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Diffusion MRI uses the random displacement of water molecules to sensitize the signal to brain microstructure and to properties such as the density and shape of cells. Microstructure modeling techniques aim to estimate these properties from acquired data by separating the signal between virtual tissue 'compartments' such as the intra-neurite and the extra-cellular space. A key challenge is that the diffusion MRI signal is relatively featureless compared with the complexity of brain tissue. Another challenge is that the tissue microstructure is wildly different within the gray and white matter of the brain. In this review, we use results from multidimensional diffusion encoding techniques to discuss these challenges and their tentative solutions. Multidimensional encoding increases the information content of the data by varying not only the b-value and the encoding direction but also additional experimental parameters such as the shape of the b-tensor and the echo time. Three main insights have emerged from such encoding. First, multidimensional data contradict common model assumptions on diffusion and T 2 relaxation, and illustrates how the use of these assumptions cause erroneous interpretations in both healthy brain and pathology. Second, many model assumptions can be dispensed with if data are acquired with multidimensional encoding. The necessary data can be easily acquired in vivo using protocols optimized to minimize Cramér-Rao lower bounds. Third, microscopic diffusion anisotropy reflects the presence of axons but not dendrites. This insight stands in contrast to current 'neurite models' of brain tissue, which assume that axons in white matter and dendrites in gray matter feature highly similar diffusion. Nevertheless, as an axon-based contrast, microscopic anisotropy can differentiate gray and white matter when myelin alterations confound conventional MRI contrasts., Competing Interests: Declaration of Competing Interest Markus Nilsson and Filip Szczepankiewicz declare ownership interests in Random Walk Imaging, which holds patents pertaining to the methods presented herein. Remaining authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Delineation of malformations of cortical development (MCD) is central in presurgical evaluation of drug-resistant epilepsy. Delineation using magnetic resonance imaging (MRI) can be ambiguous, however, because the conventional T 1 - and T 2 -weighted contrasts depend strongly on myelin for differentiation of cortical tissue and white matter. Variations in myelin content within both cortex and white matter may cause MCD findings on MRI to change size, become undetectable, or disagree with histopathology. The novel tensor-valued diffusion MRI (dMRI) technique maps microscopic diffusion anisotropy, which is sensitive to axons rather than myelin. This work investigated whether tensor-valued dMRI may improve differentiation of cortex and white matter in the delineation of MCD., Methods: Tensor-valued dMRI was performed on a 7 T MRI scanner in 13 MCD patients (age = 32 ± 13 years) featuring periventricular heterotopia, subcortical heterotopia, focal cortical dysplasia, and polymicrogyria. Data analysis yielded maps of microscopic anisotropy that were compared with T 1 -weighted and T 2 -fluid-attenuated inversion recovery images and with the fractional anisotropy from diffusion tensor imaging., Results: Maps of microscopic anisotropy revealed large white matter-like regions within MCD that were uniformly cortex-like in the conventional MRI contrasts. These regions were seen particularly in the deep white matter parts of subcortical heterotopias and near the gray-white boundaries of focal cortical dysplasias and polymicrogyrias., Significance: By being sensitive to axons rather than myelin, mapping of microscopic anisotropy may yield a more robust differentiation of cortex and white matter and improve MCD delineation in presurgical evaluation of epilepsy., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL). Diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI) are MRI techniques that quantify microstructural changes in brain white matter (WM) and DKI is regarded as the more sensitive of them. Our aim was to more thoroughly understand the nature of cognitive deficits after cranial radiotherapy (CRT) in adulthood after childhood ALL. Material and methods: Thirty-eight (21 women) ALL survivors, median age 38 (27-46) years, were investigated at median 34 years after diagnosis. All had been treated with a CRT dose of 24 Gy and with 11 years of complete hormone supplementation. DTI and DKI parameters were determined and neurocognitive tests were performed in ALL survivors and 29 matched controls. Results: ALL survivors scored lower than controls in neurocognitive tests of vocabulary, memory, learning capacity, spatial ability, executive functions, and attention ( p  < .001). The survivors had altered DTI parameters in the fornix, uncinate fasciculus, and ventral cingulum (all p  < .05) and altered DKI parameters in the fornix, uncinate fasciculus, and dorsal and ventral cingulum ( p  < .05). Altered DTI parameters in the fornix were associated with impaired episodic verbal memory ( r = -0.40, p  < .04). The left and right uncinate fasciculus ( r  = 0.6, p  < .001), ( r = -0.5, p  < .02) as well as the right ventral cingulum ( r  = 0.5, p  < .007) were associated with impaired episodic visual memory. Altered DKI parameters in the fornix, right uncinate fasciculus ( r  = 0.3, r  = 0.05, p  = .02), and ventral cingulum ( r  = 0.3, p  = .02) were associated with impaired results of episodic visual memory. Conclusion: ALL survivors with cognitive deficits demonstrated microstructural damage in several WM tracts that were more extensive with DKI as compared to DTI; this might be a marker of radiation and chemotherapy neurotoxicity underlying cognitive dysfunction.

Context: Patients with craniopharyngioma (CP) and hypothalamic lesions (HL) have cognitive deficits. Which neural pathways are affected is unknown., Objective: To determine whether there is a relationship between microstructural white matter (WM) alterations detected with diffusion tensor imaging (DTI) and cognition in adults with childhood-onset CP., Design: A cross-sectional study with a median follow-up time of 22 (6-49) years after operation., Setting: The South Medical Region of Sweden (2.5 million inhabitants)., Participants: Included were 41 patients (24 women, ≥17 years) surgically treated for childhood-onset CP between 1958-2010 and 32 controls with similar age and gender distributions. HL was found in 23 patients., Main Outcome Measures: Subjects performed cognitive tests and magnetic resonance imaging, and images were analyzed using DTI of uncinate fasciculus, fornix, cingulum, hippocampus and hypothalamus as well as hippocampal volumetry., Results: Right uncinate fasciculus was significantly altered ( P  ≤ 0.01). Microstructural WM alterations in left ventral cingulum were significantly associated with worse performance in visual episodic memory, explaining approximately 50% of the variation. Alterations in dorsal cingulum were associated with worse performance in immediate, delayed recall and recognition, explaining 26-38% of the variation, and with visuospatial ability and executive function, explaining 19-29%. Patients who had smaller hippocampal volume had worse general knowledge ( P  = 0.028), and microstructural WM alterations in hippocampus were associated with a decline in general knowledge and episodic visual memory., Conclusions: A structure to function relationship is suggested between microstructural WM alterations in cingulum and in hippocampus with cognitive deficits in CP., (© 2018 The authors.)