Longitudinal inference of multiscale markers in psychosis: from hippocampal centrality to functional outcome.

Multiscale neuroscience conceptualizes mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales. We leverage this framework to propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impairments in episodic memory and social cognition, which lead to more severe negative symptoms and lower functional outcome. As psychosis represents a heterogeneous collection of biological and behavioral alterations that evolve over time, we further predict this disease progression for a subtype of the patient sample, with other patients showing normal-range performance on all variables. We sampled data from two cross-sectional datasets of first- and multi-episode psychosis, resulting in a sample of 163 patients and 119 non-clinical controls. To address our proposed disease progression model and evaluate potential heterogeneity, we applied a machine-learning algorithm, SuStaIn, to the patient data. SuStaIn uniquely integrates clustering and disease progression modeling and identified three patient subtypes. Subtype 0 showed normal-range performance on all variables. In comparison, Subtype 1 showed lower episodic memory, social cognition, functional outcome, and higher negative symptoms, while Subtype 2 showed lower hippocampal-cortical connectivity and episodic memory. Subtype 1 deteriorated from episodic memory to social cognition, negative symptoms, functional outcome to bilateral hippocampal-cortical dysconnectivity, while Subtype 2 deteriorated from bilateral hippocampal-cortical dysconnectivity to episodic memory and social cognition, functional outcome to negative symptoms. This first application of SuStaIn in a multiscale psychiatric model provides distinct disease trajectories of hippocampal-cortical connectivity, which might underlie the heterogeneous behavioral manifestations of psychosis.

Perception of social inclusion/exclusion and response inhibition in adolescents with past suicide attempt: a multidomain task-based fMRI study.

The occurrence of suicidal behaviors increases during adolescence. Hypersensitivity to negative social signals and deficits in cognitive control are putative mechanisms of suicidal behaviors, which necessitate confirmation in youths. Multidomain functional neuroimaging could enhance the identification of patients at suicidal risk beyond standard clinical measures. Three groups of adolescents (N = 96; 78% females, age = 11.6-18.1) were included: patients with depressive disorders and previous suicide attempts (SA, n = 29); patient controls with depressive disorders but without any suicide attempt history (PC, n = 35); and healthy controls (HC, n = 32). We scanned participants with 3T-MRI during social inclusion/exclusion (Cyberball Game) and response inhibition (Go-NoGo) tasks. Neural activation was indexed by the blood-oxygenation-level dependent (BOLD) of the hemodynamic response during three conditions in the Cyberball Game ("Control condition", "Social Inclusion", and "Social Exclusion"), and two conditions in Go-NoGo task ("Go" and "NoGo" blocks). ANCOVA-style analysis identified group effects across three whole-brain contrasts: 1) NoGo vs. Go, 2) Social inclusion vs. control condition, 3) Social exclusion vs. control condition. We found that SA had lower activation in the left insula during social inclusion vs. control condition compared to PC and HC. Moreover, SA compared to PC had higher activity in the right middle prefrontal gyrus during social exclusion vs. control condition, and in bilateral precentral gyri during NoGo vs. Go conditions. Task-related behavioral and self-report measures (Self-reported emotional reactivity in the Cyberball Game, response times and number of errors in the Go-NoGo Task) did not discriminate groups. In conclusion, adolescent suicidal behaviors are likely associated with neural alterations related to the processing of social perception and response inhibition. Further research, involving prospective designs and diverse cohorts of patients, is necessary to explore the potential of neuroimaging as a tool in understanding the emergence and progression of suicidal behaviors.

Strategies for Achieving Better Cognitive Health in Individuals with Schizophrenia Spectrum: A Focus on the Canadian Landscape: Stratégies pour atteindre une meilleure santé cognitive chez les personnes souffrant du spectre de la schizophrénie : un regard sur le paysage canadien.

BACKGROUND: Schizophrenia spectrum disorders (SSDs) are a group of psychiatric disorders characterized by positive and negative symptoms as well as cognitive impairment that can significantly affect daily functioning. METHOD: We reviewed evidence-based strategies for improving cognitive function in patients with SSDs, focusing on the Canadian landscape. RESULTS: Although antipsychotic medications can address the positive symptoms of SSDs, cognitive symptoms often persist, causing functional impairment and reduced quality of life. Moreover, cognitive function in patients with SSDs is infrequently assessed in clinical practice, and evidence-based recommendations for addressing cognitive impairment in people living with schizophrenia are limited. While cognitive remediation (CR) can improve several domains of cognitive function, most individuals with SSDs are currently not offered such an intervention. While the development of implementation strategies for CR is underway, available and emerging pharmacological treatments may help overcome the limited capacity for psychosocial approaches. Furthermore, combining pharmacological with non-pharmacological interventions may improve outcomes compared to pharmacotherapy or CR alone. CONCLUSION: This review highlights the challenges and discusses the potential solutions related to the assessment and management of cognitive impairment to help mental health-care practitioners better manage cognitive impairment and improve daily functioning in individuals with SSDs.

Improving Thinking Skills in People With Schizophrenia: A Focus on CanadaPlain Language SummarySchizophrenia spectrum disorders (SSDs) are mental health conditions that can cause a mix of symptoms making everyday life difficult for people. For example, some people might experience positive symptoms like seeing and hearing things that are not there, having false believes, or feeling suspicious. Others might experience negative symptoms like isolating from social interactions, having trouble showing emotion, or finding it hard to connect with others. Finally, they might also have trouble with thinking skills, like paying attention, planning and organizing, remembering things, or understanding social cues. While some medicines can help with some of the symptoms, they often do not help with improving thinking skills. In addition, these thinking problems are not checked often enough in patients with SSDs. In fact, there are not many proven ways to help with these issues. One method that can help with thinking skills is called cognitive remediation (CR), but it is not offered to most people with SSDs. There are ongoing efforts to make CR more available. It is also possible that CR may be combined with new medicines to make it work better than using just one treatment. This article looks at ways to improve thinking skills in people with SSDs, with a focus on what is happening in Canada. We present the challenges and possible solutions for checking and managing thinking problems, to help health-care workers better care for people with SSDs.

An intersectional perspective on the sociodemographic and clinical factors influencing the status of not in Education, Employment, or training (NEET) in patients with first-episode psychosis (FEP).

PURPOSE: High rates of Not in Education, Employment or Training (NEET) are seen in people with first episode of psychosis (FEP). Sociodemographic and clinical factors were reported to be associated with NEET status in FEP patients. This study follows Intersectionality to examine the independent and additive effects, and most importantly the intersections of sociodemographic and clinical variables concerning NEET status in FEP patients. It was hypothesized that NEET status in FEP patients would be described by the intersection between at least two predictor variables. METHODS: Secondary analyses with chi-square tests, multiple logistic regression and Chi-squared Automatic Interaction Detection (CHAID) analyses were performed on 440 participants with FEP. RESULTS: Chi-square tests indicated that patient socioeconomic status and negative symptom severity were significantly and independently associated with their NEET status. Multiple logistic regression suggested additive effects of age (odds ratio = 1.61), patient socioeconomic status (odds ratio = 1.55) and negative symptom severity (odds ratio = 1.75) in predicting patients' NEET status. CHAID detected an intersection between patients' negative symptom severity and socioeconomic status in shaping their NEET status. CONCLUSION: This study explored how the NEET status of patients with FEP was explained not only by the separate effects of negative symptom severity and socioeconomic status but also by the unique intersections of their clinical and social identities. Findings indicated that functional outcomes of patients appear co-constructed by the intersections of multiple identities. Crucial clinical implications of complementing care for negative symptom severity with vocational resources to improve functional outcomes of patients are discussed.

Navigating Social Cognitive Impairments in Schizophrenia Spectrum Disorders: Protocol for a Pilot Pre-Post Quasi-Experimental Study for Remote Avatar-Assisted Cognitive Remediation Therapy.

BACKGROUND: Social cognitive impairments are prevalent in schizophrenia spectrum disorder (SSD) and have detrimental effects on functioning. Cognitive remediation (CR) has shown its efficacy in improving social cognitive impairments, although the transfer of these skills to daily life and the personalization of these interventions remain challenging. RC2S (Remédiation Cognitive de la Cognition Sociale dans la Schizophrénie; Cognitive remediation of social cognition in Schizophrenia) is a French CR that combines the learning of strategies and practice using paper-and-pencil exercises and digital relational simulations. This French program was designed as an in-person intervention. OBJECTIVE: This project aims to culturally adapt the RC2S program, in French-Canadian and North American English and to assess the feasibility, acceptability, safety, and implementation of a remote version in people with SSD. An exploratory objective is to assess the preliminary effect of remote RC2S on goal attainment, social cognition, and psychosocial outcomes. METHODS: We will use a pre-post quasi-experimental design. First, the translation and cultural adaptation in North American English and French-Canadian of RC2S is presented. Then, 20 participants aged ≥18 years with a diagnosis of SSD, presenting with a subjective or an objective impairment in social cognition, will be included to receive RC2S. In addition, 5 therapists will be included as research participants to assess their perspective on RC2S. Participants with SSD will undergo a baseline remote assessment of their social cognition, clinical symptoms, and functioning. They will then start remote RC2S for 24 biweekly individual 1-hour sessions with a therapist. Following the case formulation and goal setting, participants will complete personalized paper-and-pencil exercises to develop strategies and integrative digital relational simulations, during which they will help an avatar navigate through a variety of social contexts and relationships. The last 2 sessions are dedicated to the transfer to daily life. All participants will complete in-session questionnaires assessing therapeutic alliance, motivation, acceptability, feasibility, and implementation. Following RC2S, the participants with SSD will repeat the same assessment as the baseline. Descriptive statistics will be used to summarize the data about acceptability, feasibility, safety, and implementation. To assess the preliminary effect of RC2S, an intention-to-treat approach will be used with linear mixed models for repeated measures with fixed effects of time. RESULTS: So far, 45% (9/20) of participants with SSD (mean age 37.9, SD 9.3 years) have completed the project. They received a mean of 20.5 out of 24 (SD 3.5) sessions of RC2S. A total of 5 therapists also completed the project. CONCLUSIONS: Improving social cognitive impairments is an important target in SSD to promote functional recovery. Using digital technologies to address these impairments and deliver the intervention is a promising approach to increase the ecological validity of CR and access to the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05017532; https://classic.clinicaltrials.gov/ct2/show/NCT05017532. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54251.

The role of motivation in clinical presentation, treatment engagement and response in schizophrenia-spectrum disorders: A systematic review.

Schizophrenia, a debilitating psychiatric disorder, has a long-term impact on social and occupational functioning. While negative symptoms, notably amotivation, are recognized as poor prognostic factors, the positive force of patient motivation (autonomous motivation) remains underexplored. This systematic review, guided by Self-Determination Theory (SDT), investigated the impact of motivation on clinical presentation, and treatment engagement and response in schizophrenia-spectrum disorders. Fifty-five independent studies (N = 6897), using 23 different motivation scales, met inclusion criteria. Results were categorized into cross-sectional and longitudinal correlates of autonomous motivation, and the effects of motivational interventions. Cross-sectionally, autonomous motivation was positively associated with social/occupational functioning, and negatively associated with negative and positive symptom severity. In longitudinal studies, baseline autonomous motivation predicted engagement in and response to social/occupational treatments, with mixed results in cognitive interventions. In the 16 randomized controlled trials (RCTs), the most common motivational interventions were individualized goal setting and goal attainment support, followed by increasing sense of competence by challenging defeatist beliefs, and enhancing relatedness by increasing contact time. Motivational interventions consistently increased autonomous motivation, treatment engagement and response. More studies are needed, particularly studies that monitor motivation during treatment: proximal assessments could facilitate the identification of treatment elements that impact motivation and engagement and inform treatment modifications to enhance the patient experience and improve treatment efficacy.

Using virtual reality to improve verbal episodic memory in schizophrenia: A proof-of-concept trial.

Background: Schizophrenia is associated with impairments in verbal episodic memory. Strategy for Semantic Association Memory (SESAME) training represents a promising cognitive remediation program to improve verbal episodic memory. Virtual reality (VR) may be a novel tool to increase the ecological validity and transfer of learned skills of traditional cognitive remediation programs. The present proof-of-concept study aimed to assess the feasibility, acceptability, and preliminary efficacy of a VR-based cognitive remediation module inspired by SESAME principles to improve the use of verbal episodic memory strategies in schizophrenia. Methods: Thirty individuals with schizophrenia/schizoaffective disorder completed this study. Participants were randomized to either a VR-based verbal episodic memory training condition inspired by SESAME principles (intervention group) or an active control condition (control group). In the training condition, a coach taught semantic encoding strategies (active rehearsal and semantic clustering) to help participants remember restaurant orders in VR. In the active control condition, participants completed visuospatial puzzles in VR. Attrition rate, participant experience ratings, and cybersickness questionnaires were used to assess feasibility and acceptability. Trial 1 of the Hopkins Verbal Learning Test - Revised was administered pre- and post-intervention to assess preliminary efficacy. Results: Feasibility was demonstrated by a low attrition rate (5.88 %), and acceptability was demonstrated by limited cybersickness and high levels of enjoyment. Although the increase in the number of semantic clusters used following the module did not reach conventional levels of statistical significance in the intervention group, it demonstrated a notable trend with a medium effect size (t = 1.48, p = 0.15, d = 0.54), in contrast to the control group where it remained stable (t = 0.36, p = 0.72, d = 0.13). These findings were similar for the semantic clustering ratio in the intervention (t = 1.61, p = 0.12, d = 0.59) and control (t = 0.36, p = 0.72, d = 0.13) groups. There was no significant change in the number of recalled words in either group following VR immersion. Discussion: This VR intervention was feasible, acceptable, and may be useful for improving the use of semantic encoding strategies. These findings support the use of more ecological approaches for the treatment of cognitive impairments in schizophrenia, such as VR-based cognitive remediation.

Sociodemographic and clinical correlates of hallucinations in patients entering an early intervention program for first episode psychosis.

Hallucinations are a core feature of psychosis, and their severity during the acute phase of illness is associated with a range of poor outcomes. Various clinical and sociodemographic factors may predict hallucinations and other positive psychotic symptoms in first episode psychosis (FEP). Despite this, the precise factors associated with hallucinations at first presentation to an early intervention service have not been extensively researched. Through detailed interviews and chart reviews, we investigated sociodemographic and clinical predictors in 636 minimally-medicated patients who entered PEPP-Montréal, an early intervention service for FEP, between 2003 and 2018. Hallucinations were measured using the Scale for the Assessment of Positive Symptoms (SAPS), while negative symptoms were assessed using the Scale for the Assessment of Negative symptoms (SANS). Depressive symptoms were evaluated through the Calgary Depression Scale for Schizophrenia (CDSS), and anxiety symptoms via the Hamilton Rating Scale for Anxiety (HAS). A majority (n = 381, 59.9 %) of the sample presented with clinically significant hallucinations (SAPS global hallucinations score ≥ 3) at program entry. These patients had an earlier age at onset, fewer years of education, and a higher severity of delusions, depression and negative symptoms than those without clinical-level hallucinations. These results suggest that individuals with clinically significant hallucinations at admission tend to be younger and have a greater overall symptom burden. This makes it especially important to monitor hallucinations alongside delusions, depression and negative symptoms in order to identify who might benefit from targeted interventions. The implications of these findings for early intervention and person-centered care are discussed.

Consistency of Delusion Themes Across First and Subsequent Episodes of Psychosis.

Importance: Despite growing interest in the phenomenology of delusions in psychosis, at present little is known about their content and evolution over time, including whether delusion themes are consistent across episodes. Objective: To examine the course of delusions and thematic delusion content across relapse episodes in patients presenting to an early intervention service for psychosis. Design, Setting, and Participants: This longitudinal, observational study used clinical data systematically collected from January 2003 to March 2018 from a cohort of consenting patients with affective or nonaffective first-episode psychosis, followed up naturalistically for up to 2 years in an early intervention service for psychosis in Montréal, Quebec, Canada. Data included the thematic content and severity of delusions (scores ≥3 using the Scale for the Assessment of Positive Symptoms) and associated psychotic and nonpsychotic symptoms, both across an initial episode and, in the event of remission, a potential relapse. Data were analyzed from September 2021 to February 2023. Exposure: An early intervention service for psychosis, organized around intensive case management and a multidisciplinary team approach, which observed each patient for up to 2 years of care. Main Outcomes and Measures: The primary outcome was positive symptom relapse and remission, including the presence and content of delusions, which was coded per the Scale for the Assessment of Positive Symptoms and accepted definitions. The main statistical measures included repeated paired-sample t tests and binary logistic regression analyses. Results: Of 636 consenting patients, mean (SD) age was 23.8 (4.75) years; 191 patients were female, 444 were male, and 1 patient was nonbinary. Remission rates were high, and relapse rates were relatively low: 591 individuals had baseline delusions, of which 558 (94.4%) achieved remission. Of these 558 patients, only 182 (32.6%) had a subsequent relapse to a second or later episode of psychosis. Of the 182 patients who did relapse, however, a large proportion (115 [63.2%]) reported threshold-level delusions. Of these 115, 104 patients (90.4%) had thematic delusion content consistent with that reported during the index (first) episode. Those who relapsed with delusions had fewer delusion themes present during subsequent episodes of psychosis compared with the index episode and lower levels of other psychotic and nonpsychotic symptoms. Conclusions and Relevance: Specialized early intervention services for psychosis can achieve high rates of sustained remission. However, in this study, the minority of individuals with delusions who later relapsed experienced similar delusion themes during subsequent episodes. These findings raise important considerations for the conceptualization of delusions and have clinical implications for trajectories of illness and care.

Speech markers to predict and prevent recurrent episodes of psychosis: A narrative overview and emerging opportunities.

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2-4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention.

Overlap between individual differences in cognition and symptoms of schizophrenia.

BACKGROUND: Neurocognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs), and the relationship between cognition and symptoms in SSDs has been widely researched. Negative symptoms are related to a wide range of cognitive impairments; however, the aspects of negative symptoms that underpin this relationship have yet to be specified. STUDY DESIGN: We used iterative Constrained Principal Component Analysis (iCPCA) to explore the relationship between 18 cognitive measures (including processing speed, attention, working, spatial and verbal memory and executive functions) and 46 symptoms in schizophrenia at the individual item level while minimizing the risk of Type I errors. ICPCA was conducted on a sample of SSD patients in the early stages of psychiatric treatment (n = 121) to determine the components of cognition overlapping with symptoms measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS). RESULTS: We found that a verbal memory component was associated with items from SANS and SAPS related to impoverished and disorganized emotional communication, language, and thought. In contrast, a working memory component was associated with SANS items related to motor system impoverishment. CONCLUSIONS: The iCPCA allowed us to explore the associations between individual items, optimized to understand the overlap between symptoms and cognition. The specific symptoms linked to verbal and working memory impairments imply distinct brain networks, which further investigation may lead to our deeper understanding of the illness and the development of treatment methods.

Manualized Group Cognitive-Behavioral Therapy for Social Anxiety in At-Risk Mental State and First Episode Psychosis: A Pilot Study of Feasibility and Outcomes.

Social anxiety has received scant attention in studies of schizophrenia and related psychoses. However, some data suggest it may be an obstacle to vocational and functional outcome. This pilot study investigated the feasibility of a group-based cognitive behavioral therapy (CBGT) to reduce social anxiety in those at risk for developing psychosis or in the early phase. Twenty-nine patients with first-episode psychosis (FEP) or at ultra high risk for developing psychosis or often referred to as at-risk mental state (ARMS) with comorbid social anxiety attended a CBGT intervention weekly for 14 weeks in 90-minute sessions. Baseline, post-treatment, and follow-up ratings of social anxiety were measured using the Social Interaction Anxiety Scale, the Social Phobia Inventory, and the Brief Social Phobia Scale. Psychotic symptoms and general psychopathology were also measured before and after the intervention. Results suggest that the proposed CBGT is feasible and beneficial for socially anxious patients at risk, or with experience of, psychosis. Participants significantly improved on three outcome measures of social anxiety after completing this intervention (all p's < .002). Participants who completed treatment also showed a significant reduction on measures of depression and negative symptoms. Future research should examine the relative efficacy of this brief manualized CBGT intervention for the treatment of social anxiety and psychotic symptoms in a larger randomized controlled trial.

Disfunción estructural del lóbulo temporal en pacientes con un primer episodio psicótico de esquizofrenia

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Abstract: Magnetic resonance imaging (MRI) has been useful in revealing subtle structural differences in the brains of schizophrenic patients compared with healthy controls. MR structural analyses have revealed a number of brain abnormalities including ventricular enlargement, total brain volume reduction, and regional reductions in brain volume in frontal, parietal and temporal regions. However, it is still unknown whether the brain abnormalities observed with MRI in schizophrenia are confounded by chronicity or whether there is a continual degenerative process. Evaluation of the brain structure during the first episode of psychosis (FEP) is a powerful strategy for investigating these fundamental questions. The first-episode design avoids the confusion of chronicity of illness, longstanding substance abuse, and the effects of treatment. Structural MRI studies of patients experiencing a first-episode psychosis have revealed a similar pattern of brain abnormalities as in samples of chronic patients, although deficits may be less extensive. The temporal lobe, a brain structure traditionally implicated in the pathophyisiology of schizophrenia, has been examined often in first-episode studies. Many studies have reported significant abnormalitites in the medial areas and superior temporal gyri. However, most studies examining the whole temporal lobe have been unable to show such significant abnormalities. In the light of the increasing amount of ambiguous findings regarding structural temporal lobe abnormalities in patients with schizophrenia experiencing their first-episode of psychosis, a quantitative review of the existing literature was needed to better characterize the temporal lobe deficits observed with MRI in those patients. Thus we conducted a systematic review of structural MRI studies of patients with first-episode schizophrenia in which volume measurements of temporal lobe structures were reported. Using meta-analytical methods, we carried out an analysis of the temporal lobe volumes in these FEP patients and the comparison subjects. In addition to solving the problems of traditional narrative reviews, a meta-analysis provides tools for integrating quantitative data from multiple studies, improving the overall effect size of variables of interest, and increasing statistical power. Eighteen studies were identified as suitable for the present analysis. These studies included 575 FEP patients and 738 control subjects. The average number of patients across studies was 32. The majority of patients in the studies were male (62%) and the average age of patients was 27 years old. In terms of structural brain findings, and assuming a volume of 100% in the comparison group, we found that the mean temporal volume of subjects with FEP was smaller (95%), as well as the analysis of regional structures such as left amygdala (95%), hippocampus-amygdala (left 92%, right 94%), hippocampus (left 85%, right 96%), and left temporal lobe (97%). Right temporal lobe volume was slightly greater (104%) and there was no difference in the volume of the right amygdala. Although this review was focused on evaluating the findings on temporal lobe deficits in patients with a first episode of psychosis, other brain region volumes were analyzed. The whole brain volume (95%) and frontal lobe volume (right 98%, left 99%) were lower in patients than in the comparison subjects. It is important to consider several potential limitations of this study. The first one has to do with the methodology employed to analyze structural MRI data. The method of choice in investigating the distribution of subtle cerebral pathology in schizophrenia has been an examination of anatomically defined regions of interest (ROI) within the brain. This method has some limitations, including the manual tracing of ROI on successive brain slices, a time consuming process that does not easily allow for the comparison of many brain regions or for the examination of volume differences in large samples of subjects. Furthermore, the question of validity is relevant as the ROI is investigator-determined and depends on the complex interindividual variability of the brain. The other method used in two studies included in this review is the voxel-based morphometry (VBM). This is an automated statistical method for examining structural MR images of the brain. VBM methodology makes voxel-wise comparisons of the local concentrations of grey matter between two groups of subjects and offers a more rapid and extensive survey of grey matter abnormalities in patients than ROI analysis. An important limitation of this methodology is that it has less regional sensitivity compared to the ROI technique and that these differences have to be considered in the interpretation of the results. Secondly, although our review only considered studies with patients experiencing a first episode of psychosis in schizophrenia (and not affective psychotic disorders), the fact that different investigators used somewhat different criteria when making their diagnoses could have introduced a potential bias in our inclusion process. Thus, it is possible that our results can not be generalized to the full population of first-episode patients. For instance, although most of the studies included used either DSM-IV diagnostic criteria (16 studies) or the Research Diagnostic Criteria (2 studies), variability may arise because many authors did not consider previous psychotic episodes in which patients were treated with antipsychotic medications for less than 30 days. In conclusion, this meta-analysis suggests that schizophrenic patients present temporal lobe differences, mainly diminished volume values in mesial temporal lobe structures during the initial presentation of a first episode of their illness. However, our results indicated that there was also evidence of global volume changes and regional volume decreases in the frontal lobes of these patients. This data, derived from patients in the early courses of their illness, is compatible with developmental hypotheses of schizophrenic abnormalities and with the view of schizophrenia as a neuropsychiatric disorder with marked deficits in the temporal lobes. However, the central questions in schizophrenia research regarding which brain abnormalities are independent of psychosis and which evolve before and after psychosis begins still remain unanswered. We think that these questions can be addressed by longitudinal neuroimaging studies beginning in the prodromal phase of the illness or by evaluating high-risk subjects during the critical period of transition to first-episode psychosis.