Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Application of the Audio Recorded Cognitive Screen and its relation to functioning in schizophrenia.

OBJECTIVE: This study investigated the ability of the Audio Recorded Cognitive Screen (ARCS) to detect cognitive deficit in individuals with schizophrenia, relative to the Mini Mental State Examination (MMSE) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and explored the associations between the ARCS and functional outcomes. We hypothesised that the ARCS would be able to better discriminate between individuals with schizophrenia and healthy controls than the MMSE, and that ARCS performance would be correlated with measures of social and vocational functioning. METHODS: The participants were 19 community-dwelling individuals with schizophrenia or schizoaffective disorder and 19 healthy controls recruited from the Australian Schizophrenia Research Bank (ASRB). Participants completed the ARCS, MMSE, and self-report measures of social and vocational functioning. Clinical and diagnostic data stored by the ASRB were also utilised. RESULTS: The schizophrenia group performed worse than the control group on the ARCS, with memory, t(36)=2.49, p=0.02, 95% CI [-1.84, -18.79] and fluency, t(36)=2.40, p=0.02, 95% CI [-1.87, -22.24] domains being the main discriminating measures. The RBANS also discriminated between the two groups, and ARCS and RBANS total scores were moderately to strongly correlated. There was no difference between the two groups on the MMSE after controlling for demographic variables. ARCS performance was associated with employment status [χ2(1)=7.16, p=0.007]. CONCLUSION: The ARCS may be sensitive to the cognitive deficits in outpatients with schizophrenia and an indicator of functional outcomes in this population.

Divergent patterns of social cognition performance in autism and 22q11.2 deletion syndrome (22q11DS).

Individuals with developmental disorders frequently report a range of social cognition deficits including difficulties identifying facial displays of emotion. This study examined the specificity of face emotion processing deficits in adolescents with either autism or 22q11DS compared to typically developing (TD) controls. Two tasks (face emotion recognition and weather scene recognition) were used to explore group differences in visual scanpath strategy and concurrent recognition accuracy. For faces, the autism and 22q11DS groups demonstrated lower emotion recognition accuracy and fewer fixations compared to the TD group. Individuals with autism demonstrated fewer fixations to some weather scene stimuli compared to 22q11DS and TD groups, yet achieved a level of recognition accuracy comparable to the TD group. These findings provide evidence for a divergent pattern of social cognition dysfunction in autism and 22q11DS.

Relationship between childhood adversity and clinical and cognitive features in schizophrenia.

Childhood adversity is associated with elevated risk for a wide range of adult psychiatric disorders, and has significant and sustained negative effects on adult behavioural and social functioning. Elevated rates of childhood adversity have been reported for people with a diagnosis of schizophrenia. The aim of the present study was to assess rates of retrospectively reported childhood adversity among adults with schizophrenia and to examine the relationship between childhood adversity and clinical and cognitive features. Data were available for 408 schizophrenia participants and 267 healthy control participants recruited through the Australian Schizophrenia Research Bank (ASRB). History of childhood adversity was obtained using the Childhood Adversity Questionnaire (CAQ). A five-factor solution was identified from the CAQ. Schizophrenia participants reported experiencing more childhood adversities than controls. In both groups, those reporting childhood adversity were more likely to be female and older. Among participants with schizophrenia, positive symptom severity and fewer years of education were associated with childhood adversity. Lower IQ scores and personality traits were associated with reporting a greater number of childhood adversities and with adversity sub-types of abusive, neglectful and dysfunctional parenting. The rate of childhood adversity reported in this sample was high which suggests greater exposure to adverse childhood events among participants with schizophrenia in comparison with healthy controls. We identified unique groups amongst CAQ items that provided a salient framework from which to investigate the connection between childhood adversity and clinical and cognitive features.

Brief neuropsychological profiles in psychosis: a pilot study using the Audio Recorded Cognitive Screen (ARCS).

UNLABELLED: Loughland CM, Allen J, Gianacas L, Schofield PW, Lewin TJ, Hunter M, Carr VJ. Brief neuropsychological profiles in psychosis: a pilot study using the Audio Recorded Cognitive Screen (ARCS). OBJECTIVE: This pilot study examines the utility of a novel, standardised brief neuropsychological assessment tool (the ARCS, Audio Recorded Cognitive Screen) in a different clinical setting to that in which it was initially developed. We hypothesised that the ARCS would be feasible to administer to individuals with a psychotic illness and that it would detect cognitive deficits similar to those identified by an established instrument (the RBANS, Repeatable Battery for the Assessment of Neuropsychological Status). METHODS: Twenty-five people with psychosis (mean age = 43.72, SD = 9.78) and 25 age- and gender-matched controls were recruited from the Newcastle community (NSW, Australia). The ARCS and RBANS were completed about 1 week apart in a counterbalanced order. RESULTS: The ARCS was well received, performed satisfactorily and both the ARCS and RBANS were sensitive to deficits typically associated with psychosis (e.g. memory and attention). After controlling for memory deficits, the largest disparity between the psychosis and control groups was on the ARCS fluency domain [p < 0.001, partial Eta-squared (η p 2) = 0.21]. CONCLUSION: The ARCS uses audio administration (approximately 34 min) to reduce clinician time (to 3-5 min for scoring) and appears to be a useful brief assessment tool for examining the cognitive deficits associated with psychosis. However, the potential clinical utility of the ARCS needs to be investigated further in larger samples drawn from a wider variety of specialist and non-specialist settings.

Emotional face processing in schizophrenia.

PURPOSE OF REVIEW: Recent studies of face processing deficits in people with schizophrenia have begun to shed light on the answers to four important questions: What is the major component of the deficit? Does it have a neurobiological basis? When does it appear in development? Can it be remediated? RECENT FINDINGS: Eye contact is especially important for recognizing fearful expressions. Patients with schizophrenia avoid gazing at important facial feature regions (especially eyes) and are particularly impaired in recognizing fear. Patients were thought to exhibit decreased amygdala activity when viewing fearful faces; however, more recent studies have revealed limbic hyperactivity in patients when viewing nonfearful and fearful faces compared with baseline. Amygdala hyperactivity can also be detected when people with schizophrenia fail to appropriately recognize fear faces. Studies indicate that there are developmental changes in amygdala activation, including limbic hyperactivity to fear faces during adolescence, a critical time for the onset of schizophrenia. New treatment strategies can increase gaze to the eye region, which could improve emotional recognition in patients. SUMMARY: These findings suggest that there may soon be more options for overcoming specific problems in emotional face evaluation in people who have schizophrenia.

Aggression and trauma experiences among carer-relatives of people with psychosis.

BACKGROUND: Exposure to aggression and associated psychological outcomes are poorly characterised among carer-relatives of people with psychosis. METHOD: Carer-relatives (N = 106) completed questionnaires assessing socio-demographics and perceived prevalence of aggression in their caring role in the last 12 months. Carers exposed to moderate-severe levels of aggression were re-approached to assess PTSD and coping strategies. RESULTS: Most respondents (77.4%) reported experiencing moderate-severe levels of aggression. Increased contact with (M = 15.12 vs. M = 6.71 days per month), and significantly higher ratings of affective, antisocial, negative and psychotic symptomology in affected relatives were associated with experiences of moderate-severe aggression. Approximately half of the moderate-severe respondents reported potentially significant levels of PTSD (52%, N = 34), which was associated with greater exposure to verbal aggression and increased usage of coping strategies. CONCLUSIONS: Comparable ratios of physical to non-physical aggression to those reported by professional carers working in acute psychiatric treatment settings were reported. Carer-relatives require greater levels of information and support to assist them in their community caring roles.

RBANS neuropsychological profiles within schizophrenia samples recruited from non-clinical settings.

BACKGROUND: This paper examines the potential impact of recruitment source differences in schizophrenia research by comparing the neuropsychological performance of volunteers from the NISAD Schizophrenia Research Register with recently published schizophrenia normative data for the Repeatable Battery for Neuropsychological Status (RBANS). METHODS: The Register sample comprised 285 volunteers with schizophrenia or schizoaffective disorder. Their RBANS performance was compared with US data from 575 predominantly outpatient-recruited schizophrenia patients. RESULTS: The Register sample displayed impairments in immediate and delayed memory, but near-normal language, attention and visuospatial-constructional performance (mean RBANS total score=88.72, SD=16.35). By contrast, health service-recruited schizophrenia patients displayed impairments on all RBANS scales (mean RBANS total score=70.54, SD=14.80). Within the Register sample, volunteers with low levels of current functioning had immediate and delayed memory performance comparable to the US schizophrenia sample. Gender and school completion status were also associated with different RBANS profiles. CONCLUSIONS: These findings reinforce the notion that a severity/functioning gradient exists across schizophrenia recruitment sources, which has important implications for research design and generalizability. Memory impairments have emerged as a central feature of schizophrenia.

Potential sampling and recruitment source impacts in schizophrenia research.

Most schizophrenia research is undertaken on clinical samples in current contact with mental health services. It is not clear to what extent such samples are representative of the population of people with schizophrenia or whether they differ significantly, for example, from those who are being treated predominantly in primary care settings or who are recruited from non-clinical sources. Data from a volunteer schizophrenia research register and two recent Australian studies are reported, the Low Prevalence (psychotic) Disorders Study and an associated study of schizophrenia in general practice, in which all participants completed the same clinical assessment interview. Participants meeting criteria for schizophrenia or schizoaffective disorder were classified according to their source of recruitment: volunteer research register (n=128), general practice (n=123), community (n=236) or public inpatient (n=178) mental health services. Hierarchical discriminant function analyses revealed significant differences between these recruitment sources with respect to illness-onset factors, relationship and support factors, current functioning and course of illness. A severity/functioning gradient was observed across the four recruitment sources, possibly reflecting a spectrum of neurobiological impairment from good to poor prognosis. The implications of these findings for sampling strategies in schizophrenia research are discussed.

Visual scanpath dysfunction in first-degree relatives of schizophrenia probands: evidence for a vulnerability marker?

Previous research demonstrates that people with schizophrenia have abnormally 'restricted' visual scanpaths to face and facial expression stimuli, which appear to be diagnostically specific to schizophrenia [Schizophr. Res. 55 (2002) 159; Biol. Psychiatry 52 (2002) 338]. This study examined the familial transmission of 'restricted' scanpaths in first-degree relatives of schizophrenia subjects. We recorded visual scanpaths for 65 schizophrenia subjects, 37 biological first-degree relatives and 61 nonrelated 'healthy' control subjects in two experiments: 'face recognition' and 'facial affect recognition'. Concurrent behavioral tasks were face matching and expression matching, each under two multiple-choice conditions (seven or three options). As predicted, first-degree relatives generally showed an attenuated form of the markedly 'restricted' scanpaths of schizophrenia subjects across all face stimuli. The notable exception to this pattern was the relatives' extreme avoidance of facial features (compared to both schizophrenia and healthy control groups). Our results offer the first evidence that some components of visual scanpath dysfunction may represent a trait marker in the familial transmission of schizophrenia, but that first-degree relatives may have additional disturbances in social cognition associated with the perception of facial features.

The five symptom dimensions and depression in schizophrenia.

The aim of this study was to investigate the relationship between the five-factor model of psychopathology and depression in schizophrenia. Symptoms were rated using the Positive and Negative Syndrome Scale (PANSS) and the Montgomery and Asberg Depression Rating Scale (MADRS) in 105 chronic patients with schizophrenia. Principal-component analysis (PCA) produced a five-factor solution for the PANSS (psychomotor poverty, disorganisation, reality distortion, excitement, and depression), and a two-factor solution for the MADRS (psychological and behavioural depression). The PANSS depression factor was highly associated with the MADRS psychological depression factor but not with MADRS behavioural depression. By contrast, the PANSS excitement factor showed a strong positive correlation with the behavioural depression factor but not with psychological depression. These MADRS factors were not associated significantly with the core PANSS factors, including psychomotor poverty. It is suggested that depression exists as an independent domain, differentiated from negative symptoms, in the structure of schizophrenia symptomatology.

Emotion perception in schizophrenia: an eye movement study comparing the effectiveness of risperidone vs. haloperidol.

We used a psychophysiological marker of visual attention (the visual scanpath) to investigate the effects of atypical (risperidone) vs. typical (haloperidol) antipsychotic medication on facial emotion perception in schizophrenia (n=28) and healthy control (n=28) groups. Of the schizophrenia subjects, 15 were prescribed risperidone. Visual scanpaths to 'happy', 'sad' and 'neutral' faces were recorded using video-oculography, and concurrent emotion-recognition accuracy was assessed using multiple-option tasks. Compared to control subjects, both schizophrenia subgroups showed a restriction in visual scanning (reduced total fixation number and decreased scanpath length). Haloperidol-treated schizophrenia subjects exhibited an additional and consistent pattern of reduced attention (fixation) to salient features for neutral and happy. By contrast, risperidone-treated subjects showed a relatively greater attention to salient features for these expressions, in which they did not differ from controls. Recognition accuracy for happy and neutral showed a similar lack of impairment. These findings suggest that risperidone may play a specific role in schizophrenia in the ability to attend to salient features, and to integrate this information into an accurate percept for neutral and positive expressions in particular.

Schizophrenia and affective disorder show different visual scanning behavior for faces: a trait versus state-based distinction?

BACKGROUND: Abnormal visual scanpaths to faces and facial expressions in schizophrenia may underlie schizophrenic subjects' disturbed interpersonal communication. This study is the first to examine the specificity of these impairments to schizophrenia, by including an affective disorder psychiatric control group. METHODS: The visual scanpath performance of 65 schizophrenia, 52 affective disordered, and 61 control subjects were compared in two experiments. In the "face recognition" experiment, subjects viewed four identifiable (non-degraded) neutral faces versus four matched non-identifiable (degraded) control faces. In the "facial affect recognition" experiment, subjects viewed positive (happy), negative (sad), and neutral (control) facial emotion stimuli. Concurrent behavioral tasks were face matching (face recognition) and expression matching (facial affect recognition), each under two multiple-choice conditions (7 or 3 options). RESULTS: Scanpath disturbances were most apparent in schizophrenia subjects, who maintained a comparatively "restricted" scanpath style to all face stimuli. Schizophrenics subjects also showed the greatest recognition difficulties, particularly for neutral and happy faces. Scanpath parameters for affective disorder subjects differed only from the schizophrenia (but not the control) group, except for attention to facial features where they generally avoided facial features in all expressions and showed the greatest attentional problems of all groups for degraded faces. CONCLUSIONS: Our results suggest that a global restriction of visual scanpaths is specific to schizophrenic psychosis and might be a trait marker for this disorder, whereas scanpath abnormalities in affective disorder might instead reflect severe state-based (or discrete) attentional disturbances.

Visual scanpaths to positive and negative facial emotions in an outpatient schizophrenia sample.

We used a psychophysiological marker of visual attention (visual scanpath) to investigate facial emotion processing in schizophrenia (n= 65) and healthy control (n = 61) groups. Visual scanpaths to 'happy', *sad' and 'neutral' faces (two exposures each) were recorded using video-oculography. Emotion recognition accuracy was assessed under both 'difficult' (exposure 1) and 'limited choice' (exposure 2) conditions. Compared to controls, schizophrenia subjects showed 'restricted' scanning and reduced attention to salient facial features (eyes, nose, mouth), that was particularly apparent for happy and neutral faces: accuracy was correspondingly reduced for the 'difficult' condition. The schizophrenia deficit in positive emotion perception may reflect a failure to integrate salient features due to dysfunctions in local processing of detailed, relevant information (fewer fixations, less attention to facial features), and in the networks that synchronise local and global processing of biologically-relevant face stimuli (generally restricted scanning style).