Adults living with schizophrenia have prominent and widespread alterations in brain structure and function, but until recently little was known about the developmental timing and course of such ...changes. Prospective studies of individuals at elevated risk for developing psychosis, termed clinical high-risk (CHR) or psychosis risk syndrome patients, can address these questions, thus providing clues into neurobiological mechanisms that occur prior to illness onset. In this issue, Fortea et al.
present the results of a prospective longitudinal brain imaging investigation of 107 adolescents at CHR for developing a psychotic disorder (23% of whom developed psychosis over the follow-up period) and 102 typically developing controls. Participants were scanned at baseline and at 18-month follow-up or at the time of conversion to psychosis. Using linear mixed-effects models to measure cortical surface area over time, the authors found that youth who developed a psychotic disorder during the follow-up period experienced greater loss of cortical surface area in bilateral parietal and right frontal regions compared to CHR youth who did not develop psychosis, and in left parietal and occipital regions compared to healthy controls. Findings were not accounted for by antipsychotic medication use, cannabis use, or general intelligence. Thus, these observations suggest that emerging psychosis may have an impact on typical neuromaturational changes that occur during adolescence.
Recent years have seen an advent in population-based studies in children, adolescents, and adults that examine the prevalence, etiology, and developmental trajectories of diverse subclinical ...psychopathological symptoms that pose a risk for the later development of severe mental illnesses. It is increasingly recognized that most categorically defined psychiatric disorders occur on a spectrum or continuum, show high heterogeneity and symptom overlap, and share genetic and environmental risk factors. We discuss neurodevelopmental underpinnings of psychosis spectrum symptoms and review brain morphometric and functional alterations as well as genetic liability for psychosis in individuals experiencing psychotic symptoms (PSs) in the general population. With regard to brain structure and function, findings of qualitatively similar alterations in individuals experiencing subthreshold PSs and individuals with overt psychotic disorders support the notion of a psychosis continuum. However, genetic and epidemiological studies have emphasized the overlap of PSs and other psychiatric illnesses. In particular, PSs during adolescence appear to be a nonspecific precursor of different psychopathological outcomes. Given the evidence presented in this review, we argue that findings from population-based studies are appropriate to guide policy-making to further emphasize public health efforts. Broadly accessible mental health programs are promising to make a difference in the field of adolescent mental health. However, the specific efficacy of these programs warrants further study, and caution is advised to not overpathologize potentially transient occurrence of mental health problems.
The Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) Consortium is a global team science effort, now including over 800 scientists spread across 340 institutions in 35 countries, with ...the shared goal of understanding disease and genetic influences on the brain. This “crowdsourcing” approach to team neuroscience has unprecedented power for advancing our understanding of both typical and atypical human brain development.
Here we discuss recent progress of the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) Consortium, a global “team science” effort to understand disease and genetic influences on the brain. Quantifying the effects of common and rare variants and epigenetic factors on human brain development requires international collaboration on an unprecedented scale.
Abstract Background Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with ...individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. Results In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.
Language and speech are the primary source of data for psychiatrists to diagnose and treat mental disorders. In psychosis, the very structure of language can be disturbed, including semantic ...coherence (e.g., derailment and tangentiality) and syntactic complexity (e.g., concreteness). Subtle disturbances in language are evident in schizophrenia even prior to first psychosis onset, during prodromal stages. Using computer‐based natural language processing analyses, we previously showed that, among English‐speaking clinical (e.g., ultra) high‐risk youths, baseline reduction in semantic coherence (the flow of meaning in speech) and in syntactic complexity could predict subsequent psychosis onset with high accuracy. Herein, we aimed to cross‐validate these automated linguistic analytic methods in a second larger risk cohort, also English‐speaking, and to discriminate speech in psychosis from normal speech. We identified an automated machine‐learning speech classifier – comprising decreased semantic coherence, greater variance in that coherence, and reduced usage of possessive pronouns – that had an 83% accuracy in predicting psychosis onset (intra‐protocol), a cross‐validated accuracy of 79% of psychosis onset prediction in the original risk cohort (cross‐protocol), and a 72% accuracy in discriminating the speech of recent‐onset psychosis patients from that of healthy individuals. The classifier was highly correlated with previously identified manual linguistic predictors. Our findings support the utility and validity of automated natural language processing methods to characterize disturbances in semantics and syntax across stages of psychotic disorder. The next steps will be to apply these methods in larger risk cohorts to further test reproducibility, also in languages other than English, and identify sources of variability. This technology has the potential to improve prediction of psychosis outcome among at‐risk youths and identify linguistic targets for remediation and preventive intervention. More broadly, automated linguistic analysis can be a powerful tool for diagnosis and treatment across neuropsychiatry.
Evidence is rapidly accumulating that rare, recurrent copy number variants represent large effect risk factors for neuropsychiatric disorders. 22q11.2 deletion syndrome (22q11DS) (velocardiofacial ...syndrome or DiGeorge syndrome) is the most common known contiguous gene deletion syndrome and is associated with diverse neuropsychiatric disorders across the life span. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum, attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson’s disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated autism spectrum disorder and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here, we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder’s heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.
A barrier to preventative treatments for psychosis is the absence of accurate identification of persons at highest risk. A blood test that could substantially increase diagnostic accuracy would ...enhance development of psychosis prevention interventions.
The North American Prodrome Longitudinal Study project is a multisite endeavor that aims to better understand predictors and mechanisms for the development of psychosis. In this study, we measured expression of plasma analytes reflecting inflammation, oxidative stress, hormones, and metabolism. A "greedy algorithm" selected analytes that best distinguished persons with clinical high-risk symptoms who developed psychosis (CHR-P; n = 32) from unaffected comparison (UC) subjects (n = 35) and from those who did not develop psychosis during a 2-year follow-up (CHR-NP; n = 40).
The classifier included 15 analytes (selected from 117), with an area under the receiver operating curve for CHR-P vs UC of 0.91 and CHR-P vs CHR-NP of 0.88. Randomly scrambled group membership followed by reconstructions of the entire classifier method yielded consistently weak classifiers, indicating that the true classifier is highly unlikely to be a chance occurrence. Such randomization methods robustly imply the assays contain consistent information distinguishing the groups which was not obscured by the data normalization method and was revealed by classifier construction. These results support the hypothesis that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis.
If confirmed in other groups of persons at elevated risk of psychosis, a multiplex blood assay has the potential for high clinical utility.
Recent studies have demonstrated substantial phenotypic overlap, notably social impairment, between autism spectrum disorder (ASD) and schizophrenia. However, the neural mechanisms underlying the ...pathogenesis of social impairments across these distinct neuropsychiatric disorders has not yet been fully examined. Most neuroimaging studies to date have focused on adults with these disorders, with little known about the neural underpinnings of social impairments in younger populations. Here, we present a narrative review of the literature available through April 2020 on imaging studies of adolescents with either ASD or early-onset psychosis (EOP), to better understand the shared and unique neural mechanisms of social difficulties across diagnosis from a developmental framework. We specifically focus on functional connectivity studies of the default mode network (DMN), as the most extensively studied brain network relevant to social cognition across both groups. Our review included 29 studies of DMN connectivity in adolescents with ASD (Mean age range = 11.2–21.6 years), and 14 studies in adolescents with EOP (Mean age range = 14.2–24.3 years). Of these, 15 of 29 studies in ASD adolescents found predominant underconnectivity when examining DMN connectivity. In contrast, findings were mixed in adolescents with EOP, with five of 14 studies reporting DMN underconnectivity, and an additional six of 14 studies reporting both under- and over-connectivity of the DMN. Specifically, intra-DMN networks were more frequently underconnected in ASD, but overconnected in EOP. On the other hand, inter-DMN connectivity patterns were mixed (both under- and over-connected) for each group, especially DMN connectivity with frontal, sensorimotor, and temporoparietal regions in ASD, and with frontal, temporal, subcortical, and cerebellar regions in EOP. Finally, disrupted DMN connectivity appeared to be associated with social impairments in both groups, less so with other features distinct to each condition, such as repetitive behaviors/restricted interests in ASD and hallucinations/delusions in EOP. Further studies on demographically well-matched groups of adolescents with each of these conditions are needed to systematically explore additional contributing factors in DMN connectivity patterns such as clinical heterogeneity, pubertal development, and medication effects that would better inform treatment targets and facilitate prediction of outcomes in the context of these developmental neuropsychiatric conditions.
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