The North American Prodrome Longitudinal Study (NAPLS) is a consortium of eight programs focusing on the psychosis prodrome. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, UCLA, UCSD, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. Although the programs initially developed independently, they previously collaborated to combine their historical datasets and to produce a series of analyses on predictors of psychosis in one of the largest samples of longitudinally followed prodromal subjects worldwide. This led to the development of a five year prospective study “Predictors and Mechanisms of Conversion to Psychosis”, (also known as NAPLS-2) with three major aims: (1) to prospectively test the prediction algorithm developed in NAPLS-1, (2) to investigate the neuroanatomical, neurophysiological, neurocognitive, and neurohormonal factors that may contribute to the development of psychosis, and (3) to develop a repository of DNA, RNA, and plasma from participants meeting diagnostic criteria for a clinical high risk (CHR) state and from demographically similar healthy subjects. Funded by NIMH in 2008, NAPLS-2 will generate the largest CHR for psychosis sample with 720 CHR and 240 healthy comparison subjects, and thus will provide statistical power and scientific scope that cannot be duplicated by any single site study. This paper describes the overall methodology of the NAPLS-2 project and reports on the ascertainment and demographics at the midway point of the study with (360 CHR) and 180 controls.
22q11.2 deletion syndrome (22qDS) represents one of the largest known genetic risk factors for schizophrenia. Approximately 30% of individuals with 22qDS develop psychotic illness in adolescence or young adulthood. Given that deficits in social cognition are increasingly viewed as a central aspect of idiopathic schizophrenia, we sought to investigate abilities in this domain as a predictor of psychotic symptoms in 22qDS participants. We assessed multiple domains of social and non-social cognition in 22qDS youth to: 1) characterize performance across these domains in 22qDS, and identify whether 22qDS participants fail to show expected patterns of age-related improvements on these tasks; and 2) determine whether social cognition better predicts positive and negative symptoms than does non-social cognition. Task domains assessed were: emotion recognition and differentiation, Theory of Mind (ToM), verbal knowledge, abstract reasoning, working memory, and processing speed. Positive and negative symptoms were measured using scores obtained from the Structured Interview for Prodromal Symptoms (SIPS). 22qDS participants (N=31, mean age: 15.9) showed the largest impairment, relative to healthy controls (N=31, mean age: 15.6), on measures of ToM and processing speed. In contrast to controls, 22qDS participants did not show age-related improvements on measures of working memory and verbal knowledge. Notably, ToM performance was the best predictor of positive symptoms in 22qDS, accounting for 39% of the variance in symptom severity. Processing speed emerged as the best predictor of negative symptoms, accounting for 37% of the variance in symptoms. Given that ToM was a robust predictor of positive symptoms in our sample, these findings suggest that social cognition may be a valuable intermediate trait for predicting the development of psychosis.
22q11.2 Microdeletion Syndrome; social cognition; schizophrenia; prodromal; psychosis
Background: The “clinical high risk” (CHR) construct was developed to identify individuals at imminent risk of developing psychosis. However, most individuals identified as CHR do not convert to psychosis, and it is unknown whether these nonconverting individuals actually recover from an at-risk state.
Methods: Eighty-four prospectively identified patients meeting CHR criteria, and 58 healthy comparison subjects were followed in a 2-year longitudinal study. Analyses examined rates of conversion, clinical, and functional recovery. Proportional cause-specific hazard models were used to examine the effects of baseline and time-varying predictors on conversion and remission. Trajectories of symptoms and psychosocial functioning measures were compared across outcome groups.
Results: Competing risk survival analyses estimated that 30% of CHR subjects convert to psychosis by 2 years, while 36% symptomatically remit and 30% functionally recover by 2 years. Lower levels of negative and mood/anxiety symptoms were related to increased likelihood of both symptomatic and functional recovery. CHR subjects who remitted symptomatically were more similar to healthy controls in terms of both their baseline and longitudinal symptoms and functioning than the other outcome groups.
Conclusions: Nonconverting CHR cases represented a heterogeneous group. Given that nonconverted subjects who remitted symptomatically also presented initially with less severe prodromal symptomatology and showed a distinct normative trajectory of both symptoms and psychosocial functioning over time, it may be possible to refine the CHR criteria to reduce the number of “false positive” cases by eliminating those who present with less severe attenuated positive symptoms or show early improvements in terms of symptoms or functioning.
psychosis; prodrome; conversion; at-risk; schizophrenia; functioning
Obstetric complications, particularly fetal hypoxia, are associated with increased risk for schizophrenia later in life. Such factors are also related to increased severity of certain neuropathological features of schizophrenia, including hippocampal and cortical gray matter reduction, among individuals with a genetic susceptibility to the disorder. However, the molecular mechanisms underlying these associations are unknown. Here we sought to determine whether neurotrophic factors, which are stimulated as part of a neuroprotective response to fetal distress, are differentially expressed in cord blood samples at the time of birth following fetal hypoxia, maternal hypertension/small for gestational age status, and/or prematurity among individuals who developed schizophrenia as adults, as compared with controls.
One hundred and eleven cases with psychotic disorders (70 with schizophrenia) and 333 controls matched for gender, race, and date of birth, were drawn from the Philadelphia cohort of the National Collaborative Perinatal Project, in a nested case-control study. Brain derived neurotrophic factor (BDNF) was assayed from cord and maternal blood samples taken at delivery and stored at −20 C for 45–50 years.
Among controls, birth hypoxia was associated with a significant (10%) increase in BDNF in cord samples, while among cases, hypoxia was associated with a significant (20%) decrease in BDNF. This differential response to fetal hypoxia was specific to schizophrenia and was not explained by other obstetric complications or by the BDNF Val66Met polymorphism.
These findings provide serologically based prospective evidence of disrupted neurotrophic signaling in response to birth hypoxia in the molecular pathogenesis of schizophrenia.
Schizophrenia; Hypoxia; Brain Derived Neurotrophic Factor; Neuroprotection
This article presents the rationale, design, and preliminary findings of the North American Prodrome Longitudinal Study (NAPLS), a collaborative, multisite investigation into the earliest phase of psychotic illness. We describe how 8 independently conceived research projects were integrated methodologically, how diagnostic reliability was achieved across sites on the Structured Interview for Prodromal Syndromes, and how baseline and follow-up data were aggregated for 888 at risk and comparison subjects. Data are presented describing the demographic, academic/work, and diagnostic characteristics of 3 relevant subgroups: persons at heightened clinical risk for psychosis, help-seeking comparison subjects, and nonpsychiatric controls. The NAPLS data set will be used to explore a series of questions related to prodromal psychosis, including the descriptive phenomenology of currently accepted diagnostic criteria, conversion rates over a 30-month period, predictors of psychosis onset and functional disability, and the impact of early treatment on the course of prodromal symptoms.
psychosis; prodrome; schizophrenia; consortium; early detection; prevention; NAPLS
Introduction: Research on prediction and prevention of schizophrenia has increasingly focused on prodromal (prepsychosis) social and role dysfunction as developmentally early, stable, and treatment-resistant illness components. In this report, 2 new measures, Global Functioning: Social and Global Functioning: Role, are presented, along with preliminary findings about psychometric properties and course of social and role (academic/work) functioning in the prodromal phase of psychosis. Methods: Subjects included 69 participants from the Recognition and Prevention program and 52 from the Center for the Assessment and Prevention of Prodromal States. Ages ranged from 12 to 29 years, and all met criteria for Attenuated Positive Symptom syndrome. Retrospective (past year) and baseline data are reported for all 121 prodromal subjects and for 44 normal controls (NCs). Prospective follow-up data are reported for a subsample of patients reevaluated at both 6 and 12 months (N = 44). Results: For both scales, interrater reliability was high, and preliminary data supported construct validity. Relative to NCs, prodromal individuals displayed impaired social and role functioning at baseline. Analyses of change over time indicated that role functioning declined over the year before ascertainment and improved over 12-month follow-up, presumably with treatment. Social impairment, by contrast, was constant across time and predicted later psychosis (P = .002). Discussion: Using 2 new global measures, social functioning was found to be a stable trait, unchanged by treatment, with considerable potential to be a marker of schizophrenia. Role functioning, by contrast, may be a more direct barometer of clinical change and may be responsive to treatment and environmental change.
RAP; CAPPS; functional predictors; prodromal schizophrenia; outcome; psychosis; scale validation; Global Functioning: Social; Global Functioning: Role
Given the growth of prodromal research in the past 15 years, the time seems right for assessing whether the ultra high-risk (UHR) research paradigm has delivered on its promise as an approach to identification of individuals at risk for imminent onset of psychosis and as a platform for studies assessing protective benefits of early interventions and for elucidating predictive markers. As demonstrated by the 8 articles on this theme in the present issue, the empirical basis of the prodromal research area has advanced significantly. While there is a lower risk for transition to psychosis in recent studies compared with initial studies, most recent studies still show a 30%–35% risk for psychosis within 1–2 years of follow-up, a rate that is substantially higher than the incidence rate of psychosis among transition age youth in the general population. Moreover, the means with which to improve this predictive equation is rapidly developing, enabled by the collaborative integration of data across multiple sites, the employment of multivariate risk algorithms, and a longitudinal perspective on symptoms, cognition, and functioning. All the initial intervention studies have produced encouraging findings, albeit with small sample sizes and relatively large attrition rates. Nevertheless, the findings in this issue, together with others like them appearing at an increasing rate in the world literature, indicate that the prodromal research area is increasing in maturity and sophistication, providing a useful heuristic for early detection and intervention in those at risk for psychosis.
psychosis; prodrome; prevention
Social cognitive impairments are consistently reported in schizophrenia and are associated with functional outcome. We currently know very little about whether these impairments are stable over the course of illness. In the current study, 3 different aspects of social cognition were assessed (emotion processing, Theory of Mind [ToM], and social relationship perception) at 3 distinct developmental phases of illness: prodromal, first episode, and chronic. In this cross-sectional study, participants included 50 individuals with the prodromal risk syndrome for psychosis and 34 demographically comparable controls, 81 first-episode schizophrenia patients and 46 demographically comparable controls, and 53 chronic schizophrenia patients and 47 demographically comparable controls. Outcome measures included total and subtest scores on 3 specialized measures of social cognition: (1) emotion processing assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test, (2) ToM assessed with The Awareness of Social Inference Test, and (3) social relationship perception assessed the Relationships Across Domains Test. Social cognitive performance was impaired across all domains of social cognition and in all clinical samples. Group differences in performance were comparable across phase of illness, with no evidence of progression or improvement. Age had no significant effect on performance for either the clinical or the comparison groups. The findings suggest that social cognition in these 3 domains fits a stable pattern that has outcome and treatment implications. An accompanying article prospectively examines the longitudinal stability of social cognition and prediction of functional outcome in the first-episode sample.
social cognition; illness phase; schizophrenia
Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.
psychosis; brain development; emotion; amygdala; prefrontal cortex; fMRI
Despite evidence supporting a relationship between impulsivity and naturalistic risk-taking, the relationship of impulsivity with laboratory-based measures of risky decision-making remains unclear. One factor contributing to this gap in our understanding is the degree to which different risky decision-making tasks vary in their details. We conducted an fMRI investigation of the Angling Risk Task (ART), which is an improved behavioral measure of risky decision-making. In order to examine whether the observed pattern of neural activation was specific to the ART or generalizable, we also examined correlates of the Balloon Analog Risk Taking (BART) task in the same sample of 23 healthy adults. Exploratory analyses were conducted to examine the relationship between neural activation, performance, impulsivity and self-reported risk-taking. While activation in a valuation network was associated with reward tracking during the ART but not the BART, increased fronto-cingulate activation was seen during risky choice trials in the BART as compared to the ART. Thus, neural activation during risky decision-making trials differed between the two tasks, and this observation was likely driven by differences in task parameters, namely the absence vs. presence of ambiguity and/or stationary vs. increasing probability of loss on the ART and BART, respectively. Exploratory association analyses suggest that sensitivity of neural response to the magnitude of potential reward during the ART was associated with a suboptimal performance strategy, higher scores on a scale of dysfunctional impulsivity (DI) and a greater likelihood of engaging in risky behaviors, while this pattern was not seen for the BART. Our results suggest that the ART is decomposable and associated with distinct patterns of neural activation; this represents a preliminary step toward characterizing a behavioral measure of risky decision-making that may support a better understanding of naturalistic risk-taking.
functional impulsivity; dysfunctional impulsivity; risky decision-making; naturalistic risk-taking; ART; BART
Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well–characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.
Callosal volume reduction has been observed in patients with bipolar disorder, but whether these deficits reflect genetic vulnerability to the illness remains unresolved. Here, we used computational methods to map corpus callosum abnormalities in a population-based sample of twin pairs discordant for bipolar disorder. Twenty-one probands with bipolar I disorder (mean age 44.4 ± 7.5 years; 48% female), 19 of their non-bipolar co-twins, and 34 demographically matched control twin individuals underwent magnetic resonance imaging. Three-dimensional callosal surface models were created to visualize its morphologic variability and to localize group differences. Neurocognitive correlates of callosal area differences were additionally investigated in a subsample of study participants. Bipolar (BPI) probands, but not their co-twins, showed significant callosal thinning and area reduction, most pronounced in the genu and splenium, relative to healthy twins. Altered callosal curvature was additionally observed in BPI probands. In bipolar probands and co-twins, genu and splenium midsagittal areas were significantly correlated with verbal processing speed and response inhibition. These findings suggest that aberrant connections between cortical regions—possibly reflecting decreased myelination of white matter tracts—may be involved in bipolar pathophysiology. However, findings of callosal thinning appear to be disease related, rather than reflecting genetic vulnerability to bipolar illness.
magnetic resonance imaging; mood disorders; myelination; processing speed; twin study
The period immediately preceding the onset of overt psychosis is characterized by a range of symptoms and behaviors including emerging attenuated psychosis, spontaneous movement abnormalities, and a broad decline in role and social functioning. Recent evidence suggests that basal ganglia dysfunction, which is implicated in the development of psychotic symptomatology, may manifest in the form of both movement abnormalities and deficits in processes integral to psychosocial functioning. However, little is known about the relationship between abnormal movement function and the observed psychosocial deficits. In the present study, 40 clinical high-risk participants meeting criteria for a prodromal syndrome were assessed for movement abnormalities and global role and social functioning at baseline. Role and social functioning was then followed up after a one-year period. At baseline, the severity of spontaneous movement abnormalities was associated with poor role functioning. Further, when controlling for baseline functioning, movement abnormalities predicted changes in social functioning one-year later, with a trend in the same direction for role functioning. Exploratory analyses also indicated that elevated baseline movement abnormalities distinguished those at-risk participants who eventually converted to psychosis and that this was also the case for poorer baseline global role functioning (at the trend level). Taken together, the results suggest that movement abnormalities are closely associated with deficits in psychosocial functioning. Elucidating the link between these phenomena may serve to refine etiological models of frontal-subcortical circuit dysfunction and inform understanding of functioning and outcome of these affected youth.
Psychosis; Prodrome; Social Functioning; Role Functioning; Dyskinesia
Given the fundamental role of thought disorder in schizophrenia, subtle communication disturbance may be a valuable predictor of subsequent development of psychosis. Here we examined the contribution of thought and communication disturbance to the prediction of outcome in adolescents identified as putatively prodromal for psychosis.
Transcribed speech samples were elicited from 105 adolescents (54 identified as being at clinical high risk for a first episode of psychosis (CHR) and 51 demographically comparable comparison subjects) and coded for formal thought disorder (FTD) and linguistic cohesion. We then examined the association of baseline FTD/cohesion with conversion to psychosis and social and role outcome at follow-up, approximately one year later.
At baseline, CHR patients who subsequently converted to psychosis (CHR+) showed an elevated rate of illogical thinking and poverty of content (POC) in their speech, relative to both typically developing controls and non-converters (CHR−). CHR+ youth also used significantly less referential cohesion at baseline, indicating that they provide fewer references to people, objects, or events mentioned in preceding utterances. Multiple regression models indicated that, among measures of FTD/cohesion, illogical thinking was uniquely predictive of subsequent conversion to psychosis, whereas POC and referential cohesion were significant predictors of social and role functioning, respectively.
Despite the absence of fully psychotic symptoms, putatively prodromal individuals evidence signs of communication disturbance that are qualitatively similar to those seen in schizophrenia, and are predictive of both conversion to psychosis and psychosocial outcome. These findings suggest that FTD measures have prognostic significance for at-risk youth.
thought disorder; psychosis prodrome; schizophrenia; language; psychosocial outcome
In this study, we examined the preliminary concurrent validity of a brief version of the Prodromal Questionnaire (PQ-B), a self-report screening measure for psychosis risk syndromes. Adolescents and young adults (N=141) who presented consecutively for clinical assessment to one of two early psychosis research clinics at the University of California, San Francisco and UC Los Angeles completed the PQ-B and the Structured Interview for Prodromal Syndromes (SIPS) at intake. Endorsement of three or more positive symptoms on the PQ-B differentiated between those with prodromal syndrome and psychotic syndrome diagnoses on the SIPS versus those with no SIPS diagnoses with 89% sensitivity, 58% specificity, and a positive Likelihood Ratio of 2.12. A Distress Score measuring the distress or impairment associated with endorsed positive symptoms increased the specificity to 68%, while retaining similar sensitivity of 88%. Agreement was very similar when participants with psychotic syndromes were excluded from the analyses. These results suggest that the PQ-B may be used as an effective, efficient self-report screen for prodromal psychosis syndromes when followed by diagnostic interview, in a two-stage evaluation process in help-seeking populations.
Structural brain abnormalities are consistently found in schizophrenia (Sz) and have been associated with the familial risk for the disorder. We aim to define the relative contributions of genetic and nongenetic factors to the association between structural brain abnormalities and Sz in a uniquely powered cohort (Schizophrenia Twins and Relatives consortium).
An international multicenter magnetic resonance imaging collaboration was set up to pool magnetic resonance imaging scans from twin pairs in Utrecht (The Netherlands), Helsinki (Finland), London (United Kingdom), and Jena (Germany). A sample of 684 subjects took part, consisting of monozygotic twins (n = 410, with 51 patients from concordant and 52 from discordant pairs) and dizygotic twins (n = 274, with 39 patients from discordant pairs). The additive genetic, common, and unique environmental contributions to the association between brain volumes and risk for Sz were estimated by structural equation modeling.
The heritabilities of most brain volumes were significant and ranged between 52% (temporal cortical gray matter) and 76% (cerebrum). Heritability of cerebral gray matter did not reach significance (34%). Significant phenotypic correlations were found between Sz and reduced volumes of the cerebrum (−.22 [−.30/−.14]) and white matter (−.17 [−.25/−.09]) and increased volume of the third ventricle (.18 [.08/.28]). These were predominantly due to overlapping genetic effects (77%, 94%, and 83%, respectively).
Some of the genes that transmit the risk for Sz also influence cerebral (white matter) volume.
Brain volumes; multicenter; phenotypic correlation; schizophrenia; sMRI; twins
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
To elucidate the neuropsychology of the CHR syndrome, to determine
the association of neuropsychological function with conversion to psychosis
and family history (FH) of psychosis, and to examine whether baseline
neuropsychological functioning predicts subsequent psychosis.
Design, Setting, and Participants
Longitudinal study with 2 1/2 years follow-up of 304 prospectively
identified CHR individuals meeting Structured Interview for Prodromal
Syndromes (SIPS) criteria, 52 non-CHR persons with a FH of psychosis in
first- or second-degree relatives (“family HR”/FHR), and 193
normal controls with neither a FH of psychosis nor a CHR syndrome, all of
whom had baseline neuropsychological evaluations, recruited across eight
centers as part of the North American Prodrome Longitudinal Study
A neurocognitive composite score, eight individual neuropsychological
measures, an IQ estimate, and HR status.
Global (“composite”) neuropsychological functioning
was comparably impaired in CHR and FHR groups compared to 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 worst in the subgroup
with a FH of psychosis. Tests of processing speed and verbal learning and
memory were most sensitive in discriminating CHR 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 a further decline may occur
after baseline CHR assessment.
No objective diagnostic biomarkers or laboratory tests have yet been developed for psychotic illness. Magnetic resonance imaging (MRI) studies consistently find significant abnormalities in multiple brain structures in psychotic patients relative to healthy control subjects, but these abnormalities show substantial overlap with anatomic variation that is in the normal range and therefore nondiagnostic. Recently, efforts have been made to discriminate psychotic patients from healthy individuals using machine-learning-based pattern classification methods on MRI data.
Three-dimensional cortical gray matter density (GMD) maps were generated for 36 patients with recent-onset psychosis and 36 sex- and age-matched control subjects using a cortical pattern matching method. Between-group differences in GMD were evaluated. Second, the sparse multinomial logistic regression classifier included in the Multivariate Pattern Analysis in Python machine-learning package was applied to the cortical GMD maps to discriminate psychotic patients from control subjects.
Patients showed significantly lower GMD, particularly in prefrontal, cingulate, and lateral temporal brain regions. Pattern classification analysis achieved 86.1% accuracy in discriminating patients from controls using leave-one-out cross-validation.
These results suggest that even at the early stage of illness, psychotic patients present distinct patterns of regional cortical gray matter changes that can be discriminated from the normal pattern. These findings indicate that we can detect complex patterns of brain abnormality in early stages of psychotic illness, which has critical implications for early identification and intervention in individuals at ultra-high risk for developing psychosis/schizophrenia.
Classification; cortical pattern matching; MRI; psychosis; PyMVPA; schizophrenia
Although schizophrenia is highly heritable, the search for susceptibility genes has been challenging. The “endophenotype” approach is an alternative method for measuring phenotypic variation that may make it easier to identify susceptibility genes in the context of complexly inherited traits. Neuroimaging methods in particular offer a powerful way to bridge the neurobiology of genes and behavior. Such investigations may be further empowered by complementary strategies involving chromosomal abnormalities associated with schizophrenia, which can help to localize causative genes and better understand the genetic complexity of the illness. Here, we illustrate our use of these convergent approaches, with a focus on neuroimaging studies using novel computational brain mapping algorithms, to investigate genetic influences on brain structure in the development of psychosis. These studies provide compelling evidence that specific genetic loci suspected to predispose to schizophrenia may affect quantitative variation in neural indicators underlying the neurobehavioral phenotype, and illustrate how genetic-neuroimaging paradigms can improve our understanding of the pathogenesis of this highly disabling mental illness.
psychosis; brain mapping; genetic; neuroanatomy; chromosome 22q11.2; velocardiofacial syndrome; twin study; DISC1
Although dyskinesias may be one of the first behavioral indicators of progressive striatal dysfunction, a mechanism critically implicated in the pathogenesis of psychotic disorders, little is known about the association between striatal structures and abnormal movements in high-risk populations. Thirty participants with a prodromal syndrome were rated for dyskinetic movements and underwent structural magnetic resonance imaging (MRI). Volumes of striatal brain structures were delineated. Elevated hyperkinetic movements were found to be associated with smaller putamen and results were replicated in the antipsychotic naïve portion of the sample. Participants who converted over a two-year follow-up period showed significantly smaller striatal volumes and a trend towards elevated dyskinetic movements, relative to those who did not convert. Movement abnormalities may reflect a striatal pathology that is present before formal psychosis onset, and potentially reflective of a heightened vulnerability for conversion.
Prodromal; Dyskinesia; Putamen; Caudate; Conversion; Psychosis; Striatum; Spontaneous Dyskinesia
A major focus of early intervention research is determining the risk of conversion to psychosis and developing optimal algorithms of prediction. Although reported rates of nonconversion vary in the literature, the nonconversion rate always encompasses a majority (50%–85%) of the sample participants. Less is known about the outcome among this group, referred to as false positive individuals.
A longitudinal study was conducted of more than 300 prospectively identified treatment-seeking individuals meeting criteria for a psychosis-risk syndrome. Participants were recruited and evaluated across eight clinical research centers as part of the North American Prodrome Longitudinal Study. Over a 2.5-year follow-up assessment period, 214 (71%) participants had not made the transition to psychosis.
The sample examined included 111 individuals who had at least 1 year of follow-up data available and did not transition to psychosis within the study duration. In year 1, there was significant improvement in ratings for attenuated positive and negative symptoms. However, at least one attenuated positive symptom was still present for 43% of the sample at 1 year and for 41% at 2 years. At the follow-up timepoints, social and role functioning were significantly poorer in the clinical sample relative to nonpsychiatric comparison subjects.
Help-seeking individuals who meet prodromal criteria appear to represent those who are truly at risk for psychosis and are showing the first signs of illness, those who remit in terms of the symptoms used to index clinical high-risk status, and those who continue to have attenuated positive symptoms.
Movement abnormalities and cognitive deficits may represent external markers of an underlying neural process linked with the early etiology of psychosis. As basal ganglia function plays a governing role in both movement and cognitive processes, an understanding of the relationship between these phenomena stands to inform etiological conceptualizations of vulnerability and psychotic disorders.
In this investigation, trained raters coded movement abnormalities in videotapes from structured interviews of adolescents and young adults with a prodromal risk syndrome (n = 90). The participants were administered a neuropsychological battery including measures of verbal comprehension, perceptual organization, immediate/delayed auditory memory, and an estimate of full scale intelligence quotient. Diagnostic status was followed for a two-year period utilizing structured clinical interviews, during which time 24 high-risk participants (26.66%) converted to an Axis I psychotic disorder.
Elevated dyskinetic movements in the upper-body region were correlated with deficits in domains of verbal comprehension, perceptual organization and both immediate and delayed auditory memory. Further, discriminant function analyses indicated that baseline movement abnormalities and neurocognitive deficits significantly classified those high-risk participants who would eventually convert to a psychotic disorder (72.3%).
Results support a common cortico-striato-pallido-thalamic circuit irregularity, underlying both movement abnormalities and cognitive deficits in individuals at high-risk for psychosis. Models incorporating external markers of progressive basal ganglia dysfunction may enhance detection and preventive intervention for those high-risk individuals most in need of treatment.
Neuropsychology; Dyskinesia; Biomarker; Psychosis; Prodrome; Conversion
Early detection and prospective evaluation of individuals who will develop schizophrenia or other psychotic disorders are critical to efforts to isolate mechanisms underlying psychosis onset and to the testing of preventive interventions, but existing risk prediction approaches have achieved only modest predictive accuracy.
To determine the risk of conversion to psychosis and to evaluate a set of prediction algorithms maximizing positive predictive power in a clinical high-risk sample.
Design, Setting, and Participants
Longitudinal study with a 2½-year follow-up of 291 prospectively identified treatment-seeking patients meeting Structured Interview for Prodromal Syndromes criteria. The patients were recruited and underwent evaluation across 8 clinical research centers as part of the North American Prodrome Longitudinal Study.
Main Outcome Measure
Time to conversion to a fully psychotic form of mental illness.
The risk of conversion to psychosis was 35%, with a decelerating rate of transition during the 2½-year follow-up. Five features assessed at baseline contributed uniquely to the prediction of psychosis: a genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Prediction algorithms combining 2 or 3 of these variables resulted in dramatic increases in positive predictive power (ie, 68%–80%) compared with the prodromal criteria alone.
These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine. They provide a benchmark for the rate and shape of the psychosis risk function against which standardized preventive intervention programs can be compared.
Emotional and motivational dysfunction is fundamental to schizophrenia, and yet the nature and scope of associated deficits are not well understood. This study assessed the integrity of emotional responding from the perspective of its underlying motivational systems during different phases of schizophrenia. Evaluative, somatic, and autonomic responses were measured during viewing of pictures categorized by emotional content, including threat, mutilation, contamination, illness, pollution, mild erotica, families, food and nature. Participants were 13 patients at ultra high-risk or prodromal for psychosis, 40 first-episode schizophrenia patients, 37 chronic schizophrenia patients, and 74 healthy comparison subjects. Irrespective of phase of illness, schizophrenia patients showed a robust and normal pattern of response across multiple systems, with differential engagement of the defensive and appetitive systems as a function of the motivational significance assigned to specific emotional contexts. Although the integrity of core motivational states also appeared to be intact in prodromal patients, a less consistent pattern of response was observed. As continuing efforts are made to identify emotional and motivational abnormalities in schizophrenia, identified deficits will likely be independent of a fundamental dysfunction in basic emotion and motivation response systems and involve integration with higher order processes.
schizophrenia; emotion; motivation; attention; startle reflex