Investigating the relationship between multiple grip forces and BOLD signal in the Cerebellum and dentate nuclei of MS subjects

Abstract

Event Abstract Back to Event Altered cerebral and cerebellar functional connectivity with structurally altered brain areas in children with autism spectrum disorder Letizia Casiraghi1, 2*, Fulvia Palesi2, 3, Gloria Castellazzi1, 4, Andrea De Rinaldis2, 4, Carol Di Perri5, Claudia A. Gandini Wheeler-Kingshott2, 6, 7 and Egidio D‘Angelo1, 2 1 University of Pavia, Department of Brain and Behavioral Sciences, Italy 2 C. Mondino National Neurological Institute, Brain Connectivity Centre, Italy 3 University of Pavia, Department of Physics, Italy 4 University of Pavia, Department of Electrical, Computer and Biomedical Engineering, Italy 5 University of Liege, Coma Science Group, Belgium 6 UCL Institute of Neurology, Queen Square MS Centre, Department of Neuroinflammation, United Kingdom 7 C. Mondino National Neurological Institute, Brain MRI 3T Mondino Research Center, Italy INTRODUCTION Autism Spectrum Disorder (ASD) is a term to indicate a group of early onset neurodevelopmental disorders characterized by a variable developmental trajectory and impaired social communication and interaction (1, 2). High Functioning (HF) ASD is diagnosed when IQ (Intelligence Quotient) is greater than 70. Despite the large number of studies reporting structural and functional connectivity (FC) alterations in ASD, there is a striking lack of research attempting to integrate these aspects in children with HF-ASD (3, 4). Therefore, we assessed grey matter (GM) structural changes and corresponding FC alterations in HF-ASD compared to typically developing (TD) children. METHODS Publicly available data from Stanford University ABIDE Database have been used (http://fcon_1000.projects.nitrc.org/indi/abide/). 20 children (9.8±1.5 yrs, 16 males) who met criteria for HF-ASD on the Autism Diagnostic Observation Schedule (ADOS) or criteria for autism on the Autism Diagnostic Interview-Revised (ADI-R) and 19 TD children (10.3±1.6 yrs, 15 males) underwent the following 3T GE Signa scanner (General Electric, Milwaukee) protocol: i) resting state fMRI GE-EPI with TR = 2000 ms, TE = 30 ms, flip angle = 80°, FOV = 200 mm, voxel size = 3x3x4.5 mm3, 29 slices, 180 volumes; ii) High-resolution 3D T1-weighted (3DT1w) scan with TI = 300 ms, TR = 8.4 ms, TE = 1.8 ms, flip angle = 15°, FOV = 220 mm, slice thickness = 1.5 mm, in-plane resolution = 0.9x1.1 mm2 and 132 slices. In order to assess structural alterations, VBM (Voxel Based Morphometry) was performed using SPM8 (6). A statistical threshold of p<0.001 was considered significant and an extent threshold of 20 voxels was used to set the false discovery rate (FDR). Subsequently, the 7 peaks of the obtained GM clusters were used to define the centre of 7 spherical (radius = 4 mm) seeds to investigate the FC between every seed and the whole brain. Seed based fMRI analysis was carried out using BrainVoyager QX software version 2.8 (7) on a subgroup of 19 ASD and 15 TD. Correlation maps for each seed were created. The random effect ANCOVA was applied to compare group-specific maps. Statistical maps were finally corrected for multiple comparisons using a cluster threshold approach based on Monte Carlo simulation (significance threshold p = 0.01). A standard Pearson correlation analysis (p < 0.05) was finally performed between FC values (obtained from the seed based fMRI analysis) and ADI and ADOS subscales using SPSS 21.0 (8). RESULTS VBM analysis revealed significant GM density reductions in ASD in visual associative areas and right caudate. Increased GM volume in ASD was observed in temporal regions (Figure 1a and 1b). GM density increments and GM volume reductions didn’t survive the cluster threshold correction. Seed based fMRI analysis revealed reduced FC in insula and posterior cingulate cortex, frontal lobe, inferior occipital lobe, middle temporal gyrus, caudate and cerebellum (Figure 1a' and 1b'). Focusing on the cerebellum, we found reduced FC between the left visual areas and the left culmen (vermis, anterior cerebellar lobe). Increased FC was found in the right putamen, in the red nuclei, and in the right cerebellum linked to the left hippocampus, the right parahippocampus and the left inferior temporal lobe respectively (Figure 1b'). Focusing on the cerebellum, we found enhanced FC between the left fusiform gyrus and the right pyramis (vermis, posterior cerebellar lobe). In ASD we found correlations between FC of the limbic/subcortical system and social interactions (p=.009), verbal ability (p=.032) and repetitive behaviours (p=.038) and anti-correlations between FC of hippocampus/frontal system and socio-affective interactions (p=.030), visual/insular link and repetitive behaviours (p=.005) and visual/orbitofrontal link and ADOS (p=.037). CONCLUSIONS The structural alterations we found are located in brain areas involved in sensory perception and integration, from the early visual processing of the occipital lobe to the visuospatial and memory functions of the temporal lobe. At a deeper level we observed the structural alteration of the caudate, which seems to be implicated in the development of stereotyped and repetitive behaviors in ASD (9). The FC alterations seem to involve areas such as the insula, the prefrontal and the cingulate cortices that are necessary to integrate multiple neurocognitive systems associated with affective, interoceptive and inhibitory processes. The altered FC between the occipito-temporal system and the medial part of the cerebellum is interesting since it involves both the anterior and the posterior lobules. Correlations between FC and clinical scores indicate that the more extreme the FC value (min/max range values) from seed regions of structural abnormalities is, the more severe the impairment. Medial and inferior temporal lobe and subcortical structures are involved in flexible multidimensional association of sensory stimuli and motivational states with experience and learning (10) while visual associative cortex and insula have a role in the processing of emotional and attentional aspects of visual perception, body representation and sense of agency (11). The correlations between FC and social abilities and repetitive behaviours support the idea that temporal and subcortical areas are responsible for the sensory integration and emotional deficits in ASD while anti-correlations between FC and repetitive behaviours suggests that visual associative areas and insula are involved in ASD deficit linked to the integration of visual stimuli and self-awareness information. Further studies are warranted to assess the causal relationship between FC and structural changes in ASD. Figure 1 VBM-driven seed based functional connectivity fMRI results. x,y,z coordinates are in Talairach space (mm). Z coordinates are reported for each axial slice. a) VBM density reductions (light blue). a’) Seed based FC reductions (blue). b) VBM volume increments (orange). b’) Seed based FC reductions (blue) and increments (red). Figure 1 Acknowledgements We acknowledge the University of Pavia, the “data sharing platform for ABIDE initiative” and the Stanford University ABIDE group. This work was supported by grants of the Italian Ministry of Health to Carol Di Perri (GR-2009-1575236).