•The presence of subgroups within autism spectrum disorder (ASD) continues to be questioned .•We examined this question in children with ASD without intellectual disability.•Two subgroups with ...dissociated profiles across core ASD dimensions were identified.•The subgroups may differ in their neurobiological mechanisms and intervention needs.•Findings argue against using a purely dimensional classification system for ASD, as per DSM-5.
The heterogeneity in autism spectrum disorder (ASD) remains poorly understood, particularly in individuals without intellectual disability (ID), where phenotypic variability can be most pronounced. The presence of phenotypic subgroups continues to be questioned. This study investigated whether children with ASD without ID are differentiable into clinically meaningful subgroups.
Data from the ‘gold standard’ ASD diagnostic instruments for 61 children (5–14 years) with ASD without ID were subjected to exploratory cluster analysis. Cognition, language, pragmatic communication, and behaviour were used to explore subgroups.
Children with ASD without ID could be differentiated into Moderate and Severe Social Impairment subgroups when core ASD symptoms were more closely examined. The Moderate Social Impairment subgroup showed less severe social interaction and communication impairments but greater lifetime severity of restricted/repetitive behaviours. In contrast, the Severe Social Impairment subgroup, with poorer social interaction and communication skills, had lower lifetime severity of restricted/repetitive behaviours. This subgroup also had greater cognitive and language difficulties, and poorer adaptive functioning. Importantly, however, these neurocognitive and functional differences showed only small to moderate associations with the differentiated ASD clinical profiles.
Evidence of dissociated levels of severity across core ASD dimensions supports the idea that clinically meaningful subgroups within ASD without ID can be identified. The dissociated profiles of ASD features could represent different underlying neurobiological mechanisms for each subgroup. Identifying such subgroups in practice can improve the clinical utility of diagnostic labels in this population. Thus, both categorical and dimensional approaches may be useful in classifying ASD, with neither alone being adequate.
The notion of a "default mode of brain function" has taken on certain relevance in human neuroimaging studies and in relation to a network of lateral parietal and midline cortical regions that show ...prominent activity fluctuations during passive imaging states, such as rest. In this study, we perform three fMRI experiments that demonstrate consistency and specialization in the default mode network. Correlated activity fluctuations of default mode network regions are identified during (i) eyes-closed spontaneous rest, (ii) activation by moral dilemma, and (iii) deactivation by Stroop task performance. Across these imaging states, striking uniformity is shown in the basic anatomy of the default mode network, but with both tasks clearly and differentially modulating this activity compared with spontaneous fluctuations of the network at rest. Against rest, moral dilemma is further shown to evoke regionally specific activity increases of hypothesized functional relevance. Mapping spontaneous and task-related brain activity will help to constrain the meaning of the default mode network. These findings are discussed in relation to recent debate on the topic of default modes of brain function.
Abstract Objective Cognitive dysfunction is a common characteristic of both schizophrenia and bipolar disorder (BP). While these deficits are more severe in schizophrenia, there is a significant ...overlap between conditions. However, it was hypothesized that social cognitive deficits might be more specific to schizophrenia. Methods We conducted a meta-analysis of studies comparing facial emotion recognition and theory of mind (ToM) abilities in schizophrenia and BP. 26 studies comparing 1301 patients with schizophrenia and 1075 with BP were included. Results Schizophrenia patients significantly underperformed compared with BP patients in both facial emotion recognition ( d = 0.39) and ToM ( d = 0.57). Neurocognitive deficits significantly contributed to schizophrenia-BP group differences for ToM. However, between-group differences for social cognition were not statistically more severe than neurocognition. Conclusion Social cognitive impairment is more severe in schizophrenia in comparison to BP. However, between-group differences are modest and are comparable to other neurocognitive differences between schizophrenia and BP. There is significant overlap in social cognitive performance deficits observed in both schizophrenia and BP.
Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical ...thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
Lithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other.
To investigate the differential effect of lithium ...and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania.
Maintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry - ACTRN12607000639426.)
In total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment × visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned and
comparisons further demonstrated the superiority of lithium treatment over quetiapine.
In people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution.
The reproducibility of machine-learning analyses in computational psychiatry is a growing concern. In a multimodal neuropsychiatric dataset of antipsychotic-naïve, first-episode schizophrenia ...patients, we discuss a workflow aimed at reducing bias and overfitting by invoking simulated data in the design process and analysis in two independent machine-learning approaches, one based on a single algorithm and the other incorporating an ensemble of algorithms. We aimed to (1) classify patients from controls to establish the framework, (2) predict short- and long-term treatment response, and (3) validate the methodological framework. We included 138 antipsychotic-naïve, first-episode schizophrenia patients with data on psychopathology, cognition, electrophysiology, and structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Short-term treatment response was defined as change in Positive And Negative Syndrome Score (PANSS) after the initial antipsychotic treatment period. Baseline diagnostic classification algorithms also included data from 151 matched controls. Both approaches significantly classified patients from healthy controls with a balanced accuracy of 63.8% and 64.2%, respectively. Post-hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- nor long-term treatment response. Validation of the framework showed that choice of algorithm and parameter settings in the real data was successfully guided by results from the simulated data. In conclusion, this novel approach holds promise as an important step to minimize bias and obtain reliable results with modest sample sizes when independent replication samples are not available.
It remains unclear whether the onset of psychosis is associated with deterioration in cognitive performance. The aim of this study was to examine the course of cognitive performance in an ultrahigh ...risk (UHR) cohort, and whether change in cognition is associated with transition to psychosis and change in functioning. Consecutive admissions to Personal Assessment and Crisis Evaluation (PACE) Clinic between May 1994 and July 2000 who had completed a comprehensive cognitive assessment at baseline and follow-up were eligible (N = 80). Follow-up ranged from 7.3 to 13.4 years (M = 10.4 years; SD = 1.5). In the whole sample, significant improvements were observed on the Similarities (P = .03), Information (P < .01), Digit Symbol Coding (P < .01), and Trail Making Test-B (P = .01) tasks, whereas performance on the Rey Auditory Verbal Learning Test (Trials 1-3) declined significantly (P < .01) over the follow-up period. Change in performance on cognitive measures was not significantly associated with transition status. Taking time to transition into account, those who transitioned after 1 year showed significant decline on Digit Symbol Coding, whereas those who did not transition improved on this measure (P = .01; effect size ES = 0.85). Small positive correlations were observed between improvements in functioning and improvements in performance on Digit Symbol Coding and Arithmetic (0.24, P = .03 and 0.28, P = .01, respectively). In summary, the onset of psychosis was not associated with deterioration in cognitive ability. However, specific findings suggest that immediate verbal learning and memory, and processing speed may be relevant domains for future risk models and early intervention research in UHR individuals.
Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of ...psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders.
This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis 52 (38.5%) subsequently developed psychosis, 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups.
Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups.
These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.
Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted ...in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3′-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016–1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology.
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