuing symptoms, and attention orienting abnormalities characterizing both ASz and FHx risk profiles. Follow-up is required to determine whether these abnormalities index vulnerability for schizophrenia or an illness non-specific developmental delay.
... There are four possible explanations for these findings. One, given the small number of studies included in both at-risk meta-analyses, our results may reflect the inclusion of a study with a small sample size that utilised standardised measures of academic achievement and reported large effect sizes differences (Dickson et al., 2014). Two, children experiencing PLEs and children with a family history of schizophrenia are more likely to present with externalising and internalising psychopathology (Lancefield, Raudino, Downs, & Laurens, 2016;Laurens et al., 2020;Sandstrom et al., 2019), which in turn has been reported to be associated with academic achievement and educational attainment (Masten et al., 2005;Melkevik, Nilsen, Evensen, Reneflot, & Mykletun, 2016). ...
Background
Cognitive impairments in childhood are associated with increased risk of schizophrenia in later life, but the extent to which poor academic achievement is associated with the disorder is unclear.
Methods
Major databases were searched for articles published in English up to 31 December 2019. We conducted random-effects meta-analyses to: (1) compare general academic and mathematics achievement in youth who later developed schizophrenia and those who did not; (2) to examine the association between education level achieved and adult-onset schizophrenia; and, (3) compare general academic achievement in youth at-risk for schizophrenia and typically developing peers. Meta-regression models examined the effects of type of academic assessment, educational system, age at assessment, measurement of educational level attained, school leaving age, and study quality on academic achievement and education level among individuals with schizophrenia.
Results
Meta-analyses, comprising data of over four million individuals, found that: (1) by age 16 years, those who later developed schizophrenia had poorer general academic (Cohen's d = −0.29, p ⩽ 0.0001) and mathematics achievement ( d = −0.23, p = 0.01) than those who did not; (2) individuals with schizophrenia were less likely to enter higher education (odds ratio = 0.49, p ⩽ 0.0001); and, (3) youth reporting psychotic-like experiences and youth with a family history of schizophrenia had lower general academic achievement ( d = −0.54, p ⩽ 0.0001; d = −0.39, p ⩽ 0.0001, respectively). Meta-regression analyses determined no effect modifiers.
Discussion
Despite significant heterogeneity across studies, various routinely collected indices of academic achievement can identify premorbid cognitive dysfunction among individuals who are vulnerable for schizophrenia, potentially aiding the early identification of risk in the population.
... There are four possible explanations for these findings. One, given the small number of studies included in both at-risk meta-analyses, our results may reflect the inclusion of a study with a small sample size that utilised standardised measures of academic achievement and reported large effect sizes differences (Dickson et al., 2014). Two, children experiencing PLEs and children with a family history of schizophrenia are more likely to present with externalising and internalising psychopathology (Lancefield, Raudino, Downs, & Laurens, 2016;Laurens et al., 2020;Sandstrom et al., 2019), which in turn has been reported to be associated with academic achievement and educational attainment (Masten et al., 2005;Melkevik, Nilsen, Evensen, Reneflot, & Mykletun, 2016). ...
... Woodberry et al. [34] found differences in executive functions in the overall domain, specifically in the FAS verbal fluency score and in perseverative errors, as well as in verbal memory. Similarly, Dickson et al. [89] found impairment in executive function in subjects with low family history of schizophrenia (second-degree relative of psychosis subjects) compared to normal controls. In contrast, Ziermans et al. [30] did not see this impairment in either executive function or verbal memory. ...
Neuropsychological underperformance is well described in young adults at clinical high risk for psychosis, but the literature is scarce on the cognitive profile of at-risk children and adolescents. The aim of this study is to describe the neuropsychological profile of a child and adolescent sample of patients with psychosis risk syndrome (PRS) compared to healthy controls and to analyze associations between attenuated psychotic symptoms and cognitive impairment. Cross-sectional baseline data analysis from a longitudinal, naturalistic, case–control, two-site study is presented. Eighty-one help-seeking subjects with PRS and 39 healthy controls (HC) aged between 10 and 17 years of age were recruited. PRS was defined by: positive or negative attenuated symptoms, Brief Limited Intermittent Psychotic Symptoms (BLIPS), genetic risk (first- or second-degree relative), or schizotypal personality disorder plus impairment in functioning. A neuropsychological battery was administered to assess general intelligence, verbal and visual memory, visuospatial abilities, speed processing, attention, and executive functions. The PRS group showed lower general neuropsychological performance scores at a multivariate level and lower scores than controls in general intelligence and executive functions. Lower scores on executive function and poorer attention were associated with high scores of positive attenuated psychotic symptoms. No association with attenuated negative symptoms was found. This study provides evidence of cognitive impairment in PRS children and adolescents and shows a relationship between greater cognitive impairment in executive functions and attention tasks and severe attenuated positive symptoms. However, longitudinal studies are needed to clarify the nature of cognitive impairment as a possible vulnerability marker.
... The cerebellum has been implicated in cognitive and affective processing, although how it is involved in these functions is not clearly understood (Barch, 2014;Bernard and Mittal, 2014). ASz youth are characterised also by dyskinetic movement abnormalities and impairments in cognition and facial emotion processing relative to their TD peers (Cullen et al., 2010;Dickson et al., 2014aDickson et al., , 2014bDickson et al., , 2018MacManus et al., 2012). This body of evidence provides some support for the 'cognitive dysmetria' model of schizophrenia, which posits that cognitive, motor, and affective deficits seen among individuals with schizophrenia result from difficulties in mental coordination due to disconnections in the cortico-cerebellar-thalamic-cortical circuits in the brain (Andreasen and Pierson, 2008;Moussa-Tooks et al., 2018). ...
Premorbid motor dysfunction is one of the earliest of developmental antecedents identified among individuals who develop schizophrenia in adulthood. However, among individuals with schizophrenia, premorbid motor dysfunction is not apparent at all stages of childhood development and may reduce with increasing age. Currently, little is known about the trajectories of motor development during adolescence among youth at-risk for the disorder. One hundred and one participants were assessed repeatedly, at approximately 24-month intervals (time 1, aged 9-12 years; time 2, 11-14 years; and time 3, 13-16 years), on the Purdue Pegboard assessment, comprising four subtests: Dominant Hand (DH), Non-Dominant Hand (NDH), Both Hands (BH), and Assembly. Fine motor and coordination skills development between ages 9-16 years was compared between youth characterised by a triad of developmental antecedents of schizophrenia (ASz, N = 32); youth with at least one affected relative with schizophrenia/schizoaffective disorder (FHx; N = 26); and typically developing youth without antecedents or family history (TD, N = 43). Longitudinal mixed models for repeated measures indicated significant motor skills improvements with age in TD youth on the Assembly subtest only. Relative to TD youth, we found evidence for developmental deficits (i.e., dysfunction that emerged early and remained stable) among ASz youth on DH and BH subtests, and among FHx youth on the Assembly subtest. ASz youth were characterised by a developmental delay on the Assembly subtest (i.e., initial performance decrement in middle childhood that caught up with peers' performance during adolescence). These divergences from normative motor development may reflect differences in structural and functional neural correlates.
... The finger tapping task is a well-established neuropsychological measure of timing and motor deficits that has been validated for online use [5,6]. Critically, patients with psychosis show motor slowing [7,8] that appears early in the course of psychosis development [9][10][11][12][13][14][15][16][17]. This motor slowing in psychosis may be related to coordination among basal ganglia, cerebellar, and cortico-motor circuits [18][19][20], which is disrupted across disease stage [10,[21][22][23][24]. ...
Finger tapping is sensitive to motor slowing and emerging symptoms in individuals at clinical high risk for psychosis (CHR). A sensitive, computerized finger tapping task would be beneficial in early psychosis screening batteries. The study included 41 CHR and 32 healthy volunteers, who completed a computerized finger tapping task and clinical interviews. This computerized finger tapping task was sensitive to slowing in the CHR group compared to healthy volunteers, and as expected negative but not positive symptoms related to motor slowing. Computerized finger tapping tasks may be an easily dispersible tool for early symptom detection battery relevant to emerging negative symptoms.
... Growing evidence shows that a broad range of cognitive impairment is a hallmark of patients with schizophrenia. High heritability was found from studying the cognitive phenotypes of relatives of schizophrenia probands (Dickson et al., 2014;Scala et al., 2012;Schulze-Rauschenbach et al., 2015). Cognitive impairments, albeit less severe, are also present in a substantial number of patients with bipolar disorder in a euthymic state (Arts et al., 2008;Mann-Wrobel et al., 2011;Robinson et al., 2006). ...
22q11.2 heterozygous multigene deletions confer an increased risk of schizophrenia with marked impairment of cognition. We explored whether genes on 22q11.2 are associated with cognitive performance in patients with idiopathic schizophrenia. A total of 240 schizophrenia patients and 240 healthy controls underwent the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and were genotyped for 115 tag single-nucleotide polymorphisms (tag SNPs) at the 22q11.2 region using the golden gate assay (Illumina®). Associations between z-scores of the BACS cognitive domains and SNPs and haplotypes were analyzed using linear regression in PLINK 1.07. An additional set of 149 patients with bipolar disorder were included for cognitive assessment and selected SNPs were genotyped using real-time PCR. Patients with schizophrenia and bipolar disorder showed qualitatively comparable profiles of cognitive impairment across BACS subdomains, as revealed by significant correlation between the two groups in the resulting cognitive effect sizes relative to controls. rs4819522 (TBX1) and rs2238769 (UFD1L) were significantly and nominally associated, respectively, with symbol coding in patients with schizophrenia. Haplotype analyses revealed that haplotypes containing the A allele at rs4819522 and G allele at rs2238769 showed significant negative associations with symbol coding in patients with schizophrenia. There was no effect of any haplotypes on cognition in patients with bipolar disorder. Our results have implications for the understanding of the role of haplotypes of UFD1L and TBX1 genes associated with symbol coding in patients with schizophrenia. Further replication studies in a cohort of newly diagnosed patients and other ethnicities are warranted.
... Woodberry et al. [34] found differences in executive functions in the overall domain, specifically in the FAS verbal fluency score and in perseverative errors, as well as in verbal memory. Similarly, Dickson et al. [89] found impairment in executive function in subjects with low family history of schizophrenia (second-degree relative of psychosis subjects) compared to normal controls. In contrast, Ziermans et al. [30] did not see this impairment in either executive function or verbal memory. ...
Aim
Despite the interest in psychosis risk syndrome (PRS) in children and adolescents, information on the syndrome in this population is scarce.
Methods
Prospective naturalistic multi‐site study in which 10‐ to 17‐year‐old help‐seeking subjects who met PRS criteria (positive or negative attenuated symptoms; brief limited intermittent psychotic symptoms; genetic risk or schizotypal personality disorder plus impairment in functioning) were included, along with 45 age and sex‐matched healthy controls (HC). All subjects were clinically and functionally assessed.
Results
Ninety‐one PRS subjects (PRSS) with a mean age of 15.5 ± 1.4 met inclusion criteria (IC). Compared with HC, PRSS presented worse global and academic functioning in the previous year, had experienced more psychiatric and psychological problems, and presented gestational ages outside the normal range. More than 80% of PRSS met ≥2 IC, with 65.9% having one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis, and 61.7% of those having ≥2 diagnoses. Some 49.5% of PRSS had a first‐ or second‐degree family history (FH) of psychosis. Patients with first‐ and second‐degree FH do not differ in their clinical expression.
Conclusions
Children and adolescents with PRS are a patient group with a pattern of neurodevelopmental impairment and clinical complexity similar to patients with schizophrenia spectrum disorders, highlighting the importance of assessing these variables in child and adolescent samples. PRSS with first‐ and second‐degree relatives with FH do not present differences in their clinical presentation, suggesting that including these two groups of patients in the genetic risk criteria would enrich knowledge of these criteria.
... Additionally, while their composite cognition scores were similar, their profiles of impairment differed; individuals with clinical risk showed deficits in executive functioning and verbal memory while individuals with familial risk had deficits in vocabulary and visuospatial skills. Children with a lower familial risk (only one affected 2 nd -degree relative) have cognitive scores similar to healthy controls, but those with higher familial risk (at least one affected 1 st degree relative or at least two affected 2 nd -degree relatives) demonstrate lower full-scale IQ, scholastic achievement, verbal comprehension, working memory, verbal memory, and executive functioning (Dickson et al. 2014). When patients are stratified by the level of clinical risk, which may indicate different stages of the prodrome (Klosterkotter et al. 2001), those identified as Bbasic symptom at-risk^had better working memory and verbal memory than those at ultra-high risk and first-episode subjects (Simon et al. 2007). ...
Individuals with disorders that include psychotic symptoms (i.e. psychotic disorders) experience broad cognitive impairments in the chronic state, indicating a dimension of abnormality associated with the experience of psychosis. These impairments negatively impact functional outcome, contributing to the disabling nature of schizophrenia, bipolar disorder, and psychotic depression. The robust and reliable nature of cognitive deficits has led researchers to explore the timing and profile of impairments, as this may elucidate different neurodevelopmental patterns in individuals who experience psychosis. Here, we review the literature on cognitive deficits across the life span of individuals with psychotic disorder and psychotic-like experiences, highlighting the dimensional nature of both psychosis and cognitive ability. We identify premorbid generalized cognitive impairment in schizophrenia that worsens throughout development, and stabilizes by the first-episode of psychosis, suggesting a neurodevelopmental course. Research in affective psychosis is less clear, with mixed evidence regarding premorbid deficits, but a fairly reliable generalized deficit at first-episode, which appears to worsen into the chronic state. In general, cognitive impairments are most severe in schizophrenia, intermediate in bipolar disorder, and the least severe in psychotic depression. In all groups, cognitive deficits are associated with poorer functional outcome. Finally, while the generalized deficit is the clearest and most reliable signal, data suggests specific deficits in verbal memory across all groups, specific processing speed impairments in schizophrenia and executive functioning impairments in bipolar disorder. Cognitive deficits are a core feature of psychotic disorders that provide a window into understanding developmental course and risk for psychosis. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
... In fact, a lower pre-morbid IQ was suggested to be a potential vulnerability factor for schizophrenia (Davis et al., 2016). Intelligence, as well as the risk of developing schizophrenia, is strongly related to genetic factors (Kendler, Ohlsson, Sundquist, & Sundquist, 2015;Sullivan, Kendler, & Neale, 2003); indeed, children at high risk for schizophrenia exhibit a lower intellectual level (Dickson et al., 2014). Moreover, a lower IQ might be due to intellectual decline; in fact, about 50-70% of patients show an IQ decline of 10 points or greater after schizophrenia onset, together with a discrepancy between pre-morbid and current IQ level (Fujino et al., 2016;Weickert et al., 2000). ...
Intellectual abilities display high heterogeneity in patients with schizophrenia that might depend on the interaction among neurodevelopmental processes, environmental factors and neurocognitive decline. This study aimed to disentangle the interplay between intellectual level, cognitive status and each cognitive domain, with a focus on speed‐related abilities, also including pre‐morbid factors. In details, by means of cluster analysis, we identified both in global sample of 452 patients affected by schizophrenia and in a subsample with high pre‐morbid functioning, different profiles based on current intellectual level and global cognitive status, analysing the distribution of deficits in each cognitive domains between groups. Then, through regression models, we analysed the contribution of speed‐related domains and global cognitive profile to each other cognitive function. Considering the whole sample, results highlight three groups (high, medium and low cognitive level), while among patients with high pre‐morbid level, the heterogeneity was best captured by two groups (high and medium level). Still, within each group, a small to high percentage of patients achieved normal score in neurocognitive abilities depending on the cluster they belong to. Speed of processing and psychomotor coordination resulted impaired in all clusters, even in patients with high pre‐morbid functioning. The regression analyses revealed significant effects of both cognitive profile and speed‐dependent domains on the other cognitive abilities. This study confirms, in a large sample, previous data about the heterogeneity of intellectual and neurocognitive functioning in schizophrenia and highlights the main role of speed‐dependent neurocognitive functioning, also as an important target of rehabilitation.
... Therefore, we expect that impairments in hot executive functions will be more closely related to the propensity to experience psychotic symptoms. Previous studies in youth with psychotic symptoms have identified cognitive impairment in cold executive functions, including processing speed and working memory (Cullen et al. 2010;Blanchard et al. 2010, Kelleher et al. 2012aDickson et al. 2014). The relationship between hot executive functions and the propensity for psychotic symptoms has not yet been explored. ...
Background
Psychotic symptoms are common in children and adolescents and may be early manifestations of liability to severe mental illness (SMI), including schizophrenia. SMI and psychotic symptoms are associated with impairment in executive functions. However, previous studies have not differentiated between ‘cold’ and ‘hot’ executive functions. We hypothesized that the propensity for psychotic symptoms is specifically associated with impairment in ‘hot’ executive functions, such as decision-making in the context of uncertain rewards and losses.
Methods
In a cohort of 156 youth (mean age 12.5, range 7–24 years) enriched for familial risk of SMI, we measured cold and hot executive functions with the spatial working memory (SWM) task (total errors) and the Cambridge Gambling Task (decision-making), respectively. We assessed psychotic symptoms using the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia interview, Structured Interview for Prodromal Syndromes, Funny Feelings, and Schizophrenia Proneness Instrument – Child and Youth version.
Results
In total 69 (44.23%) youth reported psychotic symptoms on one or more assessments. Cold executive functioning, indexed with SWM errors, was not significantly related to psychotic symptoms [odds ratio (OR) 1.36, 95% confidence interval (CI) 0.85–2.17, p = 0.204). Poor hot executive functioning, indexed as decision-making score, was associated with psychotic symptoms after adjustment for age, sex and familial clustering (OR 2.37, 95% CI 1.25–4.50, p = 0.008). The association between worse hot executive functions and psychotic symptoms remained significant in sensitivity analyses controlling for general cognitive ability and cold executive functions.
Conclusions
Impaired hot executive functions may be an indicator of risk and a target for pre-emptive early interventions in youth.
... The mechanisms underlying the relationship between psychotic experiences and suicidal behaviour are not entirely clear, but a number of potentially important factors have been identified to date. Individuals with psychotic experiences, for example, have been shown to have more severe mental disorders (33), a higher degree of multimorbid psychopathology (4,34), more cognitive (35)(36)(37)(38) and social dysfunction (39,40), neurobiological abnormalities (41)(42)(43), poorer coping skills (39,44), and poorer response to treatment than individuals with psychopathology who do not report psychotic experiences (45,46). Recent research has also shown that individuals with psychotic experiences share multiple psychosocial risk factors that have been established for individuals with high levels of suicidal behaviour (47). ...
Objective:
Recent research has demonstrated a strong relationship between psychotic experiences and suicidal behaviour. No research to date, however, has investigated the role of borderline personality disorder (BPD) in this relationship, despite the fact that BPD is highly comorbid with common mental disorders and is associated with both recurrent suicidal behaviour and psychotic experiences. This paper examined the relationship between psychotic experiences and suicide attempts, including interrelationships with BPD and common mental disorders.
Method:
We used the 2007 Adult Psychiatric Morbidity Study, a stratified, multistage probability sample of households in England, which recruited a nationally representative sample aged 16 years and older. Participants were assessed for common mental disorders, BPD (clinical and subclinical), suicidal behaviour, and psychotic experiences.
Results:
Approximately 4% of the total sample (n = 323) reported psychotic experiences. Psychotic experiences were associated with increased odds of suicide attempts in individuals with BPD (OR = 2.23, 95% CI = 1.03-4.85), individuals with a common mental disorder (OR = 2.47, 95% CI = 1.37-4.43), individuals without a common mental disorder (OR = 3.99, 95% CI = 2.47-6.43), and individuals with neither a common mental disorder nor BPD (OR = 3.20, 95% CI = 1.71-5.98).
Conclusion:
Psychotic experiences are associated with high odds of suicidal behaviour in individuals with and without psychopathology. This relationship is not explained by clinical or subclinical BPD.
... This suggests that the dose of the medication did not have a significant impact on the results. Another limitation is that we did not strictly control for literacy, which is associated with poor cognitive functioning in patients (Clegg et al., 2005;Dickson et al., 2014). Although all participants reported having completed their high school training, ensuring a minimum level of literacy, we consider that further investigations are required to examine more in detail the impact of literacy on active binding deficits in patients with SZ. ...
... Relative to healthy individuals, patients are characterized by moderate-to-large deficits across multiple neurocognitive domains, with the most severe impairments observed in memory and executive function (Reichenberg and Harvey, 2007). Similar impairments, albeit smaller in magnitude, have also been observed among individuals at CHR (Fusar-Poli et al., 2012b), GHR adolescents and young adults (Agnew-Blais and Seidman, 2013) and children presenting multiple antecedents of schizophrenia (Cullen et al., 2010;Dickson et al., 2014). While it is likely that these neurocognitive deficits are influenced by genetic factors (Kahn and Keefe, 2013), there is some evidence to suggest that psychosocial stress exposure and abnormal HPA axis function may be contributors. ...
Over the past decade, our understanding of the role of stress in serious mental illness has become more sophisticated. In this paper, we revisit the neural diathesis-stress model of schizophrenia that was initially proposed in 1997 and updated in 2008. In light of cumulative research findings, we must now encompass evidence on the premorbid periods of psychosis, and our more nuanced understanding of hypothalamic-pituitary-adrenal (HPA) axis function and its association with neurodevelopmental, epigenetic, neurotransmitter, and inflammatory processes, as well as brain structure and function. Giving consideration to the methodological complexities that have become more apparent as research in this area has burgeoned, the various indices of HPA axis function, and the different stages of illness, we review relevant research published since the 2008 update of the model. We conclude by proposing an extended neural diathesis-stress model that addresses the broader neurobiological context of stress psychobiology in psychosis progression. Implications of this model for best practice, with regards to both future research and treatment strategies, are discussed.
... Whether the reported cognitive impairments reflected in IQ and scholastic underperformance are changes are due to the (early) effects of the illness, reflect neurodevelopment (Bora, 2015b) or are directly related to the (genetic) risk to develop the illness remains subject to debate. A role of familial susceptibility is suggested by studies showing that relatives of schizophrenia and bipolar patients have similar but less severe impairments in cognitive functioning as the patients (Keefe et al. 1994;Cannon et al. 2000;Kulkarni et al. 2010;Jundong et al. 2012) and studies reporting impaired scholastic performance in schizophrenia offspring (Jundong et al. 2012;Dickson et al. 2014). ...
Background
Poor educational achievement is associated with a range of psychiatric disorders. Several studies suggest that this underperformance is due to cognitive deficits that commence before disease onset and reflect a genetic risk for this disorder. However, the specificity and the familial contribution of this cognitive deficit are not clear. We analysed lifetime educational achievement of psychiatric patients diagnosed with schizophrenia, bipolar or depressive disorder and their unaffected siblings.
Method
In a register-based case-control study, 1561 patients with schizophrenia, 813 patients with bipolar disorder, 8112 patients with depression, and their siblings were each matched with eight population controls. Patients, siblings and controls were compared on the highest educational stream they completed.
Results
Lower educational achievement was present in schizophrenia patients from primary school onwards [completing primary school: odds ratio (OR) 0.69; completing secondary school: OR 0.69; completing academic education: OR 0.46], compared to patients with bipolar disorder or depression. Siblings of schizophrenia, bipolar or depressed patients showed no underachievement at primary or secondary school, but siblings of schizophrenia patients as well as siblings of depressed patients were less successful in their educational achievement after secondary school (completing academic education, schizophrenia siblings: OR 0.90; depressive disorder siblings: OR 0.91).
Conclusions
Educational underachievement from primary school onwards is specifically related to schizophrenia and not to bipolar disorder or depression. Moreover, it appears to be a harbinger of the illness, since it is not found in their siblings. These results add to evidence that early cognitive deficits are a distinct feature of the schizophrenia phenotype.
... [6] Typically, the cognitive performance in patients with schizophrenia is [1,2] standard deviation less compared to matched healthy comparison controls. [7] Healthy first-degree relatives of patients or high-risk (HR) patients, such as siblings and offsprings of patients with schizophrenia, also demonstrate significant impairments in neurocognitive functioning, [8][9][10] indicating that such cognitive deficits could be potential endophenotypes of the illness. [11] Prospective studies in HR patients have shown that verbal working memory, performance attention, and gross motor skills have predictive potential regarding conversion to psychosis. ...
Abstract
Background:
Neurocognitive impairments of attention and executive functioning are trait abnormalities in schizophrenia and these are considered to be endophenotypes. These deficits have been convinc-ingly linked to prefrontal cortical functioning. In this study, we examined the cognitive perfor-mance in the domains of attention and executive functioning among first degree relatives of Indi-an subjects with schizophrenia (high risk subjects) (HR) compared to healthy controls (HC).
Methods:
Siblings of patients with DSM IV schizophrenia, HR subjects (N=17), were compared with HC (N=30) (matched as a group for age, sex, years of education and handedness) using the following neurocognitive tests for attention and executive function- digit span test (DST), trail making test (TMT), letter number sequencing (LNS) and spatial span test.
Results:
HR subjects had significantly deficient performance in attention and executive function tasks (DST-forward (p<0.001), DST backward (p<0.001), spatial span (forward) (p<0.001), spatial span (backward) (p<0.001) and LNS (p<0.001))
Conclusions:
This study replicates the finding that neurocognitive deficits involving executive function task performance, attention and working memory which are considered as principal features in pa-tients with schizophrenia, are also significantly present in first degree relatives of patients. Thus these neurocognitive parameters can be considered as potential endophenotypes in schizophrenia.
... Transition to psychosis appears to be particularly associated with deficits in verbal fluency and memory functioning (Fusar-Poli et al. 2012). Although impairment in verbal comprehension, scholastic achievement and verbal working memory are found among children at risk for schizophrenia (Dickson et al. 2014), predictive cognitive markers that discriminate acutely ill, stabilised or recovered patients from healthy individuals are still lacking (Saoud et al. 2000;Addington and Barbato 2012). ...
Objectives:
Schizophrenia is a group of severe psychiatric disorders with high heritability but only low odds ratios of risk genes. Despite progress in the identification of pathophysiological processes, valid biomarkers of the disease are still lacking.
Methods:
This comprehensive review summarises recent efforts to identify genetic underpinnings, clinical and cognitive endophenotypes and symptom dimensions of schizophrenia and presents findings from neuroimaging studies with structural, functional and spectroscopy magnetic resonance imaging and positron emission tomography. The potential of findings to be biomarkers of schizophrenia is discussed.
Results:
Recent findings have not resulted in clear biomarkers for schizophrenia. However, we identified several biomarkers that are potential candidates for future research. Among them, copy number variations and links between genetic polymorphisms derived from genome-wide analysis studies, clinical or cognitive phenotypes, multimodal neuroimaging findings including positron emission tomography and magnetic resonance imaging, and the application of multivariate pattern analyses are promising.
Conclusions:
Future studies should address the effects of treatment and stage of the disease more precisely and apply combinations of biomarker candidates. Although biomarkers for schizophrenia await validation, knowledge on candidate genomic and neuroimaging biomarkers is growing rapidly and research on this topic has the potential to identify psychiatric endophenotypes and in the future increase insight on individual treatment response in schizophrenia.
... The abnormal TCF4 mRNA expression in psychosis patients is probably related to abnormal neurodevelopment, which includes cognitive dysfunction [32] . Interestingly, cognitive impairments are detected prior to the AAO of schizophrenia, usually before the onset of the first psychotic episode and often accompanied by language skills impairment [35,36] and white matter changes [37] . Moreover, the rate of neurocognitive impairment in Malaysian schizophrenia patients is high (80%) [38] . ...
Background:
Age at onset (AAO) is a known prognostic indicator for schizophrenia and is hypothesized to correlate with cognition and symptom severity. TCF4 and AKT1 are schizophrenia risk genes involved in cognitive functions. The current study examined the interactive effects of TCF4 and AKT1 variants with gender, family history of psychiatric disorders and ethnicity on the AAO of schizophrenia.
Methods:
This study consisted of 322 patients with schizophrenia meeting the DSM-IV criteria. Six single nucleotide polymorphisms (SNPs) of TCF4 (rs12966547, rs8766, rs2958182, rs9960767, rs10401120 and rs17512836) and seven AKT1 SNPs (rs2498804, rs3803304, rs2494732, rs3730358, rs1130214, rs2498784 and rs3803300) were genotyped using the TaqMan® SNP genotyping-based assays method. The relationship of AAO with each variant was investigated using analyses of covariance.
Results:
Among the TCF4 variants, rs12966547 (p = 0.024) and rs8766 (p = 0.021) were significantly associated with earlier AAO. We found a lower average AAO in patients with the AA genotype of rs12966547, while the CT genotype of rs8766 was demonstrated to have a protective effect on AAO. For rs8766, there was significant gene × gender interaction (p = 0.012) in influencing AAO. However, these results were not significant after false discovery rate correction. Significant gene × ethnicity interactions were observed to influence AAO (p < 0.05). The Kaplan-Meier curve of the minor AA genotype of rs12966547 displayed a significant trend (p = 0.008) for onset after 19 years of age. Similarly, the minor CC genotype of rs8766 showed a significantly (p = 0.034) lower AAO compared to the TT genotype.
Conclusion:
Our analyses suggest that individual risk genotypes may influence the risk of schizophrenia in an age-specific manner.
... In this study, the FDR group showed cognitive deficits, but less pronounced than the FE groups, which is also consistent with earlier findings (Dickson et al., 2014). A recent meta-analysis suggested that cognitive functions are significantly impaired in both UHR and FDR Table 1 Demographic and clinical characteristics of the ultra-high risk, first-degree relatives, patients with first-episode schizophrenia and healthy control groups. ...
Objective:
The aim of the present study was to investigate and compare cognitive functioning of first-degree relatives of people with schizophrenia who were also at ultra-high risk (UHR) for psychosis with patients with first-episode (FE) schizophrenia, first degree relatives of patients not fulfilling UHR criteria (FDR), and healthy control (HC) subjects.
Method:
Forty subjects in each group were included, underwent a face-to-face interview and completed a neurocognitive test battery, including the Trail Making Test-A (TMT-A, psychomotor functions), Stroop Color Word Test (attention), Digit Symbol Coding Test (DST, processing speed and working memory) and Hopkins Verbal Leaning Test-Revised (HVLT-R, verbal memory).
Results:
Functioning in all the cognitive test domains displayed a gradual decrease from the HC, FDR, UHR to FE groups. After controlling for covariates, there were still significant differences in TMT-A (F(7160)=35.4, P<0.001), DST (F(7160)=38.9, P<0.001), Stroop Color Word Test (F(7160)=35.0, P<0.001), Stroop Word Test (F(7160)=36.2, P<0.001), Stroop Color Test (F(7160)=40.9, P<0.001) and HVLT-R (F(7160)=62.5, P<0.001) between the four groups, indicating that the cognitive functioning in the UHR group was intermediate between the FE and FDR groups, while the FDR group had poorer performance than the HC group, and the FE group had the poorest cognitive functioning across all four examined domains.
Conclusion:
The results indicate that impairments in processing speed, attention, working memory and verbal memory exist in both UHR and FDR subjects. In order to clarify the associations between cognitive functioning and UHR and schizophrenia, longitudinal studies are warranted.
... The few studies that have examined the scholastic performance of the children of parents with schizophrenia have demonstrated that those children show poorer scholastic performance [8][9][10] and have lower teacher ratings, 11 than the offspring of unaffected parents. The literature on school performance and the later development of schizophrenia is large but inconsistent: some population-based studies have reported poorer school performance prior to schizophrenia onset, [12][13][14][15] others have not. ...
Objective:
We examined the academic performance at age 12 years of children of mothers diagnosed with schizophrenia or other severe mental illness using a large whole-population birth cohort born in Western Australia. We investigated the association between academic performance and the subsequent development of psychotic illness.
Method:
The sample comprised 3169 children of mothers with severe mental illness (schizophrenia, bipolar disorder, unipolar major depression, delusional disorder or other psychoses; ICD-9 codes 295-298), and 88 353 children of comparison mothers without known psychiatric morbidity. Academic performance of children was indexed on a mandatory state-wide test of reading, spelling, writing and numeracy.
Results:
A larger proportion of children (43.1%) of mothers with severe mental illness performed below the acceptable standard than the reference group (30.3%; children of mothers with no known severe mental illness). After adjusting for covariates, children of mothers with any severe mental illness were more likely than the reference group to perform below-benchmark on all domains except reading. For all children, poor spelling was associated with the later development of psychosis, but particularly for those at familial risk for severe mental illness (hazard ratio [HR] = 1.81; 95% CI for HR = 1.21, 2.72).
Conclusions:
Children of mothers with a severe mental illness are at increased risk for sub-standard academic achievement at age 12 years, placing these children at disadvantage for the transition to secondary school. For children with familial risk for severe mental illness, very poor spelling skills at age 12 years may be an indicator of risk for later psychotic disorder.
... Furthermore, minor WM impairment is evident in first-degree relatives of people with schizophrenia and other individuals at familial-risk [21][22][23], suggesting a genetic contribution [24,25]. Reduced WM capacity has also been found in those help-seeking individuals deemed to be at Ultra-High Risk (UHR) [26] or to have an At-Risk Mental State (ARMS) for psychosis, especially in those who convert to psychotic disorder [27][28][29][30]. Finally, a large body of work reports on the association of WM deficits with schizotypy with mixed results, possibly due to the heterogeneity of the instruments used [31]. ...
Psychotic Experiences (PEs) during adolescence index increased risk for psychotic disorders and schizophrenia in adult life. Working memory (WM) deficits are a core feature of these disorders. Our objective was to examine the relationship between PEs and WM in a general population sample of young people in a case control study. 4744 individuals of age 17-18 from Bristol and surrounding areas (UK) were analyzed in a cross-sectional study nested within the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. The dependent variable was PEs, assessed using the semi-structured Psychosis-Like Symptom Interview (PLIKSi). The independent variable was performance on a computerized numerical n-back working memory task. Signal-Detection Theory indices, including standardized hits rate, false alarms rate, discriminability index (d') and response bias (c) from 2-Back and 3-Back tasks were calculated. 3576 and 3527 individuals had complete data for 2-Back and 3-Back respectively. Suspected/definite PEs prevalence was 7.9% (N = 374). Strongest evidence of association was seen between PEs and false alarms on the 2-Back, (odds ratio (OR) = 1.17 [95% confidence intervals (CI) 1.01, 1.35]) and 3-back (OR = 1.35 [1.18, 1.54]) and with c (OR = 1.59 [1.09, 2.34]), and lower d' (OR = 0.76 [0.65, 0.89]), on the 3-Back. Adjustment for several potential confounders, including general IQ, drug exposure and different psycho-social factors, and subsequent multiple imputation of missing data did not materially alter the results. WM is impaired in young people with PEs in the general population. False alarms, rather than poor accuracy, are more closely related to PEs. Such impairment is consistent with different neuropsychological models of psychosis focusing on signal-to-noise discrimination, probabilistic reasoning and impaired reality monitoring as a basis of psychotic symptoms.
... Whether the reported cognitive impairments reflected in IQ and scholastic underperformance are changes are due to the (early) effects of the illness, reflect neurodevelopment (Bora, 2015b) or are directly related to the (genetic) risk to develop the illness remains subject to debate. A role of familial susceptibility is suggested by studies showing that relatives of schizophrenia and bipolar patients have similar but less severe impairments in cognitive functioning as the patients (Keefe et al. 1994;Cannon et al. 2000;Kulkarni et al. 2010;Jundong et al. 2012) and studies reporting impaired scholastic performance in schizophrenia offspring (Jundong et al. 2012;Dickson et al. 2014). ...
... In initial cross-sectional analyses conducted in ASz and TD groups 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Laurens & Cullen; p. 9 only, we observed impairments in general intelligence, verbal memory, working memory, and executive function among ASz children aged 9-12 years [38] which were less pervasive and smaller in magnitude than those characterising adults with schizophrenia [39], but similar to those observed among CHR individuals [40,41]. In subsequent analyses performed on a larger, partially overlapping sample, ASz children performed at a level intermediate to FHx children with high familial loading (≥ 1 first-degree or ≥ 2 seconddegree relatives) and FHx children with low familial loading (1 affected second-degree relative only) across a range of neurocognitive subtests [42]. Preliminary analysis of longitudinal neurocognitive data collected across three biennial assessments (9-12, 11-14, and 13-16 years) indicates that ASz and FHx children show different patterns of cognitive development through adolescence relative to TD children. ...
Prevention is particularly important for those disorders whose course is chronic and disabling. Schizophrenia and other psychotic disorders have high levels of disability [1] and challenges with treatment non-adherence and the associated risk of iatrogenic harm from antipsychotic medication makes prevention an urgent imperative. Initial studies identifying adolescents and young adults at ultrahigh risk of psychosis were accompanied by optimism that transition to schizophrenia could be prevented [2]. However, pharmacological interventions in the prodromal phase have been of no benefit, cognitive behavioural therapy has shown limited benefits to date in preventing psychosis transition [3] and one study demonstrating effectiveness of omega-3-polyunsaturated fatty acids in preventing transition to psychosis [4] has yet to be replicated. The delivery of interventions to those adolescents and young adults in the prodromal phase of psychosis may be too late to prevent illness progression. It is well established that in some
... With regards to familial association and cosegregation, recent studies and meta-analysis of unaffected relatives of individuals with schizophrenia showed that relatives performed more poorly than controls [25,26]. This suggested that GCA deficits vary quantitatively with degree of genetic risk for psychosis, as would be expected if there is substantial overlap in genes contributing to GCA and psychosis. ...
Intermediate phenotypes (IPs) are defined as measurable liability traits underlying complex phenotypes, posited to be more genetically tractable than the phenotypes themselves. Here we review evidence for cognition as an IP of psychosis, and highlight topical advances in the literature: first, heritability estimation of cognitive abilities using genomewide complex-trait analysis; second, evidence that cognition lies upstream to schizophrenia liability; third, use of polygenic risk scores rather than single genetic variants to examine genetic overlap between cognitive IPs and schizophrenia; and fourth, use of cognitive IPs for schizophrenia risk gene discovery and functional characterization. We end with future directions in using cognitive IPs to study genetic risk of psychosis, including methodological refinements and shifting research focus from identifying IPs to using them.
... Therefore, the IQ-schizophrenia association could plausibly arise because of genetic and/or familial-environment factors predisposing both to low IQ and risk for schizophrenia. This hypothesis is consistent with evidence that: i) several candidate genes for schizophrenia are associated with lowered IQ (19;20); ii) identified copy number variants increase risk both for schizophrenia and intellectual disability (21); iii) an exome study in schizophrenia found enrichment in intellectual disability loss-of-function de novo mutations (22); iv) children at high genetic risk for schizophrenia were shown to have lowered IQ (23) and v) one prior twin study demonstrated a strong negative genetic correlation between IQ and schizophrenia liability (24). ...
The authors sought to clarify the relationship between IQ and subsequent risk for schizophrenia.
IQ was assessed at ages 18-20 in 1,204,983 Swedish males born between 1951 and 1975. Schizophrenia was assessed by hospital diagnosis through 2010. Cox proportional hazards models were used to investigate future risk for schizophrenia in individuals as a function of their IQ score, and then stratified models using pairs of relatives were used to adjust for familial cluster. Finally, regression models were used to examine the interaction between IQ and genetic liability on risk for schizophrenia.
IQ had a monotonic relationship with schizophrenia risk across the IQ range, with a mean increase in risk of 3.8% per 1-point decrease in IQ; this association was stronger in the lower than the higher IQ range. Co-relative control analyses showed a similar association between IQ and schizophrenia in the general population and in cousin, half-sibling, and full-sibling pairs. A robust interaction was seen between genetic liability to schizophrenia and IQ in predicting schizophrenia risk. Genetic susceptibility for schizophrenia had a much stronger impact on risk of illness for those with low than high intelligence. The IQ-genetic liability interaction arose largely from IQ differences between close relatives.
IQ assessed in late adolescence is a robust risk factor for subsequent onset of schizophrenia. This association is not the result of a declining IQ associated with insidious onset. In this large, representative sample, we found no evidence for a link between genius and schizophrenia. Co-relative control analyses showed that the association between lower IQ and schizophrenia is not the result of shared familial risk factors and may be causal. The strongest effect was seen with IQ differences within families. High intelligence substantially attenuates the impact of genetic liability on the risk for schizophrenia.
... For other disorders, including schizophrenia, the family history could be adequately assessed using a simple dichotomous measure. 25,28 Some combine scores across kinship by giving the weight of 1 to first-degree relatives and the weight of 0.5 to second-degree relatives 25,29 ; however, these weights may not generalize across populations and disorders. Therefore, we decided to study a simple hierarchical score, where any mental disorder with psychosis overruled the event of any nonpsychotic disorder among relatives, and to examine first-degree relatives and second-degree relatives separately and then test whether the data could be meaningfully collapsed across kinship to create one single measure of familial liability. ...
Psychotic experiences (PE) in individuals of the general population are hypothesized to mark the early expression of the pathology underlying psychosis. This notion of PE as an intermediate phenotype is based on the premise that PE share genetic liability with psychosis. We examined whether PE in childhood was predicted by a family history of mental disorder with psychosis rather than a family history of nonpsychotic mental disorder and whether this association differed by severity of PE. The study examined data on 1632 children from a general population birth cohort assessed at age 11-12 years by use of a semistructured interview covering 22 psychotic symptoms. The Danish national registers were linked to describe the complete family history of hospital-based psychiatric diagnoses. Uni- and multivariable logistic regressions were used to test whether a family history of any mental disorder with psychosis, or of nonpsychotic mental disorder, vs no diagnoses was associated with increased risk of PE in offspring (hierarchical exposure variable). The occurrence of PE in offspring was significantly associated with a history of psychosis among the first-degree relatives (adjusted relative risk [RR] = 3.29, 95% CI: 1.82-5.93). The risk increased for combined hallucinations and delusions (adjusted RR = 5.90, 95% CI: 2.64-13.16). A history of nonpsychotic mental disorders in first-degree relatives did not contribute to the risk of PE in offspring nor did any mental disorder among second-degree relatives. Our findings support the notion of PE as a vulnerability marker of transdiagnostic psychosis. The effect of psychosis in first-degree relatives may operate through shared genetic and environmental factors.
© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
... 25 PLEs in the general population are generally transient and only a small proportion (8-10%) evolve into psychotic and nonpsychotic disorders each year, 28 but they may share an etiological background with psychotic disorders. 25,[29][30][31] The PLEs phenotype is not a clinical outcome but has the important advantage, from a research perspective, of (1) being much more prevalent than schizophrenia and (2) not being dependent on help-seeking, thus allowing for true population-based epidemiological enquiry. These advantages mean that PLEs are suitable for epidemiological research into the pathophysiology, course, and treatment of psychotic symptoms in representative populationbased contexts. ...
Background:
Associations between self-control in adolescence and adult mental health are unclear in the general population; to our knowledge, no study has investigated self-control in relation to psychotic-like symptoms.
Aims:
To investigate the relationship between adolescent self-control and the midlife mental health outcomes of anxiety and depression symptoms and psychotic-like experiences (PLEs), controlling for the effect of adolescent conduct and emotional problems and for parental occupational social class and childhood cognition.
Methods:
A population-based sample, the MRC National Survey of Health and Development (the British 1946 birth cohort) was contacted 23 times between ages 6 weeks and 53 years. Teachers completed rating scales to assess emotional adjustment and behaviors, from which factors measuring self-control, behavioral, and emotional problems were extracted. At age 53 years, PLEs were self-reported by 2918 participants using 4 items from the Psychosis Screening Questionnaire; symptoms of anxiety and depression were assessed using the scaled version of the General Health Questionnaire (GHQ-28).
Results:
After adjustment for the above covariates, poor adolescent self-control was associated with the presence of PLEs in adulthood, specifically hallucinatory experiences at age 53 years, even after adjustment for GHQ-28 scores.
Conclusions:
Lower self-control in adolescence is a risk factor for hallucinatory experiences in adulthood.
Background
Among adults with schizophrenia, evidence suggests that premorbid deficits in different cognitive domains follow distinct developmental courses during childhood and adolescence. The aim of this study was to delineate trajectories of adolescent cognitive functions prospectively among different groups of youth at‐risk for schizophrenia, relative to their typically developing (TD) peers.
Method
Using linear mixed models adjusted for sex, ethnicity, parental occupation and practice effects, cognitive development between ages 9 and 16 years was compared for youth characterised by a triad of well‐replicated developmental antecedents of schizophrenia (ASz; N = 32) and youth with a least one affected relative with schizophrenia or schizoaffective disorder (FHx; N = 29), relative to TD youth (N = 45). Participants completed measures of IQ, scholastic achievement, memory and executive function at three time‐points, separated by approximately 24‐month intervals.
Results
Compared to TD youth, both ASz and FHx youth displayed stable developmental deficits in verbal working memory and inhibition/switching executive functions. ASz youth additionally presented with stable deficits in measures of vocabulary (IQ), word reading, numerical operations, and category fluency executive function, and a slower rate of growth (developmental lag) on spelling from 9 to 16 years than TD peers. Conversely, faster rates of growth relative to TD peers (developmental delay) were observed on visual and verbal memory, and on category fluency executive function (ASz youth only) and on matrix reasoning (IQ) and word reading (FHx youth only).
Conclusions
These differential patterns of deviation from normative adolescent cognitive development among at‐risk youth imply potential for cognitive rehabilitation targeting of specific cognitive deficits at different developmental phases.
Similar to adults with schizophrenia, youth at high risk for developing schizophrenia present difficulties in recognizing emotions in faces. These difficulties might index vulnerability for schizophrenia and play a role in the development of the illness. Facial emotion recognition (FER) impairments have been implicated in declining social functioning during the prodromal phase of illness and are thus a potential target for early intervention efforts. This study examined 9- to 14-year-old children: 34 children who presented a triad of well-replicated antecedents of schizophrenia (ASz), including motor and/or speech delays, clinically relevant internalizing and/or externalizing problems, and psychotic-like experiences (PLEs), and 34 typically developing (TD) children who presented none of these antecedents. An established FER task (ER40) was used to assess correct recognition of happy, sad, angry, fearful, and neutral expressions, and facial emotion misperception responses were made for each emotion type. Relative to TD children, ASz children presented an overall impairment in FER. Further, ASz children misattributed neutral expressions to face displaying other emotions and also more often mislabeled a neutral expression as sad compared with healthy peers. The inability to accurately discriminate subtle differences in facial emotion and the misinterpretation of neutral expressions as sad may contribute to the initiation and/or persistence of PLEs. Interventions that are effective in teaching adults to recognize emotions in faces could potentially benefit children presenting with antecedents of schizophrenia.
Distributed abnormalities of gray matter (GM) and white matter (WM) volume characterize individuals experiencing their first episode of schizophrenia. Regions of abnormality are present already, albeit less extensively, during the prodromal phase of illness. This study aimed to determine whether putatively at-risk children, aged 9-12 years, who present multiple antecedents of schizophrenia (ASz), display GM and WM volume abnormalities relative to typically developing (TD) children presenting no antecedents. Structural magnetic resonance images were acquired for 20 ASz children and 20 TD children matched on age, sex, and IQ. Whole-brain differences in GM and WM volume were determined using voxel-based morphometry. Relative to the TD group, ASz children showed significantly decreased GM volume in the right middle temporal gyrus (MTG) and increased GM volume in the left superior-middle temporal gyri (P < 0.05, cluster correction). WM volume was significantly increased in ASz children relative to TD children in a cluster encompassing the left inferior parietal lobe, occipital lobe, and superior temporal gyrus. Post-hoc analyses indicated that these abnormalities were not limited to ASz children who self-reported auditory hallucinations on questionnaire. Our findings suggest that children aged 9-12 years who present multiple ASz are characterized by abnormalities of GM and WM volume in the temporal lobes, comprising a subset of the regions affected in first-episode schizophrenia and in the prodromal phase of illness. These preliminary findings indicate that structural brain abnormalities associated with schizophrenia may be detected in putatively at-risk, preprodromal children. Prospective studies following the brain development of at-risk children are needed.
(
This reprinted article originally appeared in the Journal of Experimental Psychology,
1935, Vol 18, 643–662. The following abstract of the original article appeared in PA, Vol 10:1863.) In this study pairs of conflicting stimuli, both being inherent aspects of the same symbols, were presented simultaneously (a name of one color printed in the ink of another color—a word stimulus and a color stimulus). The difference in time for reading the words printed in colors and the same words printed in black is the measure of the interference of color stimuli on reading words. The difference in the time for naming the colors in which the words are printed and the same colors printed in squares is the measure of the interference of conflicting word stimuli on naming colors. The interference of conflicting color stimuli on the time for reading 100 words (each word naming a color unlike the ink-color of its print) caused an increase of 2.3 sec or 5.6% over the normal time for reading the same words printed in black. This increase is not reliable, but the interference of conflicting word stimuli on the time for naming 100 colors (each color being the print of a word which names another color) caused an increase of 47.0 sec or 74.3% of the normal time for naming colors printed in squares.… (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Introduction:
A wide variety of neurocognitive deficits have been reported for help-seeking individuals who are at clinical or ultra high risk for psychosis based on fulfilling set criteria for prodromal syndromes/at risk mental states. We wished to extend this research by conducting the first population-based assessment of prodromal syndromes and associated neurocognition.
Methods:
A sample of 212 school-based adolescents were assessed for prodromal syndromes using the criteria of prodromal syndromes from the Structured Interview for Prodromal Syndromes. The MATRICS consensus neurocognitive battery was used to assess cognitive functioning in this sample.
Results:
A total of 8% of the population sample of adolescents met criteria for a prodromal syndrome. These adolescents performed significantly more poorly than controls on two tests of processing speed-Trail-Making Test Part A, F=4.54, p < .01, and the Brief Assessment of Cognition in Schizophrenia Symbol Coding task, F=8.26, p < .0001-and on a test of nonverbal working memory-the Wechsler Memory Scale Spatial Span task, F=3.29, p < .05.
Conclusions:
Adolescents in the community who fulfil criteria for prodromal syndromes demonstrate deficits on a number of neurocognitive tasks. Deficits are particularly pronounced in symbol coding performance, supporting processing speed as a central deficit associated with psychosis risk.
Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15-16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms.
This study evaluated the impact of two interventions—a training program and stimulant medication—on working memory (WM) function in children with attention deficit hyperactivity disorder (ADHD). Twenty-five children aged between 8 and 11 years participated in training that taxed WM skills to the limit for a minimum of 20 days, and completed other assessments of WM and IQ before and after training, and with and without prescribed drug treatment. While medication significantly improved visuo-spatial memory performance, training led to substantial gains in all components of WM across untrained tasks. Training gains associated with the central executive persisted over a 6-month period. IQ scores were unaffected by either intervention. These findings indicate that the WM impairments in children with ADHD can be differentially ameliorated by training and by stimulant medication. Copyright © 2009 John Wiley & Sons, Ltd.
A substantial proportion of people at clinical high risk (HR) of psychosis will develop a psychotic disorder over time. Cognitive deficits may predate the onset of psychosis and may be useful as markers of increased vulnerability to illness.
To quantitatively examine the cognitive functioning in subjects at HR in the literature to date.
Electronic databases were searched until January 2011. All studies reporting cognitive performance in HR subjects were retrieved.
Nineteen studies met the inclusion criteria, comprising a total of 1188 HR subjects and 1029 controls.
Neurocognitive functioning and social cognition as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors.
Subjects at HR were impaired relative to controls on tests of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Processing speed domain was also affected, although the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The studies included reported relatively homogeneous findings. There was no publication bias and a sensitivity analysis confirmed the robustness of the core results.
The HR state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition. Subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.
It has been suggested that neurocognitive impairment is a core deficit in schizophrenia. However, it appears that some patients with schizophrenia have intelligence quotients (IQs) in the superior range. In this study, we sought out schizophrenia patients with an estimated premorbid Intelligence Quotient (IQ) of at least 115 and studied their neuropsychological profile.
Thirty-four patients meeting diagnostic criteria for schizophrenia or schizoaffective disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV), with mean estimated premorbid IQ of 120, were recruited and divided into two subgroups, according to whether or not their IQ had declined by at least 10 points from their premorbid estimate. Their performance on an extensive neuropsychological battery was compared with that of 19 IQ-matched healthy controls and a group of 16 "typical" schizophrenia patients with estimated premorbid IQ <110, using one way ANOVAs and profile analysis using MANOVAs.
Schizophrenia patients whose estimated premorbid and current IQ both lay in the superior range were statistically indistinguishable from IQ-matched healthy controls on all neurocognitive tests. However, their profile of relative performance in subtests was similar to that of typical schizophrenia patients. Patients with superior premorbid IQ and evidence of intellectual deterioration had intermediate scores.
Our results confirm the existence of patients meeting DSM-IV diagnostic criteria for schizophrenia who have markedly superior premorbid intellectual level and appear to be free of gross neuropsychological deficits. We discuss the implications of these findings for the primacy of cognitive deficits in schizophrenia.
Psychotic-like experiences (PLEs) in the general population are common, particularly in childhood, and may constitute part of a spectrum of normative development. Nevertheless, these experiences confer increased risk for later psychotic disorder, and are associated with poorer health and quality of life.
This study used factor analytic methods to determine the latent structure underlying PLEs, problem behaviours and personal competencies in the general child population, and used item response theory (IRT) to assess the psychometric properties of nine PLE items to determine which items best represented a latent psychotic-like construct (PSY). A total of 7966 children aged 9-11 years, constituting 95% of eligible children, completed self-report questionnaires.
Almost two-thirds of the children endorsed at least one PLE item. Structural analyses identified a unidimensional construct representing psychotic-like severity in the population, the full range of which was well sampled by the nine items. This construct was discriminable from (though correlated with) latent dimensions representing internalizing and externalizing problems. Items assessing visual and auditory hallucination-like experiences provided the most information about PSY; delusion-like experiences identified children at more severe levels of the construct.
Assessing PLEs during middle childhood is feasible and supplements information concerning internalizing and externalizing problems presented by children. The hallucination-like experiences constitute appropriate items to screen the population to identify children who may require further clinical assessment or monitoring. Longitudinal follow-up of the children is required to determine sensitivity and specificity of the PLE items for later psychotic illness.
Previous reviews have reported cognitive and motor deficits in childhood and adolescence among individuals who later develop schizophrenia. However, these reviews focused exclusively on studies of individuals with affected relatives or on population/birth cohorts, incorporated studies with estimated measures of pre-morbid intelligence, or included investigations that examined symptomatic at-risk participants or participants 18 years or older. Thus, it remains unclear whether cognitive and motor deficits constitute robust antecedents of schizophrenia. Meta-analyses were conducted on published studies that examined cognitive or motor function in youth aged 16 years or younger who later developed schizophrenia or a schizophrenia spectrum disorder (SSD) and those who did not.
Twenty-three studies fulfilled the following inclusion criteria: (1) written in English; (2) prospective investigations of birth or genetic high-risk cohorts, or follow-back investigations of population samples; (3) objective measures of cognitive or motor performance at age 16 or younger; (4) results provided for individuals who did and who did not develop schizophrenia/SSD later in life; and (5) sufficient data to calculate effect sizes. Four domains of function were examined: IQ; Motor Function; General Academic Achievement; and Mathematics Achievement.
Meta-analyses showed that, by age 16, individuals who subsequently developed schizophrenia/SSD displayed significant deficits in IQ (d=0.51) and motor function (d=0.56), but not in general academic achievement (d=0.25) or mathematics achievement (d=0.21). Subsidiary analysis indicated that the IQ deficit was present by age 13.
These results demonstrate that deficits in IQ and motor performance precede the prodrome and the onset of illness.
Both involuntary dyskinetic movements and psychotic-like experiences (PLEs) are reported to be antecedents of schizophrenia that may reflect dysfunctional dopaminergic activity in the striatum. The present study compared dyskinetic movement abnormalities displayed by children with multiple antecedents of schizophrenia (ASz), including speech and/or motor developmental lags or problems, internalising/externalising problems in the clinical range, and PLEs, with those displayed by children with no antecedents (noASz).
The sample included 21 ASz and 31 noASz children, aged 9-12 years old. None had taken psychotropic medication or had relatives with psychosis. The antecedents of schizophrenia were assessed using questionnaires completed by children and caregivers. A trained rater, blind to group status, coded dyskinetic movement abnormalities using a validated tool from videotapes of interviews with the children.
ASz children reported, on average, 'certain experience' of 2.5 PLEs, while noASz children, by definition, reported none. The ASz children, as compared with noASz children, displayed significantly more dyskinetic movement abnormalities in total, and in the facial and the upper-body regions, after controlling for sex and age. Receiver operator characteristics analyses yielded high area under the curve values for the total score (0.94), facial score (0.91) and upper-body score (0.86), indicating that these scores distinguished between the ASz and noASz children with great accuracy.
Brief questionnaires identified children with multiple antecedents of schizophrenia who displayed significantly more involuntary dyskinetic movement abnormalities than children without antecedents. The presence of PLEs and dyskinesias could reflect early disruption of striatal dopamine circuits.
Offspring of patients with schizophrenia exhibit poorer school performance compared with offspring of non-schizophrenic parents. We aimed to elucidate the mechanisms behind this association.
We linked longitudinal national population registers in Sweden and compared school performance among offspring of schizophrenic parents with offspring of non-schizophrenic parents (1 439 215 individuals with final grades from compulsory school 1988-2006). To investigate the mechanisms, we studied offspring of schizophrenic patients and controls within the same extended families. We investigated genetic effects by stratifying analyses of parent-child associations according to genetic relatedness (half-cousins, full cousins and half-siblings). Environmental effects were investigated by comparing school performance of offspring of schizophrenic fathers and of schizophrenic mothers, respectively, and by stratifying the analyses according to environmental relatedness while controlling genetic relatedness (paternal and maternal half-cousins, paternal and maternal half-siblings).
Offspring of parents with schizophrenia had poorer overall school performance than unrelated offspring of non-schizophrenic parents (-0.31 s.d.). Variability in genetic relatedness greatly moderated the strength of the within-family association (β=-0.23 within exposure-discordant half-cousins, β=-0.13 within exposure-discordant full cousins, β=0.04 within exposure-discordant half-siblings), while no evidence was found that the environment affected offspring school performance.
Genetic factors account for poorer school performance in children of parents with schizophrenia. This supports that cognitive deficits found in individuals with schizophrenia and their relatives might be genetically inherited. Early detection of prodromal signs and impaired functioning of offspring of patients with schizophrenia could lead to earlier and better tailored interventions.
In a baseline study among 7- and 8-year-old children with auditory vocal hallucinations, only limited functional impact was observed.
To assess 5-year course and predictors of auditory vocal hallucinations, as well as 5-year incidence and its risk factors.
A sample of 337 children, 12 and 13 years of age, were reassessed on auditory vocal hallucinations and associated symptoms after a mean follow-up period of 5.1 years.
The 5-year persistence and incidence rates were 24% and 9% respectively, with more new cases arising in urban areas.Both persistent and incident auditory vocal hallucinations were associated with problem behaviour in the clinical range of psychopathology as measured with the Child Behavior Checklist, particularly at follow-up, as well as with other psychotic symptoms, particularly at baseline. Persistence was predicted by baseline auditory vocal hallucinations severity,particularly in terms of external attribution of voices and hearing multiple voices, and was associated with worse primary school test scores and lower secondary school level.
First onset of auditory vocal hallucinations in middle childhood is not uncommon and is associated with psychopathological and behavioural comorbidity. Similarly,persistence of auditory vocal hallucinations in childhood is not uncommon and is associated with psychopathological,behavioural and cognitive alterations.
This study is one of very few that has investigated the neuropsychological functioning of both familial and clinical high risk subjects for psychosis. Participants (N = 164) were members of the Northern Finland 1986 Birth Cohort in the following four groups: familial risk for psychosis (n = 62), clinical risk for psychosis (n = 20), psychosis (n = 13), and control subjects (n = 69). The neurocognitive performance of these groups was compared across 19 cognitive variables. The two risk groups did not differ significantly from controls, but differed from the psychosis group in fine motor function. Neuropsychological impairments were not evident in a non-help-seeking high-risk sample.
Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions.
To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis.
Longitudinal study with 2(1/2) years of follow-up.
Eight centers participating in the North American Prodrome Longitudinal Study.
Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations.
A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status.
Global ("composite") neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion.
These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.
Neurocognitive deficits in schizophrenia (SZ) are thought to be stable trait markers that predate the illness and manifest in relatives of patients. Adolescence is the age of maximum vulnerability to the onset of SZ and may be an opportune "window" to observe neurocognitive impairments close to but prior to the onset of psychosis. We reviewed the extant studies assessing neurocognitive deficits in young relatives at high risk (HR) for SZ and their relation to brain structural alterations. We also provide some additional data pertaining to the relation of these deficits to psychopathology and brain structural alterations from the Pittsburgh Risk Evaluation Program (PREP). Cognitive deficits are noted in the HR population, which are more severe in first-degree relatives compared to second-degree relatives and primarily involve psychomotor speed, memory, attention, reasoning, and social-cognition. Reduced general intelligence is also noted, although its relationship to these specific domains is underexplored. Premorbid cognitive deficits may be related to brain structural and functional abnormalities, underlining the neurobiological basis of this illness. Cognitive impairments might predict later emergence of psychopathology in at-risk subjects and may be targets of early remediation and preventive strategies. Although evidence for neurocognitive deficits in young relatives abounds, further studies on their structural underpinnings and on their candidate status as endophenotypes are needed.
We reviewed potential neuropsychological risk indicators for schizophrenia by addressing two broad questions about neuropsychological performance in biological relatives of schizophrenia patients: (1) Is there evidence of deficits, and, if so, (2) are those deficits similar to deficits found in schizophrenia patients themselves? There has not yet been adequate validation of most neuropsychological risk indicators, but promising leads have emerged from studies of relatives of persons with schizophrenia. The strongest evidence of impairment in relatives was in sustained attention, perceptual-motor speed, and concept formation and abstraction; to a slightly lesser extent, mental control/encoding (primarily with distraction) was implicated as well. Impairments in verbal memory and verbal fluency were also found, although these have been less well studied. The pattern of deficits paralleled that found in schizophrenia patients, thus suggesting dysfunction in prefrontal, temporal-limbic, and attentional systems. Findings were similar for children and adult relatives of schizophrenia patients. It is suggested that future studies (1) emphasize comprehensive test batteries, (2) develop composite neuropsychological measures, (3) use profile and deviant-responder analyses, (4) include psychiatric comparison groups, and (5) integrate neuropsychological assessments with brain imaging techniques.
Working memory plays a crucial role in supporting learning, with poor progress in reading and mathematics characterizing children with low memory skills. This study investigated whether these problems can be overcome by a training program designed to boost working memory. Children with low working memory skills were assessed on measures of working memory, IQ and academic attainment before and after training on either adaptive or non-adaptive versions of the program. Adaptive training that taxed working memory to its limits was associated with substantial and sustained gains in working memory, with age-appropriate levels achieved by the majority of children. Mathematical ability also improved significantly 6 months following adaptive training. These findings indicate that common impairments in working memory and associated learning difficulties may be overcome with this behavioral treatment.
Compromised neurocognition is a core feature of schizophrenia. Following Heinrichs and Zakzanis's (1998) seminal meta-analysis of middle-aged and predominantly chronic schizophrenia samples, the aim of this study is to provide a meta-analysis of neurocognitive findings from 47 studies of first-episode (FE) schizophrenia published through October 2007. The meta-analysis uses 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age- and gender-matched control participants. FE samples demonstrated medium-to-large impairments across 10 neurocognitive domains (mean effect sizes from -0.64 to -1.20). Findings indicate that impairments are reliably and broadly present by the FE, approach or match the degree of deficit shown in well-established illness, and are maximal in immediate verbal memory and processing speed. Larger IQ impairments in the FE compared to the premorbid period, but comparable to later phases of illness suggests deterioration between premorbid and FE phases followed by deficit stability at the group level. Considerable heterogeneity of effect sizes across studies, however, underscores variability in manifestations of the illness and a need for improved reporting of sample characteristics to support moderator variable analyses.
Working memory disturbances are a frequently replicated finding in schizophrenia and less consistent also in schizoaffective disorder. Working memory dysfunctions have been shown to be heritable and have been proposed to represent a promising endophenotype of schizophrenic psychoses.
In the present study, we investigated the effects of familial loading on performance rates in circuit-specific verbal and visuospatial working memory tasks in matched samples of schizophrenic patients (from multiply affected or uniaffected families), schizoaffective patients (from multiply affected or uniaffected families), and healthy subjects.
We found a significant interaction effect between familial loading and diagnosis in terms of a diagnosis-specific detrimental effect of familial loading on the performance of schizophrenic (but not schizoaffective) patients in the articulatory rehearsal task.
This finding of a circuit-specific verbal working memory deficit in schizophrenic patients with additional familial loading is consistent with prior studies, which provided evidence for the existence of specific subgroups of schizophrenic patients with selective working memory impairments and for diagnosis-specific dysfunctions of the articulatory rehearsal mechanism in schizophrenic, but not in schizoaffective patients. Together, these findings suggest that the genetic risk for (a subtype of) schizophrenia may be associated with dysfunctions of the brain system, which underlies the articulatory rehearsal mechanism, the probably phylogenetically youngest part of human working memory.
Memory impairment is being recognized increasingly as an important feature of the neuropsychology of schizophrenia. Dysfunction of working memory, a system for the short-term storage and manipulation of information, may relate to a number of core symptoms of schizophrenia. Many studies have examined working memory function in schizophrenia but a clear understanding of the nature and extent of any deficit has been elusive.
A systematic review and meta-analysis of studies comparing working memory function in subjects with schizophrenia and healthy controls was performed. Following a comprehensive literature search, meta-analyses were conducted on 36 measures of phonological, visuospatial and central executive working memory functioning, encompassing 441 separate results from 187 different studies.
Statistically significant effect sizes were found for all working memory measures, indicating deficits in schizophrenia groups. Some of these were robust findings in the absence of evidence of significant heterogeneity or publication bias. Meta-regression analyses showed that the working memory deficit was not simply explained by discrepancies in current IQ between schizophrenia and control groups.
Large deficits in working memory were demonstrated in schizophrenia groups across all three working memory domains. There were, however, no clear differences across subdomains or between particular working memory tasks. There was substantial heterogeneity across results that could only be partly explained.
Introduction:
Neurocognitive dysfunction is a central feature of schizophrenia and is observed during all phases of the illness. Because schizophrenia is known to run in families, studying neurocognitive function in first-degree, nonpsychotic relatives has been a widely utilised strategy for almost 50 years for understanding presumed "genetic risk". Studying nonpsychotic relatives ("familial high-risk", or FHR) allows for identification of cognitive vulnerability markers independent of confounds associated with psychosis.
Methods:
Prior meta-analyses have elucidated the level and pattern of cognitive deficits in the premorbid, prodromal, and postonset periods of psychosis, and in relatives regardless of age. However, no prior quantitative analyses have specifically focused on studies of young first-degree relatives of individuals with schizophrenia who have not passed through the peak age illness risk (<age 30). The English language literature of neuropsychological studies of first-degree relatives for schizophrenia was identified up to 15 May 2011.
Results:
From 33 studies, 28 studies met our criteria for quantitative review, utilising >70 individual tests and 250 variables.
Conclusions:
In general, young FHR individuals demonstrated deficits with a moderate level of severity compared with healthy controls. The largest average effect sizes (ESs), based on tests given in at least three independent studies, were on estimates of Full Scale IQ (d= -0.777), followed by Vocabulary (d= -0.749) and single word reading tests (d= -0.698) (often used as estimates of IQ). Measures of declarative memory, sustained attention, working memory and others had more modest ESs. Deficits were milder than in established schizophrenia, but often as severe as in clinical high-risk or putatively prodromal participants and in older relatives examined in prior meta-analyses. Additionally, while assessed from a more limited literature, youth at FHR for schizophrenia tended to show worse neurocognitive functioning than those at FHR for affective psychosis. This suggests that genetic risk for schizophrenia as reflected in a positive FHR carries an especially heavy impact on cognitive ability.
Social withdrawal is a robust childhood risk factor for later schizophrenia. The aims of this paper were to assess the evidence for childhood social withdrawal among adults with schizophrenia and, comparatively, in children aged 9-14 years who are putatively at-risk of developing schizophrenia. We conducted a meta-analysis, including cohort and case-control studies reporting social withdrawal measured by the Child Behavior Checklist (CBCL) in adults with schizophrenia vs. controls. Further, an experimental study compared CBCL withdrawal scores from typically-developing children with scores from two groups of putatively at-risk children: (i) children displaying a triad of replicated antecedents for schizophrenia, and (ii) children with at least one first- or second-degree relative with schizophrenia or schizoaffective disorder. Six studies met inclusion criteria for the meta-analysis (N = 3828), which demonstrated a large effect of increased childhood social withdrawal in adults with schizophrenia (standardized mean difference [SMD] score = 1.035, 95% CI = 0.304-1.766, p = 0.006), with no indication of publication bias, but considerable heterogeneity (I(2) = 91%). Results from the experimental study also indicated a large effect of increased social withdrawal in children displaying the antecedent triad (SMD = 0.743, p = 0.001), and a weaker effect in children with a family history of schizophrenia (SMD = 0.442, p = 0.051). Childhood social withdrawal may constitute a vulnerability marker for schizophrenia in the presence of other antecedents and/or genetic risk factors for schizophrenia.
Although it is well established that cognitive impairment is a common feature of schizophrenia, only recently has cognitive functioning been prospectively studied in individuals at clinical high risk (CHR) for developing psychosis. To date, both cross-sectional and longitudinal studies have been conducted in the CHR population and in the context of later conversion to psychosis. A comprehensive review of the literature suggests that CHR individuals have general and specific baseline cognitive deficits compared to healthy controls. As a group, their cognitive course, tends to remain stable over time and in this way does not differ from healthy controls. For those who go on to develop a full-blown psychotic illness compared to those who do not convert, there appeared to be minimal differences at baseline with respect to cognition, although over time the converters may show deterioration in certain cognitive abilities compared to the non-converters. However, for many cognitive domains results are mixed, and may result from methodological limitations.
Memory is one of the central ingredients in determining who we are and become. Without it, we would struggle to make sense of the present and would have no past or future. And yet, while so critical, memory is an extremely vulnerable cognitive system, and therefore its evaluation is especially important following acute or progressive insults to the brain, such as those resulting from motor vehicle accidents, blast injuries, multiple sclerosis, brain tumors, infections, and strokes. Memory also normally exhibits measurable differences within and across the age range, with the greatest variability seen in younger children and older adults. The Wide Range Assessment of Memory and Learning, second edition (WRAML2), is an individually administered test battery designed to assess memory ability across the age range (5 to 90 years). Consequently, the battery can prove useful in assessment settings often found in hospitals, schools, rehabilitation centers, and neuropsychologists' offices.
Keywords:
memory;
assessment;
WRAML2
BACKGROUND: Persons developing schizophrenia (SCZ) manifest various pre-morbid neuropsychological deficits, studied most often by measures of IQ. Far less is known about pre-morbid neuropsychological functioning in individuals who later develop bipolar psychoses (BP). We evaluated the specificity and impact of family history (FH) of psychosis on pre-morbid neuropsychological functioning.Method
We conducted a nested case-control study investigating the associations of neuropsychological data collected systematically at age 7 years for 99 adults with psychotic diagnoses (including 45 SCZ and 35 BP) and 101 controls, drawn from the New England cohort of the Collaborative Perinatal Project (CPP). A mixed-model approach evaluated full-scale IQ, four neuropsychological factors derived from principal components analysis (PCA), and the profile of 10 intelligence and achievement tests, controlling for maternal education, race and intra-familial correlation. We used a deviant responder approach (<10th percentile) to calculate rates of impairment. RESULTS: There was a significant linear trend, with the SCZ group performing worst. The profile of childhood deficits for persons with SCZ did not differ significantly from BP. Neuropsychological impairment was identified in 42.2% of SCZ, 22.9% of BP and 7% of controls. The presence of psychosis in first-degree relatives (FH+) significantly increased the severity of childhood impairment for SCZ but not for BP. CONCLUSIONS: Pre-morbid neuropsychological deficits are found in a substantial proportion of children who later develop SCZ, especially in the SCZ FH+ subgroup, but less so in BP, suggesting especially impaired neurodevelopment underlying cognition in pre-SCZ children. Future work should assess genetic and environmental factors that explain this FH effect.
A simple procedure for multiple tests of significance based on individual p-values is derived. This simple procedure is sharper than Holm's (1979) sequentially rejective procedure. Both procedures contrast the ordered p- values with the same set of critical values. Holm's procedure rejects an hypothesis only if its p-value and each of the smaller p-values are less than their corresponding critical-values. The new procedure rejects all hypotheses with smaller or equal p-values to that of any one found less than its critical value.
Background:
We previously reported that the nonpsychotic relatives of schizophrenic patients exhibited disturbances in executive functioning, verbal and visual memory, auditory attention, mental control, and verbal ability. In a 4-year follow-up, we showed that the discriminating power of most of these tests was stable over time.
Methods:
In this report we compare 41 nonpsychotic persons who have only one schizophrenic first-degree relative (simplex families) with 36 nonpsychotic persons who have two schizophrenic first-degree relatives (multiplex families). Our goal was to test a hypothesis that neuropsychologic deficits would be worse among the latter.
Results:
Relatives from multiplex families differed significantly from controls on estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. In contrast, in comparisons with controls, relatives from simplex families only differed on immediate logical memories. Comparisons between relatives from multiplex and simplex families showed that the former group had significantly worse scores for estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. We also found group x gender interactions: the worse performance of the multiplex group was seen for females.
Conclusions:
These results are consistent with the idea that neuropsychologic deficits in relatives of schizophrenic patients reflect their degree of genetic predisposition to schizophrenia. They also suggest hypotheses about gender differences in the familial transmission of the disorder.
Identifying the relative strength of evidence associated with non-genetic risk factors and putative antecedents of schizophrenia will guide research and may inform the design of early detection and intervention strategies.
To present and quality assess current evidence for non-genetic risk factors and putative antecedents derived from well-conducted systematic reviews that report pooled data.
Medline, Embase, CINAHL, Current Contents, and PsycINFO databases were searched systematically, and supplemented by hand searching. Review reporting quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, review methodology was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist, and evidence quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Twenty-four reviews met inclusion criteria. The risk factors with the highest quality evidence, reporting medium effect sizes, were advanced paternal age, obstetric complications, and cannabis use. The strongest evidence among the putative antecedents was identified for motor dysfunction and low IQ.
More research is required that applies sound methodological practices, taking into consideration specificity for schizophrenia and possible confounding factors, to robustly identify the non-genetic risk factors and putative antecedents of schizophrenia.
Characterizing neuropsychological (NP) functioning of individuals at clinical high risk (CHR) for psychosis may be useful for prediction of psychosis and understanding functional outcome. The degree to which NP impairments are associated with general cognitive ability and/or later emergence of full psychosis in CHR samples requires study with well-matched controls.
We assessed NP functioning across eight cognitive domains in a sample of 73 CHR youth, 13 of whom developed psychotic-level symptoms after baseline assessment, and 34 healthy comparison (HC) subjects. Groups were matched on age, sex, ethnicity, handedness, subject and parent grade attainment, and median family income, and were comparable on WRAT-3 Reading, an estimate of premorbid IQ. Profile analysis was used to examine group differences and the role of IQ in profile shape.
The CHR sample demonstrated a significant difference in overall magnitude of NP impairment but only a small and nearly significant difference in profile shape, primarily due to a large impairment in olfactory identification. Individuals who subsequently developed psychotic-level symptoms demonstrated large impairments in verbal IQ, verbal memory and olfactory identification comparable in magnitude to first episode samples.
CHR status may be associated with moderate generalized cognitive impairments marked by some degree of selective impairment in olfaction and verbal memory. Impairments were greatest in those who later developed psychotic symptoms. Future study of olfaction in CHR samples may enhance early detection and specification of neurodevelopmental mechanisms of risk.
We previously developed a novel method of identifying children aged 9-12 years who may be at elevated risk of developing schizophrenia and the spectrum disorders because they present a triad of putative antecedents of schizophrenia (ASz). The present study aimed to determine whether ASz children also present neurocognitive deficits that are commonly observed in patients with schizophrenia.
Twenty-eight ASz children and 28 typically-developing (TD) children without the antecedents of schizophrenia completed a battery of neurocognitive tests assessing seven domains of function: General intelligence, scholastic achievement, verbal memory, visual memory, working memory, executive function (EF)-verbal fluency, and EF-inhibition.
Relative to TD children, the ASz group showed poorer performance on all neurocognitive tests (mean Cohen's d effect size=0.52). In linear regression analyses, group status (ASz vs. TD) significantly predicted scores on the general intelligence, verbal memory, working memory, and EF-inhibition domains (p<0.05). The severity of problems on each of the individual antecedents comprising the antecedent triad did not relate strongly to performance on the neurocognitive domains.
Children aged 9-12 years who present multiple antecedents of schizophrenia display poorer neurocognition than healthy peers on several domains showing pronounced deficits in schizophrenia, first-episode psychosis, and youth with prodromal symptoms. Longitudinal follow-up is necessary to determine the extent to which poorer neurocognitive performance is specific to those who develop schizophrenia.
Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders?
Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects.
Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression.
These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7-13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older.
For many multifactorial diseases, aetiology is poorly understood. A major research aim is the identification of disease predictors (environmental, biological, and genetic markers). In order to achieve this, a two-stage approach is proposed. The initial or synthesis stage combines observed pedigree data with previous genetic epidemiological research findings, to produce estimates of pedigree members' disease risk and predictions of their disease liability. A further analysis stage uses the latter as inputs to look for associations with potential disease markers. The incorporation of previous research findings into an analysis should lead to power gains. It also allows separate predictions for environmental and genetic liabilities to be generated. This should increase power for detecting disease predictors that are environmental or genetic in nature. Finally, the approach brings pragmatic benefits in terms of data reduction and synthesis, improving comprehensibility, and facilitating the use of existing statistical genetics tools. In this article we present a statistical model and Gibbs sampling approach to generate liability predictions for multifactorial disease for the synthesis stage. We have implemented the approach in a software program. We apply this program to a specimen disease pedigree, and discuss the results produced, comparing its results with those generated under a more naïve model. We also detail simulation studies that validate the software's operation.
Intervention aimed at preventing schizophrenia may be most effective if targeted at specific, but modifiable, functional impairments that present during childhood. We have developed a novel method of screening community samples aged 9 to 12 years to identify children who present a triad of putative antecedents of schizophrenia (ASz), defined as 1) speech and/or motor development lags/problems; 2) internalizing, externalizing, and/or peer-relationship problems in the clinical range; and 3) psychotic-like experiences. This study examined whether ASz children display brain function abnormalities during error processing that are similar to those exhibited by adults with schizophrenia.
Twenty-two ASz children and 26 typically developing (TD) children with no antecedents of schizophrenia completed an error-inducing Go/NoGo task during event-related potential recording. Group differences were examined in the amplitude and latency of four event-related potential components: the initial error-related negativity (ERN) and later error-positivity (Pe) elicited on false-alarm responses to NoGo trials, and the corresponding initial correct response negativity (CRN) and later correct response positivity (Pc) elicited during processing of correct responses to Go trials.
Relative to TD children, ASz children were characterized by reduced ERN amplitude but unaffected CRN, Pe, and Pc amplitudes. No group differences were observed in the latency of any component.
Children presenting a triad of putative antecedents of schizophrenia show error-processing dysfunction mimicking that observed in adults with schizophrenia using the same Go/NoGo paradigm. The ASz children displayed specific early error-processing deficits rather than a generalized deficit in self-monitoring.
An association analysis was made of the responses of young adults to a hand-preference questionnaire. Many patterns of preference were distinguished and there were no marked differences between adjacent classes. These findings are believed to demonstrate that hand preference is distributed continuously and not discretely. When it is necessary to classify handedness, the preference continuum can be divided at several levels of discrimination. A second study of hand preference and manual speed showed that it is possible to order the main preference groups for asymmetry of manual skill. Some of the problems of studies of laterality are examined as possible consequences of the treatment of a continuous distribution as if it were discrete.
In our prior work with a young sample (age < 60), we showed that three neuropsychological functions were impaired among relatives of schizophrenic patients: abstraction, verbal memory, and auditory attention. In the present work we show that these results do not generalize to an older sample aged 60 years and greater. Thus, although we and others have put forth measures of neuropsychological function as indicators of the schizophrenia genotype, the present study suggests that conclusions may be limited to non-elderly samples. Further work is needed to address this issue definitively.
High-risk research in schizophrenia incorporates several different strategies for studying individuals who are defined by different criteria as being at risk for future development of schizophrenia. Variables from a wide range of domains have been included in these studies. Several reviews of high-risk research have attempted to cover the field broadly, whereas others have been more sharply focused on research subjects defined by specific criteria or on particular classes of variables. Among the review articles and collections of project reports on high-risk research in the past two decades are: Watt et al. [1984: Children at risk for schizophrenia: a longitudinal perspective]; Nuechterlein and Dawson [1984: Schizophr Bull 10:160-203]; Nuechterlein [1986: J Child Psychol Psychiatr 27:133-144]; Erlenmeyer-Kimling and Cornblatt [1987: J Psychiatr Res 26:405-426]; Goldstein and Tuma [1987: Schizophr Bull 13:369-371]; Asarnow [1988: Schizophr Bull 14:613-631]; Moldin and Erlenmeyer-Kimling [1994: Schizophr Bull 20:25-29]; Mirsky [1995: Schizophr Bull 21:179-182]; Gooding and Iacono [1995: Manual of developmental psychopathology] McNeil [1995: Epidemiol Rev 17:107-112] Olin and Mednick [1996: Schizophr Bull 22:223-240]; Cornblatt and Obuchowski [1997: Intl Rev Psychiatry 9:437-447]. This paper presents an overview of findings from recent (the past decade and a half) prospective studies of children of schizophrenic parents, with a focus on neurobehavioral (neurocognitive, neuromotor, and neurophysiological) variables that may reflect aspects of the genetic liability to schizophrenia and related disorders. The few neuroimaging studies on children of schizophrenic parents are also briefly mentioned. Because of space limitations, the overview is not intended as a comprehensive or detailed review of this area of high-risk research.
Childhood neurobehavioral deficits in offspring of schizophrenic, affectively ill, and psychiatrically normal parents were evaluated as predictors of schizophrenia-related psychoses in adulthood.
The offspring were tested with neurobehavioral measures at 7-12 years of age and assessed in mid-adulthood for axis I diagnoses. The relationships of childhood deficits in attention, verbal memory, and gross motor skills to adulthood schizophrenia-related psychoses were examined in separate path analyses by using logistic regression equations. Sensitivity and specificity were determined for each of the childhood dysfunctions.
For the offspring of schizophrenic parents, childhood deficits in verbal memory, gross motor skills, and attention identified 83%, 75%, and 58%, respectively, of the subjects with schizophrenia-related psychoses; 50% were identified by all three variables combined. False positive rates in subjects who did not develop schizophrenia-related psychoses ranged from 18% for those with deficits in attention during childhood to 28% for those with deficits in memory. The three variables had low deficit rates in the offspring of the other two parental groups and were not associated with other psychiatric disorders in any group.
Schizophrenia-related psychoses in adulthood are distinguished in subjects at risk for schizophrenia by childhood deficits in verbal memory, gross motor skills, and attention. The findings suggest that deficits in these variables are relatively specific to schizophrenia risk and may be indicators of the genetic liability to schizophrenia.
To describe the psychometric properties of the Strengths and Difficulties Questionnaire (SDQ), a brief measure of the prosocial behavior and psychopathology of 3-16-year-olds that can be completed by parents, teachers, or youths.
A nationwide epidemiological sample of 10,438 British 5-15-year-olds obtained SDQs from 96% of parents, 70% of teachers, and 91% of 11-15-year-olds. Blind to the SDQ findings, all subjects were also assigned DSM-IVdiagnoses based on a clinical review of detailed interview measures.
The predicted five-factor structure (emotional, conduct, hyperactivity-inattention, peer, prosocial) was confirmed. Internalizing and externalizing scales were relatively "uncontaminated" by one another. Reliability was generally satisfactory, whether judged by internal consistency (mean Cronbach a: .73), cross-informant correlation (mean: 0.34), or retest stability after 4 to 6 months (mean: 0.62). SDQ scores above the 90th percentile predicted a substantially raised probability of independently diagnosed psychiatric disorders (mean odds ratio: 15.7 for parent scales, 15.2 for teacher scales, 6.2 for youth scales).
The reliability and validity of the SDQ make it a useful brief measure of the adjustment and psychopathology of children and adolescents.
According to cohort studies, individuals who develop schizophrenia in adulthood show developmental abnormalities in childhood. These include delays in attainment of speech and motor milestones, problems in social adjustment, and poorer academic and cognitive performance. Another method of investigating developmental abnormalities associated with schizophrenia is the high-risk (HR) method, which follows up longitudinally the development of children at high risk for schizophrenia. Most HR studies have investigated children who have a parent with schizophrenia. This review summarizes findings concerning childhood and adolescent development from 16 HR studies and compares them with findings from cohort, conscript, and family studies. We specifically addressed two questions: (1) Does the development of HR children differ from that of control children? (2) Which developmental factors, if any, predict the development of schizophrenia-spectrum disorders in adulthood? While the answer to the first question is affirmative, there may be other mechanisms involved in addition to having a parent with schizophrenia. Factors which appear to predict schizophrenia include problems in motor and neurological development, deficits in attention and verbal short-term memory, poor social competence, positive formal thought disorder-like symptoms, higher scores on psychosis-related scales in the MMPI, and severe instability of early rearing environment.