[Show abstract][Hide abstract] ABSTRACT: 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.
Schizophrenia Research 02/2012; 137(1-3):58-65. · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progressive loss of brain gray matter (GM) has been reported in childhood-onset schizophrenia; however, it is uncertain whether these changes are shared by pediatric patients with different psychoses.
To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up.
Prospective, multicenter, naturalistic, 2-year follow-up study.
Six child and adolescent psychiatric units in Spain.
A total of 110 patients and 98 healthy controls were recruited between March 1, 2003, and November 31, 2005. Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia (n = 25), bipolar disorder (n = 16), or other psychoses (n = 20) and 70 controls (both at baseline and after 2 years of follow-up). Mean age at baseline was 15.5 years (patients) and 15.3 years (controls).
The GM and cerebrospinal fluid (CSF) volumes in the total brain and frontal, parietal, and temporal lobes.
Compared with controls, patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2-year follow-up (left: -3.3 vs -0.6 cm(3), P = .004; right: -3.7 vs -0.8 cm(3), P = .005) and left frontal CSF volume increase (left: 6.7 vs 2.4 cm(3), P = .006). In addition to frontal volume, changes for total GM (-37.1 vs -14.5 cm(3), P = .001) and left parietal GM (-4.3 vs -2.2 cm(3), P = .04) were significantly different in schizophrenic patients compared with controls. No significant differences emerged for patients with bipolar disease. Greater left frontal GM volume loss was related to more weeks of hospitalization, whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia.
Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls. Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder. These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis.
Archives of general psychiatry 01/2012; 69(1):16-26. · 12.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
We compare raw cerebral blood volume (CBV) values obtained by MRI with normalized data using four different reference regions: mean cerebellum CBV, mean grey matter (GM) CBV, mean white matter (WM) CBV, and mean centrum semiovale CBV. These four data sets are used to analyze the differences between Alzheimer’s disease patients and controls.
METHOD AND MATERIALS
Three groups of subjects with a different level of clinical dementia rating (CDR) were included in the study: AD patients (CDR=1; n=12 mean age=78.2), MCI patients (CDR=0.5; n=19; mean age=70.7) and controls (CDR=0; n=16; mean age=72.3). MRI data were acquired on a 1.5 T system. The imaging protocol included an anatomical scan 3D GE T1-WI (1x1x1.5mm) and parametric maps of CBV using TSE T2-WI (1.8 x 1.8 x 5mm) after the injection of a bolus of gallium chelate. Quantification of CBV maps, we applied a semiautomatic method based on the Talairach proportional grid system that uses the anatomical information of structural MR images to segment CBV maps. This method allowed us to obtain volume and CBV data for the whole brain and for the frontal, and temporal lobes, for each hemisphere. Tissue segmentation was made using SPM2. The main criterion for a valid reference region is to show stable values across subjects and no group differences.
CBV values in the four regions of normalization considered in our study showed no differences between groups. The pattern of group differences, in CBV means, depends considerably on the choice of the reference region. In frontal and parietal lobes, patients showed hypo-perfusion when normalizing with cerebellum or WM. On the contrary, normalization with GM or centrum semiovale suggests hyper-perfusion. In the temporal lobe, normalized data showed hyper-perfusion in patients, whereas uncorrected data shows hypo-perfusion.
Description of differences between groups in CBV depends on the choice of the reference region for normalization. The cerebellum and whole brain white matter seem the most valid reference regions for normalization. MCI and AD patients showed hypo-perfusion in frontal and parietal lobes when compared to controls, whereas the opposite pattern is observed in the temporal lobe.
Perfusion MRI is a promising alternative to nuclear medicine in early detection of dementia. The large physiological variability between subjects makes normalization necessary for comparative analysis
Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 12/2011
[Show abstract][Hide abstract] ABSTRACT: Thalamic volume deficits are associated with psychosis but it is unclear whether the volume reduction is uniformly distributed or whether it is more severe in particular thalamic regions.
To quantify whole and regional thalamic volume in males with early-onset psychosis and healthy male controls.
Brain scans were obtained for 80 adolescents: 46 individuals with early-onset psychosis with a duration of positive symptoms less than 6 months and 34 healthy controls. All participants were younger than 19 years. Total thalamic volumes were assessed using FreeSurfer and FSL-FIRST, group comparisons of regional thalamic volumes were studied with a surface-based approach.
Total thalamic volume was smaller in participants with early-onset psychosis relative to controls. Regional thalamic volume reduction was most significant in the right anterior mediodorsal area and pulvinar.
In males with minimally treated early-onset psychosis, thalamic volume deficits may be most pronounced in the anterior mediodorsal and posterior pulvinar regions, adding strength to findings from post-mortem studies in adults with psychosis.
The British journal of psychiatry: the journal of mental science 11/2011; 200(1):30-6. · 6.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of the study is to determine the extent of structural brain abnormalities in a multicenter sample of children and adolescents with a recent-onset first episode of psychosis (FEP), compared with a sample of healthy controls. Total brain and lobar volumes and those of gray matter (GM), white matter, and cerebrospinal fluid (CSF) were measured in 92 patients with a FEP and in 94 controls, matched for age, gender, and years of education. Male patients (n = 64) showed several significant differences when compared with controls (n = 61). GM volume in male patients was reduced in the whole brain and in frontal and parietal lobes compared with controls. Total CSF volume and frontal, temporal, and right parietal CSF volumes were also increased in male patients. Within patients, those with a further diagnosis of "schizophrenia" or "other psychosis" showed a pattern similar to the group of all patients relative to controls. However, bipolar patients showed fewer differences relative to controls. In female patients, only the schizophrenia group showed differences relative to controls, in frontal CSF. GM deficit in male patients with a first episode correlated with negative symptoms. Our study suggests that at least part of the GM deficit in children and adolescent-onset schizophrenia and in other psychosis occurs before onset of the first positive symptoms and that, contrary to what has been shown in children-onset schizophrenia, frontal GM deficits are probably present from the first appearance of positive symptoms in children and adolescents.
[Show abstract][Hide abstract] ABSTRACT: Obsessive-compulsive disorder (OCD) emerges during childhood through young adulthood coinciding with the late phases of postnatal brain development when fine remodeling of brain anatomy takes place. Previous research has suggested the existence of subtle anatomical alterations in OCD involving focal volume variations in different brain regions including the frontal lobes and basal ganglia. We investigated whether anatomical changes might also involve variations in the shape of the frontobasal region. A total of 101 OCD patients and 101 control subjects were examined using magnetic resonance imaging. A cross-sectional image highly representative of frontal-basal ganglia anatomy was selected in each individual and 25 reliable anatomical landmarks were identified to assess shape changes. A pixel-wise morphing approach was also used to dynamically illustrate the findings. We found significant group differences for overall landmark position and for most individual landmarks delimiting the defined frontobasal region. OCD patients showed a deformation pattern involving shortening of the anterior-posterior dimension of the frontal lobes and basal ganglia, and enlargement of cerebrospinal fluid spaces around the frontal opercula. In addition, we observed significant correlation of brain tissue shape variation with frontal sinus size. Identification of a global change in the shape of the frontobasal region may further contribute to characterizing the nature of brain alterations in OCD. The coincidence of brain shape variations with morphological changes in the frontal sinus indicates a potential association of OCD to late development disturbances, as the frontal sinus macroscopically emerges during the transition between childhood and adulthood.
Human Brain Mapping 07/2011; 32(7):1100-8. · 6.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The main goal of this study was to investigate the neural substrates of fluid reasoning and visuospatial working memory in adolescents with precocious mathematical ability. The study population comprised two groups of adolescents: 13 math-gifted adolescents and 14 controls with average mathematical skills. Patterns of activation specific to reasoning tasks in math-gifted subjects were examined using functional magnetic resonance images acquired while the subjects were performing Raven's Advanced Progressive Matrices (RAPM) and the Tower of London (TOL) tasks. During the tasks, both groups showed significant activations in the frontoparietal network. In the math-gifted group, clusters of activation were always bilateral and more regions were recruited, especially in the right hemisphere. In the TOL task, math-gifted adolescents showed significant hyper-activations relative to controls in the precuneus, superior occipital lobe (BA 19), and medial temporal lobe (BA 39). The maximum differences between the groups were detected during RAPM tasks at the highest level of difficulty, where math-gifted subjects showed significant activations relative to controls in the right inferior parietal lobule (BA 40), anterior cingulated gyrus (BA 32), and frontal (BA 9, and BA 6) areas. Our results support the hypothesis that greater ability for complex mathematical reasoning may be related to more bilateral patterns of activation and that increased activation in the parietal and frontal regions of math-gifted adolescents is associated with enhanced skills in visuospatial processing and logical reasoning.
[Show abstract][Hide abstract] ABSTRACT: RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardio-facio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-RAF, MEK1, MEK2, and K-RAS. B-RAF is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-RafLSLV600E allele. This targeted allele allows low levels of expression of B-RafV600E, a constitutively active B-Raf kinase first identified in human melanoma. B-Raf+/LSLV600E mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf+/LSLV600E mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.
Proceedings of the National Academy of Sciences 03/2011; 108(12):5015-20. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence supports the important role of illness state and individual characteristics in insight.
Insight, as measured with the Scale to Assess Unawareness of Mental Disorder, over the first 2 years of early-onset first-episode psychosis and its correlations with clinical, socio-demographic, cognitive, and structural brain variables are studied.
(1) insight at 2 years is poorer in schizophrenia spectrum disorders (SSDs) than in subjects with other psychoses; (2) the more severe the psychosis, the worse the insight. In SSD, depressive symptoms, poorer baseline executive functioning, lower IQ, longer duration of untreated psychosis (DUP), and poorer premorbid infancy adjustment are associated with poorer insight; frontal and parietal gray matter (GM) reductions at baseline correlate with worse insight into having psychotic symptoms at 2 years; (3) insight into having a mental disorder (Scale to Assess Unawareness of Mental Disorder [SUMD]1) at 1 year, DUP, and baseline IQ are the most consistent variables explaining different aspects of insight at 2 years in SSD patients. IQ and SUMD1 at 1 year, together with left frontal and parietal GM volumes, explain 80% of the variance of insight into having specific psychotic symptoms in SSD patients (adjusted R(2) = 0.795, F = 15.576, P < .001).
Insight is a complex phenomenon that depends both on severity of psychopathology and also on disease and subject characteristics, such as past adjustment, IQ, DUP, cognitive functioning, frontal and parietal GM volumes, and age, gender, and ethnicity.
[Show abstract][Hide abstract] ABSTRACT: Adolescents with first-episode psychosis have increased severity of neurological soft signs when compared with controls, but it is unclear whether increased severity of neurological soft signs is an expression of specific structural brain deficits.
To examine whether increased severity of neurological soft signs was associated with decreased brain volumes in adolescents with first-episode psychosis.
Brain scans were obtained for 70 adolescents (less than 18 years of age) with first-episode psychosis (duration of positive symptoms less than 6 months). Volumes were assessed using voxel-based morphometry and through segmentation of anatomical structures.
Increased severity of sensory integration neurological soft signs correlated with smaller right and left thalamus volume, whereas increased severity of sequencing of complex motor acts neurological soft signs correlated with smaller right caudate volume.
Neurological soft signs may be an easy-to-assess marker of region-specific structural brain deficits in adolescents with first-episode psychosis.
The British journal of psychiatry: the journal of mental science 10/2009; 195(3):227-33. · 6.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psychosis is associated with volumetric decreases of cortical structures. Whether these volumetric decreases imply abnormalities in cortical thickness, surface, or cortical folding is not clear. Due to differences in cytoarchitecture, cortical gyri and sulci might be differentially affected by psychosis. Therefore, we examined differences in gyral and sulcal cortical thickness, surface, folding, and volume between a minimally treated male adolescent population with early-onset first-episode psychosis (EOP) and a healthy control group, with surface-based morphometry.
Magnetic resonance imaging brain scans were obtained from 49 adolescent EOP patients and 34 healthy control subjects. Subjects were younger than 18 years (age range 12 years-18 years), and EOP patients had a duration of positive symptoms of <6 months.
Early-onset first-episode psychosis was associated with local bilateral cortical thinning and volume deficits in both the gyri and sulci of the superior temporal cortex and the inferior, middle, medial, and superior prefrontal cortex. In the pars triangularis and opercularis cortex of patients, gyral cortical thickness was thinner, whereas sulcal thickness was not. Patients exhibited cortical thinning together with a decreased degree of cortical folding in the right superior frontal cortex.
Cortical thinning of both gyri and sulci seem to underlie most cortical volume deficits in adolescent patients with EOP. Except for the right superior frontal region, the degree of cortical folding was normal in regions showing decreased cortical thickness, suggesting that the process of cortical thinning in adolescent patients with EOP primarily takes place after the formation of cortical folds.
[Show abstract][Hide abstract] ABSTRACT: IBASPM software is an atlas-based method for automatic segmentation of brain structures, available as a freeware toolbox for the SPM package. To test the influence of the atlas when segmenting normal and pathologic brains, manual segmentation of the caudate nucleus head was compared to automatic segmentations using four different atlases: the default MNI AAL atlas; a customized atlas created from a combined sample of patients (n=20) and controls (n=18); and a customized atlas obtained separately for each group. Maximum average ratio of overlapping voxels (dice overlap) between manual and automatic segmentation was 71% for controls and 52% for patients. In both groups, overlap ratios were better when using the customized atlases, instead of the standard MNI AAL atlas. Accuracy of the method was biased between left and right hemispheres, and also between groups, individual variability being higher in patients than in controls. Volumetric measurements using the customized atlases were also more accurate than using the MNI AAL atlas. Volume data were closer to manual segmentation values than dice overlap ratio (average differences ranging from 22.7% for MNI AAL atlas to 10.1% for customized atlas of patients and controls combined). Results suggests a low overall performance of IBASPM as an automatic segmentation method for the head of the caudate nucleus. Because of the biases observed, the use of this method for analyzing caudate nucleus in patients presenting anatomical abnormalities should be cautiously carried out.
[Show abstract][Hide abstract] ABSTRACT: Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin-1 (IL-1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL-1 cluster on brain morphology in bipolar disorder. Genetic variability at IL-1B and IL-1RN genes was analyzed in 20 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole-brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A -511C/T polymorphism (rs16944) of IL-1B gene was associated with whole-brain GM deficits (P = 0.031) and left DLPFCGM deficits (P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL-1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.
Genes Brain and Behavior 11/2008; 7(7):796-801. · 3.60 Impact Factor