Showing papers by "Andrea Mechelli published in 2011"

Resting-state functional connectivity in treatment-resistant depression.

Abstract: Objective: The authors used resting-state functional connectivity MRI to evaluate brain networks in patients with refractory and nonrefractory major depressive disorder

Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study.

Abstract: Context People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent. Objective To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites. Design Case-control study. Setting Multisite. Participants A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not. Main Outcome Measures Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry. Results The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not. Conclusions Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.

Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis.

Abstract: Context Alterations in glutamatergic neurotransmission and cerebral cortical dysfunction are thought to be central to the pathophysiology of psychosis, but the relationship between these 2 factors is unclear. Objective To investigate the relationship between brain glutamate levels and cortical response during executive functioning in people at high risk for psychosis (ie, with an at-risk mental state [ARMS]). Design Subjects were studied using functional magnetic resonance imaging while they performed a verbal fluency task, and proton magnetic resonance spectroscopy was used to measure their brain regional glutamate levels. Setting Maudsley Hospital, London, England. Patients and Other Participants A total of 41 subjects: 24 subjects with an ARMS and 17 healthy volunteers (controls). Main Outcome Measures Regional brain activation (blood oxygen level–dependent response); levels of glutamate in the anterior cingulate, left thalamus, and left hippocampus; and psychopathology ratings at the time of scanning. Results During the verbal fluency task, subjects with an ARMS showed greater activation than did controls in the middle frontal gyrus bilaterally. Thalamic glutamate levels were lower in the ARMS group than in control group. Within the ARMS group, thalamic glutamate levels were negatively associated with activation in the right dorsolateral prefrontal and left orbitofrontal cortex, but positively associated with activation in the right hippocampus and in the temporal cortex bilaterally. There was also a significant group difference in the relationship between cortical activation and thalamic glutamate levels, with the control group showing correlations in the opposite direction to those in the ARMS group in the prefrontal cortex and in the right hippocampus and superior temporal gyrus. Conclusions Altered prefrontal, hippocampal, and temporal function in people with an ARMS is related to a reduction in thalamic glutamate levels, and this relationship is different from that in healthy controls.

Effects of stressful life events on human brain structure: A longitudinal voxel-based morphometry study

Abstract: Although stressful life events (SLEs) have been associated with an increased risk of illness and mental disorder, their impact on brain anatomy remains poorly understood. Using a longitudinal design, we tested the hypothesis that SLEs are significantly associated with changes in gray matter volume (GMV) in brain regions previously implicated in post-traumatic stress disorder (PTSD) in a group of clinically healthy adults. Magnetic resonance imaging was used to acquire an anatomical scan from 26 subjects (13 males and 13 females; mean age ± SD: 25.2 ± 4.3 years), with no psychiatric diagnosis, at two time points with a 3-month interval. Voxel-based morphometry was used to examine an association between SLEs and gray matter changes during this period. The number of SLEs was associated with a decrease in GMV in the anterior cingulate, hippocampus, and parahippocampal gyrus (p < 0.001). In contrast, there were no areas where the number of SLEs was associated with an increase in GMV. These results provide evidence that, in adults with no formal psychiatric diagnosis, SLEs are associated with GMV decreases in a subset of regions implicated in PTSD, and that these alterations can be observed within a period as short as 3 months.

Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first-episode psychosis

Abstract: Background: Superior temporal lobe dysfunction is a robust finding in functional neuroimaging studies of schizophrenia and is thought to be related to a disruption of fronto-temporal functional connectivity. However, the stage of the disorder at which these functional alterations Occur is unclear. We addressed this issue by using functional MRI (fMRI) to Study Subjects in the prodromal and first episode phases of schizophrenia. Methods: Subjects with an at risk mental state (ARMS) for psychosis, a first psychotic episode (FEP), and controls were studied using fMRI while performing a working memory task. Activation in the Superior temporal gyrus (STG) was assessed using statistical parametric mapping, and its relationship to frontal activation was examined using dynamic causal modeling. Results: The STG was differentially engaged across the three groups. There was deactivation of this region during the task in controls, whereas Subjects with FEP showed activation and the response in subjects with ARMS was intermediately relative to the two other groups. There were corresponding differences in the effective connectivity between the STG and the middle frontal gyrus across the three groups, with a negative coupling between these areas in controls, a positive coupling in the FEP group, and an intermediate value in the ARMS group. Conclusions: A failure to deactivate the superior temporal lobe during tasks that engage prefrontal cortex is evident at the onset of schizophrenia and may reflect a disruption of fronto-temporal connectivity. Qualitatively similar alterations are evident in people with prodromal symptoms of the disorder. Hum Brain Mapp 30:4129-4137, 2009. (C) 2009 Wiley-Liss, Inc.

Altered Medial Temporal Activation Related to Local Glutamate Levels in Subjects with Prodromal Signs of

Abstract: Both medial temporal cortical dysfunction and perturbed glutamatergic neurotransmission are regarded as fundamentalpathophysiological features of psychosis. However, although animal models of psychosis suggest that these two abnormalities areinterrelated,theirrelationshipinhumanshasyettobeinvestigated.

Prefrontal function at presentation directly related to clinical outcome in people at ultrahigh risk of psychosis

Abstract: Background: The prodromal phase of psychosis is characterized by impaired executive function and altered prefrontal activation. The extent to which the severity of these deficits at presentation predicts subsequent clinical outcomes is unclear. Methods: We employed functional magnetic resonance imaging in a cohort of subjects at clinical risk for psychosis and in healthy controls. Images were acquired at clinical presentation and again after 1 year, using a 1.5-T Signa MRI scanner while subjects were performing a verbal fluency task. SPM5 was used for the analysis of imaging data. Psychopathological assessment of the "at-risk" symptoms was performed by using the Comprehensive Assessment for the At-Risk Mental State (CAARMS) and the Positive and Negative Symptom Scale (PANSS). Results: In the at-risk mental state (ARMS) group, between presentation and follow-up, the CAARMS (perceptual disorder and thought disorder subscales) and the PANSS general scores decreased, while the Global Assessment of Functioning (GAF) score increased. Both the ARMS and control groups performed the verbal fluency task with a high degree of accuracy. The ARMS group showed greater activation in the left inferior frontal gyrus but less activation in the anterior cingulate gyrus than controls. Within the ARMS group, the longitudinal normalization of neurofunctional response in the left inferior frontal gyrus was positively correlated with the improvement in severity of hallucination-like experiences. Conclusions: The normalization of the abnormal prefrontal response during executive functioning is associated with 12-month psychopathological improvement of prodromal symptoms.

Structural covariance in the cortex of very preterm adolescents: a voxel-based morphometry study

Abstract: On the basis of findings in normative samples that different cortical brain regions covary in gray matter volume, most likely as a result of mutually trophic influences during cortical development, we aimed to study whether patterns of covariation in regional gray matter, i.e., structural covariance, differed between adolescents who were born very preterm and full-term controls. Optimized voxel-based morphometry was used to study structural magnetic resonance imaging scans from 218 very preterm adolescents (gestational age <33 weeks) and 127 controls at 14-15 years of age. Local gray matter volumes were obtained for 18 regions of interest involved in sensorimotor and higher-order cognitive functions. These were then used to predict local volumes in the remaining areas of the cortex, with total gray matter volume, age and gender used as confounding variables. Very preterm adolescents compared with controls demonstrated differential (i.e., both increased and decreased) structural covariance between medial, frontal and cingulate gyri, caudate nucleus, thalamus, primary visual cortex, cerebellum and several other cortical and subcortical regions of the cortex. These findings support previous research indicating that preterm birth is associated with altered cortical development, and suggest that developmental changes in one brain region may result in a cascade of alterations in multiple regions.

Structural brain abnormalities in first-episode psychosis: differences between affective psychoses and schizophrenia and relationship to clinical outcome.

Abstract: de Castro-Manglano P, Mechelli A, Soutullo C, Landecho I, Gimenez-Amaya JM, Ortuno F, McGuire P. Structural brain abnormalities in first-episode psychosis: differences between affective psychoses and schizophrenia and relationship to clinical outcome. Bipolar Disord 2011: 13: 545–555. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Several studies have described volumetric brain abnormalities in first-episode psychosis. The extent to which these differ in patients with schizophrenia and affective psychoses, or are related to subsequent clinical outcome, is unclear. We examined volumetric magnetic resonance imaging (MRI) abnormalities in young patients with a first episode of psychosis, and compared these volumetric abnormalities in patients with schizophrenia versus affective psychosis. We then assessed whether baseline MRI abnormalities in the entire sample predicted subsequent clinical outcome. Methods: A total of 28 adolescent patients with first-episode psychosis and 20 age-matched healthy volunteers were scanned using a 1.5 T scanner. MRI data were processed and analysed using voxel-based morphometry (VBM). We assessed clinical outcome three years after the initial scan. Results: Patients had smaller grey matter (GM) volumes than controls in frontal, insular, parietal, and cerebellar cortex. Patients with an affective psychosis had greater GM volume in the right posterior cingulate than both controls and patients with schizophrenia, but less GM volume in the left cerebellum and insula. In the sample as a whole, smaller right hippocampus GM volume was associated with poor clinical outcome at three-year follow-up. Conclusions: Volumetric brain abnormalities are evident in young adults presenting with a first episode of both affective psychoses and schizophrenia, but there are also significant differences between these two patient groups. Clinical outcome after the first episode may be related to the severity of volumetric abnormalities at presentation.

Small, but not perfectly formed: decreased white matter concentration in boys with psychopathic tendencies

Abstract: Neuroimaging studies on adult psychopaths have shown white matter abnormalities in fronto-temporal neural circuitry critical for emotional processing, but it is not known if children who show psychopathic tendencies exhibit white matter abnormalities. In this study, we found that boys with psychopathic tendencies showed decreased white matter concentration (WMC) compared with typically developing boys.

Forensic neurosciences: from basic research to applications and pitfalls

Abstract: PURPOSE OF REVIEW In recent years, there has been growing interest in the application of genetic and neuroscientific methods to the investigation of the criminal mind. Here we summarize the results of recent studies and discuss their potential implications for the criminal system. RECENT FINDINGS The results of studies published so far have implications for theoretical aspects of the law. For example, a series of studies have indicated that conscious sense of volition may not be a driving force in the initiation of willed behavior but rather may arise as a consequence of such behavior. According to some, this challenges the very notion of conscious will on which the criminal system is based. The results also have implications for practical aspects of the law. For instance, genetic and neuroscientific methods may provide objective, biological data which can be used to reduce controversy in forensic psychiatric evaluations of mental insanity and minimize errors in detecting malingering. Another potential practical application is lie and memory detection, which at present appears to be susceptible to countermeasures. SUMMARY Genetic and neuroimaging techniques may provide information which, when considered in combination with other sources of evidence, might prove useful in advancing knowledge about mens rea.

Longitudinal changes in brain structure following the first episode of psychosis.

Abstract: Both schizophrenia and bipolar disorder have been associated with progressive changes in grey matter (GM) volume. However, the temporal trajectories of these changes are poorly understood. The aim of this study was to assess longitudinal changes in grey matter volume subsequent to the first episode of schizophrenia and of affective psychoses. Adolescent patients with a first episode psychosis (n=26) were scanned twice using magnetic resonance imaging, at first presentation and after a 3-year follow-up period. An age-matched group of healthy volunteers (n=17) was scanned at the same time points. Within-group and between-group changes in regional grey matter volume were examined using voxel-based morphometry. There were significant group by time interactions (p(FDRcorr)<0.05) in the frontal, temporal, parietal, cerebellar cortex, and in the thalamus, mainly reflecting longitudinal reductions in the controls but not in the patients. Subdivision of the patient group revealed that there were similar longitudinal reductions in patients with affective psychoses as in the controls but no volumetric changes in patients with schizophrenia. Psychosis with onset in adolescence or early adulthood may be associated with a delay or a loss of longitudinal reductions in regional grey matter volume that normally occur at this stage of development. These changes may be specific to schizophrenia.

No association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder

Abstract: The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.

Effects of DTNBP1 genotype on brain development in children.

Abstract: Background: Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin-binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain development is poorly understood. The present investigation examined for the first time the effects of DTNBP1 on brain structure in children. Our hypothesis was that a genetic variation in DTNBP1 (i.e., the single nucleotide polymorphism rs2619538) would be associated with differences in both gray and white matter brain regions previously implicated in schizophrenia. Methods: Magnetic resonance imaging and voxel-based morphometry were used to examine brain structure in 52 male children aged between 10 and 12 years. Statistical inferences on the effects of DTNBP1 genotype on gray and white matter volume (GMV and WMV) were made at p < .05 after family-wise error correction for multiple comparisons across the whole brain. Results: Individuals homozygous for the schizophrenia high-risk allele (AA) compared with those homozygous for the low-risk allele (TT) expressed reduced GMV in the left anterior cingulate gyrus and reduced WMV in the left medial frontal area. Conclusions: Our results suggest that genetic variation in DTNBP1 is associated with differences in gray and white matter; and that these effects are already evident in children as young as 10–12 years. These findings are consistent with the notion that the DTNBP1 genotype influences brain development and may thereby modulate vulnerability to schizophrenia.