Rationale and Objectives Tuberous Sclerosis Complex (TSC) is a genetic neurocutaneous syndrome in which cognitive and social-behavioral outcomes for patients vary widely in an unpredictable manner. The cause of adverse neurological outcome remains unclear. We investigated the hypothesis that disordered white matter and abnormal neural connectivity are associated with adverse neurological outcome. Materials and Methods Structural and diffusion magnetic resonance imaging was carried out in 40 subjects with TSC (age range 0.5 – 25 years, mean age 7.2 and median age 5 years), 12 of whom had autism spectrum disorders (ASD), and in 29 age-matched controls. Tractography of the corpus callosum was used to define a 3-dimensional volume of interest. Regional averages of four diffusion scalar parameters of the callosal projections were calculated for each subject. These were the average fractional anisotropy (AFA) and average mean, radial and axial diffusivity (AMD, ARD, AAD). Results Subjects with TSC had significantly lower AFA and higher AMD, ARD and AAD values compared to controls. Subjects with TSC and ASD had significantly lower AFA values compared to those without ASD, and compared to controls. TSC subjects without ASD had similar AFA values compared to controls. Conclusion Diffusion tensor scalar parameters provided measures of properties of the three-dimensional callosal projections. In TSC, changes in these parameters may reflect microstructural changes in myelination, axonal integrity, or extracellular environment. Alterations in white matter microstructural properties were associated with TSC and larger changes were associated with TSC and ASD, thus establishing a relationship between altered white matter microstructural integrity and brain function.

Diffusion-weighted imaging (DWI) enables non-invasive investigation and characterization of the white matter but suffers from a relatively poor spatial resolution. Increasing the spatial resolution in DWI is challenging with a single-shot EPI acquisition due to the decreased signal-to-noise ratio and T2* relaxation effect amplified with increased echo time. In this work we propose a super-resolution reconstruction (SRR) technique based on the acquisition of multiple anisotropic orthogonal DWI scans. DWI scans acquired in different planes are not typically closely aligned due to the geometric distortion introduced by magnetic susceptibility differences in each phase-encoding direction. We compensate each scan for geometric distortion by acquisition of a dual echo gradient echo field map, providing an estimate of the field inhomogeneity. We address the problem of patient motion by aligning the volumes in both space and q-space. The SRR is formulated as a maximum a posteriori problem. It relies on a volume acquisition model which describes how the acquired scans are observations of an unknown high-resolution image which we aim to recover. Our model enables the introduction of image priors that exploit spatial homogeneity and enables regularized solutions. We detail our SRR optimization procedure and report experiments including numerical simulations, synthetic SRR and real world SRR. In particular, we demonstrate that combining distortion compensation and SRR provides better results than acquisition of a single isotropic scan for the same acquisition duration time. Importantly, SRR enables DWI with resolution beyond the scanner hardware limitations. This work provides the first evidence that SRR, which employs conventional single shot EPI techniques, enables resolution enhancement in DWI, and may dramatically impact the role of DWI in both neuroscience and clinical applications.

The characterization of the complex diffusion signal arising from the brain remains an open problem. Many representations focus on characterizing the global shape of the diffusion profile at each voxel and are limited to the assessment of connectivity. In contrast, Multiple Fascicle Models (MFM) seek to represent the contribution from each white matter fascicle and may be useful in the investigation of both white matter connectivity and diffusion properties of each individual fascicle. However, the most appropriate representation of multiple fascicles remains unclear. In particular, a multiple tensor representation of multiple fascicles has frequently been reported to be numerically challenging and unstable. We provide here the first analytical demonstration that when using a diffusion MRI acquisition with only one non-zero b-value, such as in conventional single-shell HARDI acquisition, a co-linearity in model parameters makes the precise model estimation impossible. Motivated by this theoretical result, we propose the novel CUSP (CUbe and SPhere) optimal acquisition scheme to achieve multiple non-zero b-values. It combines the gradients of a single-shell HARDI with gradients in its enclosing cube, in which varying b-values can be acquired by modulation of the gradient strength, without modifying the minimum echo time. Compared to a multi-shell HARDI acquisition, our scheme has significantly increased signal-to-noise ratio. We propose a novel estimation algorithm that enables efficient, robust and accurate estimation of the parameters of a multi-tensor model. In conjunction with a CUSP acquisition, it enables full estimation of the multi-tensor model. We present an evaluation of CUSP-MFM on both synthetic phantoms and invivo data. We report qualitative and quantitative experimental evaluations which demonstrate the ability of CUSP-MFM to characterize multiple fascicles from short duration acquisitions. CUSP-MFM enables rapid and effective investigation of multiple white matter fascicles, in both normal development and in disease and injury, in research and clinical practice.

AFM Téléthon and Trophos SA.

The purpose of this study was to examine the relationship between language pathways and autism spectrum disorders (ASDs) in patients with tuberous sclerosis complex (TSC). An advanced diffusion-weighted magnetic resonance imaging (MRI) was performed on 42 patients with TSC and 42 age-matched controls. Using a validated automatic method, white matter language pathways were identified and microstructural characteristics were extracted, including fractional anisotropy (FA) and mean diffusivity (MD). Among 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD had a lower FA than controls in the arcuate fasciculus (AF); TSC patients with ASD had even a smaller FA, lower than the FA for those without ASD. Similarly, TSC patients without ASD had a greater MD than controls in the AF; TSC patients with ASD had even a higher MD, greater than the MD in those without ASD. It remains unclear why some patients with TSC develop ASD, while others have better language and socio-behavioral outcomes. Our results suggest that language pathway microstructure may serve as a marker of the risk of ASD in TSC patients. Impaired microstructure in language pathways of TSC patients may indicate the development of ASD, although prospective studies of language pathway development and ASD diagnosis in TSC remain essential.