Papers by Sergi Costafreda
Journal of clinical …, 1998
Epidemiologic studies on exocrine pancreatic cancer show a large heterogeneity in diagnostic crit... more Epidemiologic studies on exocrine pancreatic cancer show a large heterogeneity in diagnostic criteria applied to define "caseness." Reanalyses conducted after review of diagnostic information have yielded substantially different results than those based on more crude classifications of disease. During a multicenter prospective study on mutations in the K-ras gene in pancreatic and biliary diseases, hospital diagnoses from 602 patients were reviewed by a panel of experts. There were two main motivations to do so: a generic interest for the quality of the diagnostic data, and the anticipation that a firm diagnosis could be needed to assess whether patients whose tumors did not harbor the mutation were true negatives or false negatives. In addition, the review of diagnoses was helpful to minimize tissue misclassification, and it had a high educational value for clinicians and epidemiologists. This article illustrates why and how this was so through a brief presentation of the 10 most significant cases. With respect to selection and classification of subjects, the main issues that studies on pancreatic cancer need to address are the differential diagnosis of exocrine pancreatic cancer and pancreatitis, the differential diagnosis of exocrine pancreatic cancer and other abdominal tumors, and the use of survival as a hallmark of pancreatic cancer. In epidemiologic studies of pancreatic cancer, it is warranted that a panel of experts centrally reviews all the existing diagnostic evidence (cytohistological and other) of all patients, regardless of whether they have cytohistological confirmation and of their hospital discharge diagnosis. j clin epidemiol 51;12: 1215-1221, 1998.
BMC psychiatry, Jan 14, 2015
Longitudinal neuroimaging studies of major depressive disorder (MDD) have most commonly assessed ... more Longitudinal neuroimaging studies of major depressive disorder (MDD) have most commonly assessed the effects of antidepressants from the serotonin reuptake inhibitor class and usually reporting a single measure. Multimodal neuroimaging assessments were acquired from MDD patients during an acute depressive episode with serial measures during a 12-week treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine. Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state fu...
Schizophrenia Research, 2012
Frontiers in neuroinformatics, 2009
The quantitative analysis of pooled data from related functional magnetic resonance imaging (fMRI... more The quantitative analysis of pooled data from related functional magnetic resonance imaging (fMRI) experiments has the potential to significantly accelerate progress in brain mapping. Such data-pooling can be achieved through meta-analysis (the pooled analysis of published results), mega-analysis (the pooled analysis of raw data) or multi-site studies, which can be seen as designed mega-analyses. Current limitations in function-location brain mapping and how data-pooling can be used to remediate them are reviewed, with particular attention to power aggregation and mitigation of false positive results. Some recently developed analysis tools for meta- and mega-analysis are also presented, and recommendations for the conduct of valid fMRI data pooling are formulated.
The British journal of psychiatry : the journal of mental science, Jan 5, 2015
Background Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to the deve... more Background Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to the development of depression (major depressive disorder, MDD), but it is unclear whether neural effects observed in healthy individuals are sustained in MDD. Aims To investigate BDNF Val66Met effects on key regions in MDD neurocircuitry: amygdala, anterior cingulate, middle frontal and orbitofrontal regions. Method Magnetic resonance imaging scans were acquired in 79 persons with MDD (mean age 49 years) and 74 healthy volunteers (mean age 50 years). Effects on surface area and cortical thickness were examined with multiple comparison correction. Results People who were Met allele carriers showed reduced caudal middle frontal thickness in both study groups. Significant interaction effects were found in the anterior cingulate and rostral middle frontal regions, in which participants in the MDD group who were Met carriers showed the greatest reduction in surface area. Conclusions Modulatory effect...
Journal of affective disorders, Jan 15, 2013
Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy ... more Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression. Subjects with recurrent depression (n=67) and matched healthy controls (n=49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated. Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main e...
Brain imaging and behavior, Jan 7, 2015
Diabetes is associated with macrovascular and microvascular complications and is a major risk fac... more Diabetes is associated with macrovascular and microvascular complications and is a major risk factor for neurological and psychiatric disorders, such as dementia and depression. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) have distinct etiologies and pathophysiological effects while sharing a common endpoint of persistent hyperglycemia. Neuroimaging studies in T1DM have revealed reductions in numerous regions, including the parahippocampal and occipital regions, while in T2DM there have been numerous reports of hippocampal atrophy. This meta-analysis aimed to identify consistent regional abnormalities in cerebral structures in T1DM and T2DM respectively, and also to examine the impact of potential confounds, including age, depression and vascular risk factors. Neuroimaging studies of both voxel-based morphometry (VBM) data and volumetric data were included. Ten T1DM studies (n = 613 patients) and 23 T2DM studies (n = 1364 patients) fulfilled inclusion criteria. The T1DM meta-a...
Communications in Statistics-simulation and Computation, 2008
Most studies involving statistical time series analysis rely on assumptions of linearity, which b... more Most studies involving statistical time series analysis rely on assumptions of linearity, which by its simplicity facilitates parameter interpretation and estimation. However, the linearity assumption may be too restrictive for many practical applications. The implementation of nonlinear models in time series analysis involves the estimation of a large set of parameters, frequently leading to overfitting problems. In this article, a
Background: Depression is experienced as a persistent low mood or anhedonia accompanied by behavi... more Background: Depression is experienced as a persistent low mood or anhedonia accompanied by behavioural and cognitive disturbances which impair day to day functioning. However, the diagnosis is largely based on self-reported symptoms, and there are no neurobiological markers to guide the choice of treatment. In the present study, we examined the prognostic and diagnostic potential of the structural neural correlates of depression.
Hippocampal abnormalities have been demonstrated in schizophrenia. It is unclear whether these ab... more Hippocampal abnormalities have been demonstrated in schizophrenia. It is unclear whether these abnormalities worsen with age, and whether they affect cognition and function. To determine whether hippocampal abnormalities in chronic schizophrenia are associated with age, cognition and socio-occupational function. Using 3 T magnetic resonance imaging we scanned 100 persons aged 19-82 years: 51 were out-patients with stable schizophrenia at least 2 years after diagnosis and 49 were healthy volunteers matched for age and gender. Automated analysis was used to determine hippocampal volume and shape. There were differential effects of age in the schizophrenia and control samples on total hippocampal volume (group × age interaction: F(1,95) = 6.57, P = 0.012), with steeper age-related reduction in the schizophrenia group. Three-dimensional shape analysis located the age-related deformations predominantly in the mid-body of the hippocampus. In the schizophrenia group similar patterns of morphometric abnormalities were correlated with impaired cognition and poorer socio-occupational function. Hippocampal abnormalities are associated with age in people with chronic schizophrenia, with a steeper decline than in healthy individuals. These abnormalities are associated with cognitive and functional deficits, suggesting that hippocampal morphometry may be a biomarker for cognitive decline in older patients with schizophrenia.
The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimer's... more The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimer's disease (AD). Individuals with Mild Cognitive Impairment (MCI) are at increased risk of AD. Hippocampal volume has been shown to predict which MCI subjects will convert to AD. Our aim in the present study was to produce a fully automated prognostic procedure, scalable to high throughput clinical and research applications, for the prediction of MCI conversion to AD using 3D hippocampal morphology. We used an automated analysis for the extraction and mapping of the hippocampus from structural magnetic resonance scans to extract 3D hippocampal shape morphology, and we then applied machine learning classification to predict conversion from MCI to AD. We investigated the accuracy of prediction in 103 MCI subjects (mean age 74.1 years) from the longitudinal AddNeuroMed study. Our model correctly predicted MCI conversion to dementia within a year at an accuracy of 80% (sensitivity 77%, specificity 80%), a performance which is competitive with previous predictive models dependent on manual measurements. Categorization of MCI subjects based on hippocampal morphology revealed more rapid cognitive deterioration in MMSE scores (p < 0.01) and CERAD verbal memory (p < 0.01) in those subjects who were predicted to develop dementia relative to those predicted to remain stable. The pattern of atrophy associated with increased risk of conversion demonstrated initial degeneration in the anterior part of the cornus ammonis 1 (CA1) hippocampal subregion. We conclude that automated shape analysis generates sensitive measurements of early neurodegeneration which predates the onset of dementia and thus provides a prognostic biomarker for conversion of MCI to AD.
Psychopharmacology, 2005
Rationale Glutamatergic dysfunction at N-methyl-d-aspartate (NMDA) receptors has been proposed a... more Rationale Glutamatergic dysfunction at N-methyl-d-aspartate (NMDA) receptors has been proposed as a neurochemical model for schizophrenia. A key feature of this disorder is impairments in cognitive function.Objective The present study sought to investigate the effects of ketamine, an NMDA antagonist, on the performance and neural correlates of verbal fluency, a task that engages executive function.Methods Ten healthy dextral male volunteers received intravenous placebo
Schizophrenia Research, 2003
Introduction: Phencyclidine (PCP) produces a brief psychotic state in healthy volunteers that is ... more Introduction: Phencyclidine (PCP) produces a brief psychotic state in healthy volunteers that is comparable with the symptoms of schizophrenia. A fundamental neurocognitive deficit in schizophrenia is impairments in language processing. Letter verbal fluency is a classical measure of general language abilities in which subjects are required to generate a word in response to letter cues. We sought to examine the neural correlates of an acute psychotic state induced by ketamine (an analogue of PCP) in healthy volunteers as they performed a verbal fluency task. Methods: Eleven healthy male volunteers (mean age 28 years) received either intravenous ketamine or placebo in a double-blind manner, while performing an overt verbal fluency task. FMRI data were acquired at 1.5 T. Results: During the ketamine infusion, subjects developed acute psychotic symptoms. The fMRI data reve',ded a main effect of ketamine, as compared to placebo, with increased activity in the anterior cingulate, prefrontal and parietal cortices, insula and basal ganglia. During the verbal fluency task, relative to placebo, ketamine was associated with greater activation in the prefrontal cortices and basal ganglia. Discussion: A ketamine-induced psychotic state was associated with increased activity in a distributed set of cortical and subcortical regions and a significant modulation of task-related activation during verbal fluency. The latter interaction implicates a prefrontal-striatal network that normally mediates executive aspects of language function in the pathophysiology of an acute psychotic state.
Psychopharmacology, 2005
Rationale: Glutamatergic dysfunction at Nmethyl-D-aspartate (NMDA) receptors has been proposed as... more Rationale: Glutamatergic dysfunction at Nmethyl-D-aspartate (NMDA) receptors has been proposed as a neurochemical model for schizophrenia. A key feature of this disorder is impairments in cognitive function. Objective: The present study sought to investigate the effects of ketamine, an NMDA antagonist, on the performance and neural correlates of verbal fluency, a task that engages executive function. Methods: Ten healthy dextral male volunteers received intravenous placebo normal saline or ketamine (bolus of 0.23 mg/kg and infusion of 0.65 mg/ kg), administered in a double-blind, randomized order, during two functional magnetic resonance imaging sessions. During scanning, subjects performed a verbal fluency task. Two levels of cognitive load were examined in the task, and overt responses were acquired in order to measure subject performance on-line. Results: Ketamine induced symptoms in the healthy individuals comparable to an acute psychotic state. Although ketamine did not signif-icantly impair task performance relative to placebo, an interaction of task demand with ketamine was observed in the anterior cingulate, prefrontal, and striatal regions. Conclusions: The behavioural and functional effects of ketamine during verbal fluency in healthy individuals were comparable to those evident in patients with schizophrenia. The findings support a role for glutamatergic dysfunction in the pathophysiology of schizophrenia.
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Papers by Sergi Costafreda