I. Baeza

Sustained attention impairment correlates to gray matter decreases in first episode neuroleptic-naive schizophrenic patients

Impaired sustained attention seems to be a specific neuropsychological deficit that is closely linked to schizophrenia. Voxel based morphometry has emerged as a useful tool for the detection of subtle gray matter (GM) abnormalities. The aim of our study was to identify the cerebral regions related to the Identical-Pair version of the Continuous Performance Test (CPT-IP) performance in schizophrenic patients. The study included 13 right-handed, male, first-episode, paranoic, neuroleptic-naive schizophrenic patients and 13 matched controls. High-resolution whole-brain MR images were segmented and analyzed for the whole brain and for regions of interest (ROI) using SPM99. Furthermore, the correlation between CPT-IP performance and GM density was examined. Volumetric analysis of the thalami was also carried out. GM density analysis shown decreases in patients in anterior cingulate gyrus, left inferior frontal, right claustrum, left pulvinar, and dorsomedial bilateral thalamic nuclei, and caudate nuclei as well as left hippocampus and parahippocampal gyrus. Thalamic ROIs revealed a strong correlation between groups differences. The thalamic GM density allowed a good individual classification. GM increases were detected in left insula, superior temporal gyrus, and putamen nucleus, and right supramarginal gyrus. Schizophrenic patients showed smaller left and right thalamic volumes. We found that GM density of the left thalamic nucleus, left angular, and supramarginal gyrus, and left inferior frontal and postcentral gyri correlated significantly with CPT-IP performance in patients but not in controls. Moreover, the restricted ROIs regression was strongly significant for both left and right thalamus. In summary, we provide evidence for the involvement of thalamic, inferior-parietal, and frontal regions in the attentional deficits observed in schizophrenic patients.

Decreased cerebral activation during CPT performance: structural and functional deficits in schizophrenic patients

Voxel-based morphometry (VBM) allows the output of structural data in a Statistical Parametric Map of the brain in the same way that the SPM can do with functional data. Using functional magnetic resonance (fMR), we studied brain activation in 14 patients with schizophrenia and 14 matched normal controls. We found significant hypoactivation in patients in several regions, especially in the right hemisphere, in the dorsolateral frontal and temporal regions and in the inferior parietal. Subcortically, we found strong hypoactivity in the thalamus. The optimized VBM method revealed gray matter (GM) abnormalities in the bilateral supramarginal gyrus and cingulate cortex, and in the right inferior temporal regions. Three regions involved in attentional processes showed both structural and functional deficits: the thalamus, the anterior cingulate and the inferior parietal. The results suggest that these regions may be involved in the attentional deficit in schizophrenia.

The child and adolescent first-episode psychosis study (CAFEPS): Design and baseline results ☆

OBJECTIVE The child and adolescent first-episode psychosis study (CAFEPS) is a multicenter, two-year, longitudinal project aiming to evaluate different clinical, neuropsychological, neuroimaging, biochemical, immunological, and genetic variables and treatment and prognostic factors in these patients. This paper describes the methods and rationale behind the study and the general characteristics of the sample. METHOD At six different centers, from March 2003 through November 2005, we consecutively recruited 110 patients, ages 9-17 years, who presented with a first psychotic episode. Controls were recruited from the same geographic areas and were matched for gender and age. RESULTS Patients had lower socioeconomic status (SES) (p=0.018) and parental years of education (p<0.001) than controls. The percentage of patients recruited increased with age (p<0.001) and there was a higher percentage of males (p<0.001). The total mean PANSS score was 89.03+/-20.1, the positive score 23.8+/-6.5 and the negative score 20.02+/-8.8. There were no significant differences between the genders with respect to age, parental years of education, SES, or scores in premorbid adjustment or general functioning. There were statistically significant positive correlations between age and positive symptoms and between all PANSS subscales and the Disability Assessment Schedule, and negative correlations between positive symptoms and global functioning. Diagnoses after the baseline evaluation were: psychotic disorder not otherwise specified (NOS) 35.5%, schizophreniform disorder 24.5%, mood disorder with psychotic symptoms 22.7%, schizophrenia 10%, schizoaffective disorder 2.7%, and other psychotic disorders 4.5%. Patients had worse premorbid adjustment (p<0.001) and global functioning (p<0.001) than controls after controlling for SES. CONCLUSIONS Infancy and adolescence adjustment and global functioning are lower in children and adolescents with psychotic disorders than in controls, severity of symptoms are related to general disability, and the most frequent diagnoses are psychotic disorders NOS.

Volume changes in gray matter in first-episode neuroleptic-naive schizophrenic patients treated with risperidone.

Abstract: Structural neuroimaging techniques have consistently shown that treatment of schizophrenic patients with conventional antipsychotics causes an increase in basal ganglia volume. However, findings in schizophrenic patients treated with the newer atypical antipsychotic drugs are less consistently reported. To explore this issue, the authors used a whole-brain, unbiased, and automated technique for comparing brain structural features across scans in schizophrenic patients before and after a treatment with the atypical antipsychotic risperidone. T1-weighted images from 11 first-episode neuroleptic-naive schizophrenic patients were processed and analyzed for regions of interest (basal ganglia) by using optimized voxel-based morphometry. Scans were repeated after 3 months of continuous treatment with risperidone. Region of interest-based voxel-based morphometry analyses revealed increases in gray matter volume for the right and left caudate nuclei and for the left accumbens after the treatment with risperidone. Hence, in our sample of schizophrenic patients, treatment with risperidone was associated, in contrast to the findings for other atypical antipsychotics, with an increase in basal ganglia volume. Such discrepancy could be related to the pharmacodynamics of risperidone (the atypical antipsychotic showing the higher affinity for D2 receptors) and the rather high mean doses used in our study (ie, 6.05 mg/d).

Antipsychotic Treatment in Child and Adolescent First-Episode Psychosis: A Longitudinal Naturalistic Approach

OBJECTIVE The Child and Adolescent First-Episode Psychosis Study (CAFEPS) is a naturalistic longitudinal study of early-onset first psychotic episodes. This report describes the antipsychotic treatment during the first year and compares the most frequently used agents after 6 months. METHODS Participants were 110 patients, aged 9-17 years, with a first psychotic episode attended consecutively at six different centers. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impressions (CGI), Disability Assessment Schedule (DAS), and Global Assessment of Function (GAF) scales were administered at baseline and at 6 months and the Udvalg for Kliniske Undersøgelser (UKU) Side Effects Rating Scale only at 6 months. RESULTS Diagnoses at baseline were 38.2% psychotic disorder not otherwise specified, 39.1% schizophrenia-type disorder, 11.8% depressive disorder with psychotic symptoms, and 10.9% bipolar disorder, manic episode with psychotic symptoms. The most frequently used antipsychotic agents were risperidone (n = 50), quetiapine (n = 18), and olanzapine (n = 16). Patients who were prescribed olanzapine or quetiapine had more negative and general symptoms. Using the baseline score as covariate, no significant differences were found in the reductions on any scale in patients treated with risperidone, quetiapine, or olanzapine for 6 months. Weight increase was greater with olanzapine than with risperidone (p = 0.020) or quetiapine (p = 0.040). More neurological side effects appeared with risperidone than with olanzapine (p = 0.022). All side effects were mild or moderate. CONCLUSIONS Second-generation antipsychotics, especially risperidone, quetiapine, and olanzapine, are the most used in our context in first psychotic episodes in children and adolescents. These three obtain similar clinical improvement, but differ in their side effects.

The Human Cerebral Cortex Flattens during Adolescence

The human cerebral cortex appears to shrink during adolescence. To delineate the dynamic morphological changes involved in this process, 52 healthy male and female adolescents (11–17 years old) were neuroimaged twice using magnetic resonance imaging, approximately 2 years apart. Using a novel morphometric analysis procedure combining the FreeSurfer and BrainVisa image software suites, we quantified global and lobar change in cortical thickness, outer surface area, the gyrification index, the average Euclidean distance between opposing sides of the white matter surface (gyral white matter thickness), the convex (“exposed”) part of the outer cortical surface (hull surface area), sulcal length, depth, and width. We found that the cortical surface flattens during adolescence. Flattening was strongest in the frontal and occipital cortices, in which significant sulcal widening and decreased sulcal depth co-occurred. Globally, sulcal widening was associated with cortical thinning and, for the frontal cortex, with loss of surface area. For the other cortical lobes, thinning was related to gyral white matter expansion. The overall flattening of the macrostructural three-dimensional architecture of the human cortex during adolescence thus involves changes in gray matter and effects of the maturation of white matter.

Decreased glutathione levels predict loss of brain volume in children and adolescents with first-episode psychosis in a two-year longitudinal study

Progressive loss of cortical gray matter (GM), as measured by magnetic resonance imaging, has been described early in the course of first-episode psychosis. This study aims to assess the relationship between oxidative balance and progression of cortical GM changes in a multicenter sample of first-episode early-onset psychosis (EOP) patients from baseline to two-year follow-up. A total of 48 patients (13 females, mean age 15.9±1.5 years) and 56 age- and gender-matched healthy controls (19 females, 15.3±1.5 years) were assessed. Magnetic resonance imaging (MRI) scans performed both at the time of the first psychotic episode and 2 years later were used for volumetric measurements of left and right gray matter regions (frontal, parietal, and temporal lobes) and total sulcal cerebrospinal fluid (CSF). Total glutathione (GSH) blood levels were determined at baseline. In patients, after controlling for possible confounding variables, lower baseline GSH levels were significantly associated with greater volume decrease in left frontal (B=0.034, 95% confidence interval (CI): 0.011 to 0.056, r=0.620, p=0.006), parietal (B=0.039, 95% CI: 0.020 to 0.059, r=0.739, p=0.001), temporal (B=0.026, 95% CI: 0.016 to 0.036, r=0.779, p<0.001), and total (B=0.022, 95% CI: 0.014 to 0.031, r=0.803, p<0.001) gray matter, and with greater increase in total CSF (B=-0.560, 95% CI: -0.270 to -0.850, r=-0.722, p=0.001). Controls did not show significant associations between brain volume changes and GSH levels. GSH deficit during the first psychotic episode was related to greater loss of cortical GM two years later in patients with first-episode EOP, suggesting that oxidative damage may contribute to the progressive loss of cortical GM found in patients with first-episode psychosis.

Neuropsychological evidence for abnormal neurodevelopment associated with early-onset psychoses

BACKGROUND The longitudinal neuropsychological study of first-episode early-onset psychosis (EOP) patients, whose brain maturation is still in progress at the time of illness onset, provides a unique opportunity to compare their cognitive development with that of healthy subjects, in search of specific patterns resulting from the interaction between neurodevelopmental processes and the presence of psychotic disorders. Method Seventy-five first-episode EOP patients (schizophrenia n = 35; bipolar disorder n = 17; other forms of psychosis n = 23) with a mean age of 15.53 years were assessed with a neuropsychological battery that included measures of attention, working memory, memory and executive functions within 6 months following the onset of the first psychotic symptom (baseline) and 2 years later. Psychotic symptoms were assessed at both times with the Positive and Negative Symptom Scale (PANSS). Seventy-nine healthy subjects matched for age and education served as controls. RESULTS EOP patients showed significant cognitive impairment at both baseline and the 2-year follow-up, with no significant differences between diagnostic groups at either time. Both healthy controls and EOP patients improved in all cognitive measures, except for patient working memory. Improvement in patient attention lost significance after controlling for psychotic symptom reduction. No significant time/diagnosis interaction was found among patients (p > 0.405). CONCLUSIONS Cognitive impairment in EOP is already present at the first episode, and cognitive development seems to be arrested early in EOP patients compared to their healthy peers, at least for some cognitive functions. These and previous similar results support the neurodevelopmental hypothesis of psychosis.

Two-year diagnostic stability in early-onset first-episode psychosis.

BACKGROUND Only one study has used a prospective method to analyze the diagnostic stability of first psychotic episodes in children and adolescents. The Child and Adolescent First-Episode Psychosis Study (CAFEPS) is a 2-year, prospective longitudinal study of early-onset first episodes of psychosis (EO-FEP). AIM To describe diagnostic stability and the variables related to diagnostic changes. METHODS Participants were 83 patients (aged 9-17 years) with an EO-FEP consecutively attended. They were assessed with a structured interview (Kiddie-Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version) and clinical scales at baseline and after 2 years. RESULTS The global consistency for all diagnoses was 63.9%. The small group of bipolar disorder had high stability (92.31%) as did the group with schizophrenia spectrum disorders (90.00%). Depressive disorder had lower stability (37.50%) and the lowest values were for psychotic disorder not otherwise specified (11.76%) and brief psychotic disorder (0%).The most frequent diagnostic shift was to schizophrenia spectrum and bipolar disorders. One group of patients did not meet the criteria for any diagnosis at follow-up. Independent predictors of change to schizophrenia spectrum disorders were lower scores on the Childrens Global Assessment Scale (CGAS) and the Hamilton Depression Rating Scale. Predictors of not having a diagnosis at follow-up were the CGAS and the Strauss-Carpenter Outcome Scale. CONCLUSIONS Global diagnostic stability was 63.9%. Bipolar and schizophrenia spectrum disorders were the most stable diagnoses, while depressive disorder and other psychosis the least stable. Psychosocial functioning at baseline was a good predictor of diagnosis at follow-up. These data show the need for longitudinal follow-up in EO-FEP before a stable diagnosis is reached.

Schizophrenia and frontal cortex: Where does it fail?

Schizophrenia is characterized by cognitive, social, and emotional impairments and by psychotic symptoms. Neuroimaging studies have reported abnormalities within the prefrontal cortex and it has been hypothesized that schizophrenia results from poor or miswired anatomical/functional connections. We have compared the functional connectivity within the frontal cortex in control and schizophrenic subjects during the realization of a Continuous Performance Task. The connectivity pattern within the frontal cortex was uncovered by the analysis of the correlation matrix computed from the fMRI time series in frontal areas for 14 schizophrenic patients and 14 control subjects. In control subjects, the right dorsolateral prefrontal cortex (DLFCr) activity correlated i) positively with the left dorsolateral prefrontal cortex and the posterior part of the supplementary motor area, ii) negatively with the medial and anterior/inferior part of the frontal cortex. In the schizophrenic group, these relations were abolished or strongly lowered. The negative relation between the DLFCr and the medial frontal cortex has been proposed to play a key role in setting a harmonious balance between the direction of attention to the external world and the expression of the individual believes and self-referential activities, and therefore, the impaired relation of right DLFCr with other frontal areas could explain a distorted perception of external world in relation with internal motivations.