Dataset Information

The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice.

ABSTRACT: Background:Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2? knockout (KO) model. Methods:Fixed brains of Nrxn2? KO mice underwent DTI using 9.4?T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results:DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2? KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions:Our findings demonstrate that deleting a single neurexin gene (Nrxn2?) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.

SUBMITTER: Pervolaraki E

PROVIDER: S-EPMC6394023 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in <i>Nrxn2</i> deletion mice.

Pervolaraki Eleftheria E Tyson Adam L AL Pibiri Francesca F Poulter Steven L SL Reichelt Amy C AC Rodgers R John RJ Clapcote Steven J SJ Lever Colin C Andreae Laura C LC Dachtler James J

Molecular autism 20190228

<h4>Background</h4>Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for <i>NRXN2</i> in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. T ...[more]

PMID: 30858964

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Project description:Registration of subject and control brains to a common anatomical space or template is the basis for quantitatively delineating regions of abnormality in an individual brain. Normally, a brain atlas is chosen as the template. Limitations in the registration process result in persistent differences between individual subject brains and template, which can be a source of error in an analysis. We propose a new approach to the registration process where the subject of interest is the registration template. Through this change, we eliminate errors due to differences between a brain template and a subject's brain. We applied this method to the analysis of FA values derived from DTI data of 20 individual mTBI patients as compared to 48 healthy controls. Subject-centered analysis resulted in identification of significantly fewer regions of abnormally low FA compared to two separate atlas-centered analyses, with subject-centered abnormalities essentially representing the common subset of abnormal low FA regions detected by the two atlas-centered methods. Whereas each atlas-centered approach demonstrated abnormalities in nearly every subject (19/20 and 20/20), the subject-centered approach demonstrated abnormalities in fewer than half the subjects (9/20). This reduction of diffusion abnormalities observed using the subject-centered approach is due to elimination of misregistration errors that occur when registering the subject of interest to a template. Evaluation of atlas-centered analyses demonstrated that 9.8% to 13.3% of subject GM and CSF was misregistered onto the WM of the brain atlas, resulting in the observation of additional low FA clusters compared to the subject-centered approach. Without careful evaluation, these misregistrations could be misinterpreted as pathology. An additional benefit of the subject-centered approach is that diffusion abnormalities can now be visualized directly in the subject's anatomical space, rather than interpolating results from the brain atlas space, and can thereby enhance correlation with other components of an imaging protocol.

Project description:BackgroundDynamic diffusion magnetic resonance imaging (ddMRI) metrics can assess transient microstructural alterations in tissue diffusivity but requires additional scan time hindering its clinical application.PurposeTo determine whether a diffusion gradient table can simultaneously acquire data to estimate dynamic and diffusion tensor imaging (DTI) metrics.Study typeProspective.SubjectsSeven healthy subjects, 39 epilepsy patients (15 female, 31 male, age ± 15).Field strength/sequenceTwo-dimensional diffusion MRI (b = 1000 s/mm2 ) at a field strength of 3 T. Sessions in healthy subjects-standard ddMRI (30 directions), standard DTI (15 and 30 directions), and nested cubes scans (15 and 30 directions). Sessions in epilepsy patients-two 30 direction (standard ddMRI, 10 nested cubes) or two 15 direction scans (standard DTI, 5 nested cubes).AssessmentFifteen direction DTI was repeated twice for within-session test-retest measurements in healthy subjects. Bland-Altman analysis computed bias and limits of agreement for DTI metrics using test-retest scans and standard 15 direction vs. 5 nested cubes scans. Intraclass correlation (ICC) analysis compared tensor metrics between 15 direction DTI scans (standard vs. 5 nested cubes) and the coefficients of variation (CoV) of trace and apparent diffusion coefficient (ADC) between 30 direction ddMRI scans (standard vs. 10 nested cubes).Statistical testsBland-Altman and ICC analysis using a P-value of 0.05 for statistical significance.ResultsCorrelations of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were strong and significant in gray (ICC > 0.95) and white matter (ICC > 0.95) between standard vs. nested cubes DTI acquisitions. Correlation of white matter fractional anisotropy was also strong (ICC > 0.95) and significant. ICCs of the CoV of dynamic ADC measured using repeated cubes and nested cubes acquisitions were modest (ICC >0.60), but significant in gray matter.ConclusionA nested cubes diffusion gradient table produces tensor-based and dynamic diffusion measurements in a single acquisition.Level of evidence2 TECHNICAL EFFICACY: Stage 1.

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Dataset Information

The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice.

Publications

The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in <i>Nrxn2</i> deletion mice.

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