Anna Calvo

Validation of FDG‐PET/MRI coregistration in nonlesional refractory childhood epilepsy

Purpose:  To validate the use of 18F‐fluorodeoxyglucose–positron emission tomography/magnetic resonance imaging (FDG‐PET/MRI) coregistration for epileptogenic zone detection in children with MRI nonlesional refractory epilepsy and to assess its ability to guide a second interpretation of the MRI studies.

Normal gray and white matter volume after weight restoration in adolescents with anorexia nervosa

OBJECTIVE The aim of this study was to determine whether treated, weight-stabilized adolescents with anorexia nervosa (AN) present brain volume differences in comparison with healthy controls. METHOD Thirty-five adolescents with weight-recovered AN and 17 healthy controls were assessed by means of psychopathology scales and magnetic resonance imaging. Axial three-dimensional T1-weighted images were obtained in a 1.5 Tesla scanner and analyzed using optimized voxel-based morphometry (VBM). RESULTS There were no significant differences between controls and weight-stabilized AN patients with regard to global volumes of either gray or white brain matter, or in the regional VBM study. Differences were not significant between patients with psychopharmacological treatment and without, between those with amenorrhea and without, as well as between patients with restrictive versus purgative AN. DISCUSSION The present findings reveal no global or regional gray or white matter abnormalities in this sample of adolescents following weight restoration.

Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive- compulsive disorder

BACKGROUND Alterations in white matter (WM) integrity observed in patients with obsessive-compulsive disorder (OCD) may be at least partly determined genetically. Neuroimaging measures of WM microstructure could serve as promising intermediate phenotypes for genetic analysis of the disorder. The objective of the present study was to explore the association between variability in genes related to the pathophysiology of OCD and altered WM microstructure previously identified in child and adolescent patients with the disease. METHODS Fractional anisotropy (FA) and mean diffusivity (MD) measured by diffusion tensor imaging (DTI) and 262 single nucleotide polymorphisms (SNPs) in 35 candidate genes were assessed concomitantly in 54 child and adolescent OCD patients. RESULTS Six polymorphisms located in the glutamate transporter gene (SLC1A1 rs3087879), dopamine transporter gene (SLC6A3 rs4975646), dopamine receptor D3 (DRD3 rs3773679), nerve growth factor receptor gene (NGFR rs734194 and rs2072446), and cadherin 9 gene (CDH9 rs6885387) showed significant p-values after Bonferroni correction (p≤0.00019). More specifically, the vast majority of these associations were detected with MD in the right and left anterior and posterior cerebellar lobes. LIMITATIONS Patients were under pharmacological treatment at the time of the DTI examination. Sample size is limited. CONCLUSIONS The results provide the first evidence of the involvement of genetic variants related to glutamatergic, dopaminergic, and neurodevelopmental pathways in determining the WM microstructure of child and adolescent patients with OCD, which could be related to the neurobiology of the disorder.

Microstructural brain abnormalities and symptom dimensions in child and adolescent patients with obsessive-compulsive disorder: a diffusion tensor imaging study.

The aims of this study were to determine white matter (WM) microstructure abnormalities in obsessive‐compulsive disorder (OCD) using diffusion tensor imaging, and to investigate whether these abnormalities differ according to OCD symptom dimensions.

Integrating Genetic, Neuropsychological and Neuroimaging Data to Model Early-Onset Obsessive Compulsive Disorder Severity.

We propose an integrative approach that combines structural magnetic resonance imaging data (MRI), diffusion tensor imaging data (DTI), neuropsychological data, and genetic data to predict early-onset obsessive compulsive disorder (OCD) severity. From a cohort of 87 patients, 56 with complete information were used in the present analysis. First, we performed a multivariate genetic association analysis of OCD severity with 266 genetic polymorphisms. This association analysis was used to select and prioritize the SNPs that would be included in the model. Second, we split the sample into a training set (N = 38) and a validation set (N = 18). Third, entropy-based measures of information gain were used for feature selection with the training subset. Fourth, the selected features were fed into two supervised methods of class prediction based on machine learning, using the leave-one-out procedure with the training set. Finally, the resulting model was validated with the validation set. Nine variables were used for the creation of the OCD severity predictor, including six genetic polymorphisms and three variables from the neuropsychological data. The developed model classified child and adolescent patients with OCD by disease severity with an accuracy of 0.90 in the testing set and 0.70 in the validation sample. Above its clinical applicability, the combination of particular neuropsychological, neuroimaging, and genetic characteristics could enhance our understanding of the neurobiological basis of the disorder.

Quantitative Magnetic Resonance Abnormalities in Creutzfeldt-Jakob Disease and Fatal Insomnia

BACKGROUND Quantitative neuroimaging might unveil abnormalities in prion diseases that are not perceivable at visual inspection. On the other hand, scarce studies have quantified volumetric changes in prion diseases. OBJECTIVES We aim to characterize volumetric and diffusion tensor imaging (DTI) changes in patients with prion diseases who presented with either Creutzfeldt-Jakob disease (CJD) or fatal insomnia (FI) phenotype. METHODS Twenty patients with prion diseases- 15 with CJD and 5 with fatal insomnia (FI)- and 40 healthy controls were examined with a 3-Tesla magnetic resonance imaging scanner. Images were segmented and normalized with SPM12. DTI maps were obtained with FMRIB Software Library. Whole-brain voxel-wise and region-of-interest analyses of volumetric and DTI changes were performed with SPM12. White matter (WM) changes were also analyzed with tract-based spatial statistics. Semiquantitive assessment of neuropathological parameters was compared with DTI metrics in thalamus from 11 patients. RESULTS Patients with CJD and FI presented significant atrophy in thalamus and cerebellum. In CJD, mean diffusivity (MD) was decreased in striatum and increased in subcortical WM, while both increased and decreased values were observed across different thalamic nuclei. In FI, MD was increased in thalamus and cerebellum. Spongiform change and PrPSc deposition were more intense in thalamus in CJD than in FI, although no significant correlations arose with MD values in the nuclei studied. CONCLUSION Volumetric and DTI abnormalities suggest a central common role of the thalamus in prion diseases. We report, for the first time, quantitative MRI changes in FI, and provide further evidence of WM involvement in prion diseases.

Intrinsic functional connectivity of fronto-temporal networks in adolescents with early psychosis

Adults with psychotic disorders have abnormal connectivity of fronto-temporal networks. However, whether these abnormalities are present in adolescents with early psychosis has not been fully assessed. One-hundred and thirty-nine adolescents aged 12–18 underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging. Following motion correction, data were available for 44 participants with a psychosis risk syndrome, 34 patients with a first episode psychosis (FEP) and 35 healthy controls. Independent component analysis was performed to assess functional networks showing a fronto-temporal scope; this identified a language and a salience network. Mean fractional anisotropy was measured in clusters showing between-group differences in intrinsic functional connectivity (iFC). For the language network, there was a group effect within the right middle/inferior frontal gyrus, explained by reduced iFC in patients with an FEP relative to healthy controls, while in participants with a psychosis risk syndrome values of iFC were intermediate. In this region, values of iFC were positively correlated with mean fractional anisotropy in patients with an FEP. No group differences were observed in the salience network. Reduced iFC of the language network, in association with disrupted white matter microstructure, may characterize FEP during adolescence.

Combined 18F-FDG-PET and diffusion tensor imaging in mesial temporal lobe epilepsy with hippocampal sclerosis

Objectives Several studies using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) or diffusion tensor imaging (DTI) have found both temporal and extratemporal abnormalities in patients with mesial temporal lobe epilepsy with ipsilateral hippocampal sclerosis (MTLE-HS), but data are lacking about the findings of both techniques in the same patients. We aimed to determine whether the extent of 18F-FDG-PET hypometabolism is related to DTI abnormalities. Methods Twenty-one patients with MTLE-HS underwent comprehensive preoperative evaluation; 18 (86%) of these underwent epilepsy surgery. We analyzed and compared the pattern of white matter (WM) alterations on DTI and cortical hypometabolism on 18F-FDG-PET. Results We found widespread temporal and extratemporal 18F-FDG-PET and DTI abnormalities. Patterns of WM abnormalities and cortical glucose hypometabolism involved similar brain regions, being more extensive in the left than the right MTLE-HS. We classified patients into three groups according to temporal 18F-FDG-PET patterns: hypometabolism restricted to the anterior third (n = 7), hypometabolism extending to the middle third (n = 7), and hypometabolism extending to the posterior third (n = 7). Patients with anterior temporal hypometabolism showed DTI abnormalities in anterior association and commissural tracts while patients with posterior hypometabolism showed WM alterations in anterior and posterior tracts. Conclusions Patients with MTLE-HS have widespread metabolic and microstructural abnormalities that involve similar regions. The distribution patterns of these gray and white matter abnormalities differ between patients with left or right MTLE, but also with the extent of the 18F-FDG-PET hypometabolism along the epileptogenic temporal lobe. These findings suggest a variable network involvement among patients with MTLE-HS.

T174. STRUCTURAL ABNORMALITIES IN THE CINGULATE CORTEX IN ADOLESCENTS AT ULTRA-HIGH RISK WHO LATER DEVELOP PSYCHOSIS

Abstract Background Identification of biomarkers of transition to psychosis in individuals at ultra-high risk (UHR) has the potential to improve future outcomes (McGorry, 2008). Structural MRI studies with UHR samples have revealed steeper rates of cortical thinning in temporal, prefrontal and cingulate cortices in individuals who later develop psychosis in both baseline and longitudinal comparisons (Fusar-Poli, 2011; Cannon, 2014). However, little is known about how onset of prodromal symptoms during adolescence impacts on changes in cortical thickness (CTH) (Ziermans, 2012). Methods Multicentre cross-sectional case-control study, including youth aged 10–17 years, recruited from two child and adolescent mental health centres. UHR individuals were identified using the Structured Interview for Prodromal Syndromes criteria with some modifications. Healthy controls (HC) were recruited from the same geographical area. Exclusion criteria comprised personal history of psychotic symptoms, IQ<70, autism spectrum disorder, presence of neurological disorder, or antecedents of head trauma with loss of consciousness. The study was approved by the local Ethical Review Boards. All participants underwent a comprehensive socio-demographic and clinical evaluation at baseline and after 6, 12 and 18 months follow-up to identify which individuals converted to psychosis (UHR-P) and which did not (UHR-NP). High-resolution magnetic resonance structural images were acquired at baseline on a 3Tesla and 1.5Tesla scanners. An inter-site compatibility study was conducted with healthy controls which revealed high inter-site correlation coefficients (r>.6) for CTH measures. Images were pre-processed employing automated procedures implemented in FreeSurfer 5.3.0, cortical parcellation employed the Desikan-Killiany brain atlas. Analyses: First, mean global and lobar (frontal, parietal, temporal, occipital, insula and cingulate) CTH measurements were computed. Then, within lobes showing group effects, CTH was measured for each parcellation. ANCOVA was performed to test differences between groups in SPSS 22.0, including gender, age, total intracranial volume and site as covariates. Significance was set at p<.05, corrected using the false discovery rate (FDR). Results 122 subjects were included (59 UHR-NP vs. 18 UHR-P vs. 45 HC, mean ages: 15.2 ± 1.5 vs. 15.0 ± 1.8 vs. 15.8 ± 1.5, F=1.9, p=.15; gender (%female): 61.0% vs 61.1% vs 68.9%, χ2=.76, p=.68). There were no significant differences in case-control proportion between centres: χ2=1.3, p=.25. No significant differences in global CTH in UHR-P (2.57 ± 0.13mm) relative to UHR-NP (2.56 ± 0.11mm) and HC (2.58 ± 0.09mm) were found. There was a significant group effect on the right cingulate cortex (F=6.6, pFDR=.024): UHR-P showed lower CTH in this area relative to controls (p=.007 uncorrected). Within the right cingulate cortex, a significant group effect was found in the posterior cingulate (F=5.7, pFDR=.016) and isthmus (F=4.6, pFDR=.024), and a trend level in the caudal anterior cingulate (F=2.9, p=.057): with smaller CTH in UHR-P relative to HC in the isthmus cingulate (p=.025) and the posterior cingulate (p=.066). No significant differences were observed between UHR-P and UHR-NP groups. Discussion UHR-P showed significant cortical thinning in several regions of the right cingulate cortex in comparison to HC, giving support to the notion that structural alterations in the cingulate cortex may be present in children and adolescents prior the onset of psychosis. Longitudinal changes in CTH have the potential to increase understanding of changes related to transition to clinical illness.

Typical asymmetry in the hemispheric activation during an fMRI verbal comprehension paradigm is related to better performance in verbal and non-verbal tasks in patients with epilepsy

Chronic exposure to seizures in patients with left hemisphere (LH) epileptic focus could favor higher activation in the contralateral hemisphere during language processing, but the cognitive effects of this remain unclear. This study assesses the relationship between asymmetry in hemispheric activation during language fMRI and performance in verbal and non-verbal tasks. Whereas prior studies primarily used fMRI paradigms that favor frontal lobe activation and less prominent activation of the medial or superior temporal lobes, we used a verbal comprehension paradigm previously demonstrated to activate reliably receptive language areas. Forty-seven patients with drug-resistant epilepsy candidates for surgery underwent a multidisciplinary assessment, including a comprehensive neuropsychological evaluation and an fMRI verbal comprehension paradigm. Patients were distributed in two groups depending on laterality indexes (LI): typical hemispheric asymmetry (unilateral left activation preponderance; n = 23) and atypical hemispheric asymmetry (bilateral or unilateral right preponderance; n = 24). Right-handedness and right hemisphere (RH) focus were significant predictors of typical asymmetry. Patients with typical activation pattern presented better performance intelligence quotient and verbal learning than patients with atypical hemispheric asymmetry (for all, p < 0.014). Patients with LH focus had more frequently atypical hemispheric asymmetry than patients with RH focus (p = 0.05). Specifically, they showed lower LI and this was related to worse performance in verbal and non-verbal tasks. In conclusion, an increased activation of homologous RH areas for verbal comprehension processing could imply a competition of cognitive resources in the performance of the same task, disrupting cognitive performance.