Search

Highlights • Covariant abnormalities of GM and WM occurred in SCD and MCI. • GM-WM covariant abnormalities were correlated with cognitive performance in SCD. • Multimodal fusion highlighted the interaction of sMRI and DTI in SCD and MCI., Background Previous multimodal neuroimaging studies analyzed each dataset independently in subjective cognitive decline (SCD) and mild cognitive impairment (MCI), missing the cross-information. Multi-modal fusion analysis can provide more integral and comprehensive information regarding the brain. There has been a paucity of research on fusion analysis of sMRI and DTI in SCD and MCI. Materials and Methods In the present study, we conducted fusion analysis of structural MRI and DTI by applying multimodal canonical correlation analysis with joint independent component analysis (mCCA-jICA) to capture the cross-information of gray matter (GM) and white matter (WM) in 62 SCD patients, 99 MCI patients, and 70 healthy controls (HCs). We further analyzed correlations between the mixing coefficients of mCCA-jICA and neuropsychological scores among the three groups. Results A set of joint-discriminative independent components of GM and fractional anisotropy (FA) exhibited significant links between SCD and HCs, as well as between MCI and HCs. The covariant abnormalities primarily involved the frontal lobe/middle temporal gyrus/calcarine sulcus-anterior thalamic radiation/superior longitudinal fasciculus in SCD, and middle temporal gyrus/ fusiform gyrus/caudate necleus-forceps minor/anterior thalamic radiation in MCI. There was no significant difference between SCD and MCI groups. Conclusions The covariant GM-WM abnormalities in SCD and MCI were found in specific brain regions involved in cognitive processing, which confirms the simultaneous GM and WM changes underlying cognitive decline. These findings suggest that multimodal fusion analysis allows for a more comprehensive understanding of the association among different types of brain tissues and its crucial role in the neuropathological mechanism of SCD and MCI.

Highlights • Gait and balance impairments correlated to various imaging abnormalities. • Stride length, cadence and balance varied independently in PSP. • PSP phenotype affects the associations between gait and imaging., Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

Graphical abstract, Highlights • Putamen susceptibility value was higher in PD than controls one year into diagnosis. • Putamen susceptibility value was associated with clinical motor scores in early PD. • Mean diffusivity revealed greater cellular loss in the lateral substantial nigra. • Putamen and caudate microstructural degradation were driven by radial diffusivity. • A composite putamen-caudate DKI-QSM marker classified early PD from controls., Objective To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson’s disease (PD) and their clinical correlates to aid in diagnosis of PD. Method Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). Results There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (β = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p

Highlights • Tensor-valued dMRI facilitates prediction of meningioma consistency, grade and type. • Tensor-valued dMRI corroborates findings of diffusion tensor and kurtosis imaging. • MK and MKA is associated with firm and MD with variable meningioma consistency. • Variability of MKI in the vicinity of the tumor is associated with meningioma grade. • MKA 50 and MKI 50 separates psammomatous meningiomas from other meningioma types., Background Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach. Purpose To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type. Materials and methods 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm2. The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components—the anisotropic and isotropic kurtoses (MKA and MKI). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor (“whole-tumor”) and within brain tissue in the immediate periphery outside the tumor (“rim”) by histogram analysis. Results Lower 10th percentiles of MK and MKA in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MKA 10 and p = 0.04 for MK10) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MKI in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MKI maps we observed elevated rim-like structure that could be associated with grade. Higher median MKA and lower median MKI distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MKA 50 and p = 0.03 and p = 0.04 for MKI 50). Conclusion Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.

Highlights • Quantitative MRI metrics (MD, Volume) can be combined to stage sCJD radiologically. • Quantitative multiparametric approach improves sCJD clinical-imaging correlation. • MRI Disease-Staging might be useful to track sCJD progression., Diffusion imaging is very useful for the diagnosis of sporadic Creutzfeldt-Jakob disease, but it has limitations in tracking disease progression as mean diffusivity changes non-linearly across the disease course. We previously showed that mean diffusivity changes across the disease course follow a quasi J-shaped curve, characterized by decreased values in earlier phases and increasing values later in the disease course. Understanding how MRI metrics change over-time, as well as their correlations with clinical deficits are crucial steps in developing radiological biomarkers for trials. Specifically, as mean diffusivity does not change linearly and atrophy mainly occurs in later stages, neither alone is likely to be a sufficient biomarker throughout the disease course. We therefore developed a model combining mean diffusivity and Volume loss (MRI Disease-Staging) to take into account mean diffusivity’s non-linearity. We then assessed the associations between clinical outcomes and mean diffusivity alone, Volume alone and finally MRI Disease-Staging. In 37 sporadic Creutzfeldt-Jakob disease subjects and 30 age- and sex-matched healthy controls, high angular resolution diffusion and high-resolution T1 imaging was performed cross-sectionally to compute z-scores for mean diffusivity (MD) and Volume. Average MD and Volume were extracted from 41 GM volume of interest (VOI) per hemisphere, within the images registered to the Montreal Neurological Institute (MNI) space. Each subject’s volume of interest was classified as either “involved” or “not involved” using a statistical threshold of ± 2 standard deviation (SD) for mean diffusivity changes and/or −2 SD for Volume. Volumes of interest were MRI Disease-Staged as: 0 = no abnormalities; 1 = decreased mean diffusivity only; 2 = decreased mean diffusivity and Volume; 3 = normal (“pseudo-normalized”) mean diffusivity, reduced Volume; 4 = increased mean diffusivity, reduced Volume. We correlated Volume, MD and MRI Disease-Staging with several clinical outcomes (scales, score and symptoms) using 4 major regions of interest (Total, Cortical, Subcortical and Cerebellar gray matter) or smaller regions pre-specified based on known neuroanatomical correlates. Volume and MD z-scores correlated inversely with each other in all four major ROIs (cortical, subcortical, cerebellar and total) highlighting that ROIs with lower Volumes had higher MD and vice-versa. Regarding correlations with symptoms and scores, higher MD correlated with worse Mini-Mental State Examination and Barthel scores in cortical and cerebellar gray matter, but subjects with cortical sensory deficits showed lower MD in the primary sensory cortex. Volume loss correlated with lower Mini-Mental State Examination, Barthel scores and pyramidal signs. Interestingly, for both Volume and MD, changes within the cerebellar ROI showed strong correlations with both MMSE and Barthel. Supporting using a combination of MD and Volume to track sCJD progression, MRI Disease-Staging showed correlations with more clinical outcomes than Volume or MD alone, specifically with Mini-Mental State Examination, Barthel score, pyramidal signs, higher cortical sensory deficits, as well as executive and visual-spatial deficits. Additionally, when subjects in the cohort were subdivided into tertiles based on their Barthel scores and their percentile of disease duration/course (“Time-Ratio”), subjects in the lowest (most impaired) Barthel tertile showed a much greater proportion of more advanced MRI Disease-Stages than the those in the highest tertile. Similarly, subjects in the last Time-Ratio tertile (last tertile of disease) showed a much greater proportion of more advanced MRI Disease-Stages than the earliest tertile. Therefore, in later disease stages, as measured by time or Barthel, there is overall more Volume loss and increasing MD. A combined multiparametric quantitative MRI Disease-Staging is a useful tool to track sporadic Creutzfeldt-Jakob- disease progression radiologically.

Graphical abstract, Highlights • FBA shows greater specificity in mapping injured fibers in post-stroke aphasia. • Intra-axonal volume of axons in dual streams is reduced in post-stroke aphasia. • FBA could locate more precise segments associated with language defects. • FBA could attribute language subdomain scores to fiber density of distinct tracts., Background The complex crossing-fiber characteristics in the dual-stream system have been ignored by traditional diffusion tensor models regarding disconnections in post-stroke aphasia. It is valuable to identify microstructural damage of crossing-fiber pathways and reveal accurate fiber-specific language mapping in patients with aphasia. Methods This cross-sectional study collected magnetic resonance imaging data from 29 participants with post-stroke aphasia in the subacute stage and from 33 age- and sex-matched healthy controls. Fixel-based analysis was performed to examine microstructural fiber density (FD) and bundle cross-section alterations of specific fiber populations in crossing-fiber regions. Group comparisons were performed, and relationships with language scores were assessed. Results The aphasic group exhibited significant fixel-wise FD reductions in the dual-stream tracts, including the left inferior fronto-occipital fasciculus (IFOF), arcuate fasciculus, and superior longitudinal fasciculus (SLF) III (family-wise-error-corrected p

Background: White matter (WM) impairment is a hallmark of amyotrophic lateral sclerosis (ALS). This study evaluated the capacity of mean apparent propagator magnetic resonance imaging (MAP-MRI) for detecting ALS-related WM alterations. Methods: Diffusion images were obtained from 52 ALS patients and 51 controls. MAP-derived indices [return-to-origin/-axis/-plane probability (RTOP/RTAP/RTPP) and non-Gaussianity (NG)/perpendicular/parallel NG (NG⊥/NG||)] were computed. Measures from diffusion tensor/kurtosis imaging (DTI/DKI) and neurite orientation dispersion and density imaging (NODDI) were also obtained. Voxel-wise analysis (VBA) was performed to determine differences in these parameters. Relationship between MAP parameters and disease severity (assessed by the revised ALS Functional Rating Scale (ALSFRS-R)) was evaluated by Pearson’s correlation analysis in a voxel-wise way. ALS patients were further divided into two subgroups: 29 with limb-only involvement and 23 with both bulbar and limb involvement. Subgroup analysis was then conducted to investigate diffusion parameter differences related to bulbar impairment. Results: The VBA (with threshold of P

Highlights • Cohort study of neonatal encephalopathy using continuous glucose monitoring. • Higher glucose on day 1 associated with widespread changes in brain microstructure. • Lower glucose not associated with brain microstructural changes. • No changes in MR spectroscopy found related to higher or lower glucose., Objective To identify how alterations in glucose levels are associated with regional brain injury in neonatal encephalopathy. Methods This was a prospective cohort study of 102 newborns with neonatal encephalopathy, with continuous glucose monitoring for 72 h. 97 (95%) completed 72 h of therapeutic hypothermia. Brain imaging around day 5 of life included diffusion tensor imaging and MR spectroscopy. Regions of interest were placed for both DTI and MR spectroscopy, and tractography of the optic radiation and corticospinal tract were evaluated. Linear regression models related each MR metric with minimum and maximum glucose values during each day of life, adjusting for 5-minute Apgar scores and umbilical artery pH. Results Higher maximum glucose levels on the first day of life were associated with widespread changes in mean diffusivity in the anterior and posterior white matter, splenium of the corpus callosum, lentiform nucleus, pulvinar nucleus of the thalamus, posterior limb of the internal capsule, and optic radiations, thus including regions traditionally associated with hypoxia–ischemia or hypoglycemia. No associations were found between lower minimum glucose levels and DTI changes in any regions tested, or between glucose levels and MR spectroscopy. Conclusions In this cohort of neonatal encephalopathy with therapeutic hypothermia, higher maximal glucose on the first day of life was associated with widespread microstructural changes, but lower minimum glucose levels were not associated with changes in any of the regions tested. Long-term follow-up will determine if imaging findings translate to long-term outcomes.

Highlights • LGN correlates with structural markers of the anterior and posterior visual pathway. • LGN volume may reduce after an episode of ON, shown in four patients. • LGN volume does not change over time in the absence of ON episodes. • Our findings argue against occult neurodegeneration in the visual pathway in NMO., Objectives Lateral geniculate nucleus (LGN) volume is reduced after optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD). We aimed at a longitudinal assessment of LGN volume in NMOSD. Methods Twenty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 47.8 ± 14.6 years (y), female: n = 27, history of ON (NMO-ON): n = 17, median time since ON: 3[1.2–12.1]y) and 18 healthy controls (HC; age: 39.3 ± 15.8y; female: n = 13) were included. Median follow-up was 4.1[1.1–4.7]y for patients and 1.7[0.9–3.2]y for HC. LGN volume was measured using a multi-atlas-based approach of automated segmentation on 3 Tesla magnetic resonance images. Retinal optical coherence tomography and probabilistic tractography of the optic radiations (OR) were also performed. Results At baseline, NMO-ON patients had lower LGN volumes (395.4 ± 48.9 mm3) than patients without ON (NMO-NON: 450.7 ± 55.6 mm3; p = 0.049) and HC (444.5 ± 61.5 mm3, p = 0.025). LGN volume was associated with retinal neuroaxonal loss and microstructural OR damage. Longitudinally, there was no change in LGN volumes in the absence of ON, neither in all patients (B = −0.6, SE = 1.4, p = 0.670), nor in NMO-ON (B = −0.8, SE = 1.6, p = 0.617) and NMO-NON (B = 1.7, SE = 3.5, p = 0.650). However, in four patients with new ON during follow-up, LGN volume was reduced at last visit (median time since ON: 2.6 [1.8–3.9] y) compared to the measurement before ON (352 ± 52.7 vs. 371.1 ± 55.9 mm3; t = −3.6, p = 0.036). Conclusion Although LGN volume is reduced after ON in NMOSD, this volume loss is not progressive over longer follow-up or independent of ON. Thus, our findings -at least in this relatively small cohort- do not support occult neurodegeneration of the afferent visual pathway in NMOSD.

Highlights • In aMCI, apathy severity was associated with lower FA in widespread WM pathways. • WM aberrations are related to apathy severity after controlling for depression. • Disruptions related to apathy severity are not limited to frontal-subcortical area., Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer’s Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p

Highlights • ACEs and PTSS did not significantly differ between patients and healthy controls. • Patients demonstrated greater corticolimbic connectivity compared to controls. • Greater PTSS and less corticolimbic connectivity increased headache frequency. • Less corticolimbic connectivity may indicate greater disease progression. • Patients may be more vulnerable to the effects of PTSS compared to controls., Background/aims Post-traumatic stress symptoms (PTSS) and chronic pain often co-occur at high rates in youth. PTSS may alter brain structure thereby contributing to headache chronicity. This study examined whether PTSS and altered limbic circuitry were associated with headache frequency in youth. Methods Thirty youth aged 10–18 years with chronic headaches and 30 age- and sex-matched controls underwent a 3T MRI scan. Volumes of the hippocampus and amygdala were obtained from T1-weighted images. Mean fractional anisotropy (FA, an index of white matter structure) axial and radial diffusivity values of the cingulum and uncinate fasciculus were extracted from diffusion-weighted images. Youth reported on their headaches daily, for one-month, and self-reported pubertal status, emotion regulation, adverse childhood experiences (ACEs) and PTSS using validated measures. Volumes of the hippocampus and amygdala and diffusivity values of the cingulum and uncinate were compared between patients and controls. Hierarchical linear regressions were used to examine the association between PTSS, subcortical volumes and/or diffusivity values and headache frequency. Results Mean FA values of the cingulum were higher in patients compared to controls (P = 0.02, Cohen’s d = 0.69). Greater PTSS (P = 0.04), smaller amygdala volumes (P = 0.01) and lower FA of the cingulum (P = 0.04) were associated with greater headache frequency, after accounting for age, puberty, pain duration, emotion regulation, and ACEs (Adjusted R2 ≥ 0.15). Headache frequency was associated with increases in radial diffusivity (P = 0.002, Adjusted R2 = 0.59), as opposed to axial diffusivity (n.s.). Conclusions PTSS, smaller amygdalar volume, and poorer cingulum structural connectivity were associated with headache frequency in youth, and may underlie headache chronicity.

Highlights • DTI study reveals brain-wide differences between SCA7 patients and controls. • DTI dual-compartment model controls for increased CSF-like free water in patients. • Tensor-based deformations show SCA7 tissue loss extends beyond cerebellum. • Focal atrophy, but global microstructural abnormalities were observed in SCA7., Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = −0.66, p = 0.104, FDR corrected) and global white matter pFA (r = −0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Highlights • White matter stiffness is significantly reduced in stable, shunted hydrocephalus patients vs controls. • In patients, age, sex and ventricular volume have significant associations with brain stiffness. • Lower brain stiffness, but not ventricular volume, predicts worse quality of life and depression., Introduction Hydrocephalus that develops early in life is often accompanied by developmental delays, headaches and other neurological deficits, which may be associated with changes in brain shear stiffness. However, noninvasive approaches to measuring stiffness are limited. Magnetic Resonance Elastography (MRE) of the brain is a relatively new noninvasive imaging method that provides quantitative measures of brain tissue stiffness. Herein, we aimed to use MRE to assess brain stiffness in hydrocephalus patients compared to healthy controls, and to assess its associations with ventricular size, as well as demographic, shunt-related and clinical outcome measures. Methods MRE was collected at two imaging sites in 39 hydrocephalus patients and 33 healthy controls, along with demographic, shunt-related, and clinical outcome measures including headache and quality of life indices. Brain stiffness was quantified for whole brain, global white matter (WM), and lobar WM stiffness. Group differences in brain stiffness between patients and controls were compared using two-sample t-tests and multivariable linear regression to adjust for age, sex, and ventricular volume. Among patients, multivariable linear or logistic regression was used to assess which factors (age, sex, ventricular volume, age at first shunt, number of shunt revisions) were associated with brain stiffness and whether brain stiffness predicts clinical outcomes (quality of life, headache and depression). Results Brain stiffness was significantly reduced in patients compared to controls, both unadjusted (p ≤ 0.002) and adjusted (p ≤ 0.03) for covariates. Among hydrocephalic patients, lower stiffness was associated with older age in temporal and parietal WM and whole brain (WB) (beta (SE): −7.6 (2.5), p = 0.004; −9.5 (2.2), p = 0.0002; −3.7 (1.8), p = 0.046), being female in global and frontal WM and WB (beta (SE): −75.6 (25.5), p = 0.01; −66.0 (32.4), p = 0.05; −73.2 (25.3), p = 0.01), larger ventricular volume in global, and occipital WM (beta (SE): −11.5 (3.4), p = 0.002; −18.9 (5.4), p = 0.0014). Lower brain stiffness also predicted worse quality of life and a higher likelihood of depression, controlling for all other factors. Conclusions Brain stiffness is reduced in hydrocephalus patients compared to healthy controls, and is associated with clinically-relevant functional outcome measures. MRE may emerge as a clinically-relevant biomarker to assess the neuropathological effects of hydrocephalus and shunting, and may be useful in evaluating the effects of therapeutic alternatives, or as a supplement, of shunting.

Highlights • Preterm infant white matter tracts uniquely predict later toddler language. • Neonatal medical history moderates posterior corpus callosum–language relations. • Different associations by tract may relate to brain maturation and medical history., Aim To determine whether variability in diffusion MRI (dMRI) white matter tract metrics, obtained in a cohort of preterm infants prior to neonatal hospital discharge, would be associated with language outcomes at age 2 years, after consideration of age at scan and number of major neonatal complications. Method 30 children, gestational age 28.9 (2.4) weeks, underwent dMRI at mean post menstrual age 36.4 (1.4) weeks and language assessment with the Bayley Scales of Infant Development–III at mean age 22.2 (1.7) months chronological age. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for 5 white matter tracts. Hierarchical linear regression assessed associations between tract FA, moderating variables, and language outcomes. Results FA of the left inferior longitudinal fasciculus accounted for 17% (p = 0.03) of the variance in composite language and FA of the posterior corpus callosum accounted for 19% (p = 0.02) of the variance in composite language, beyond that accounted for by post-menstrual age at scan and neonatal medical complications. The number of neonatal medical complications moderated the relationship between language and posterior corpus callosum FA but did not moderate the association in the other tract. Conclusion Language at age 2 is associated with white matter metrics in early infancy in preterm children. The different pattern of associations by fiber group may relate to the stage of brain maturation and/or the nature and timing of medical complications related to preterm birth. Future studies should replicate these findings with a larger sample size to assure reliability of the findings.

Highlights • Brain (micro-)structural differences were found in pre-adolescents who stutter. • Persistency was associated with marginally smaller left frontal gray matter volume. • Recovery was associated with higher mean diffusivity in white matter tracts. • Distinct brain structures implicated in persistence and recovery of stuttering., Background Stuttering is a complex speech fluency disorder occurring in childhood. In young children, stuttering has been associated with speech-related auditory and motor areas of the brain. During transition into adolescence, the majority of children who stutter (75–80%) will experience remission of their symptoms. The current study evaluated brain (micro-)structural differences between pre-adolescents who persisted in stuttering, those who recovered, and fluently speaking controls. Methods This study was embedded in the Generation R Study, a population-based cohort in the Netherlands of children followed from pregnancy onwards. Neuroimaging was performed in 2211 children (mean age: 10 years, range 8–12), of whom 20 persisted in and 77 recovered from stuttering. Brain structure (e.g., gray matter) and microstructure (e.g., diffusion tensor imaging) differences between groups were tested using multiple linear regression. Results Pre-adolescents who persisted in stuttering had marginally lower left superior frontal gray matter volume compared to those with no history of stuttering (β −1344, 95%CI −2407;-280), and those who recovered (β −1825, 95%CI −2999;-650). Pre-adolescents who recovered, compared to those with no history of stuttering, had higher mean diffusivity in the forceps major (β 0.002, 95%CI 0.001;0.004), bilateral superior longitudinal fasciculi (β 0.001, 95%CI 0.000;0.001), left corticospinal tract (β 0.003, 95%CI 0.002;0.004), and right inferior longitudinal fasciculus (β 0.001, 95%CI 0.000;0.001). Conclusion Findings suggest that relatively small difference in prefrontal gray matter volume is associated with persistent stuttering, and alterations in white matter tracts are apparent in individuals who recovered. The findings further strengthen the potential relevance of brain (micro-)structure in persistence and recovery from stuttering in pre-adolescents.

Highlights • T1ρ and RAFF4 - MRI protocols sensitive to slow motional regimes – are able to detect changes in T2w-defined normally appearing white matter of patients with multiple sclerosis. • RAFF4, T1ρ and T2ρ showed differences in hippocampus in patients with multiple sclerosis despite the absence of alterations in resting-state functional MRI metrics. • Hence, RAFF4, T1ρ and T2ρ hold promise as potential non-invasive tools for monitoring MS activity and eventually for the evaluation of therapeutic effects., Even though MRI visualization of white matter lesions is pivotal for the diagnosis and management of multiple sclerosis (MS), the issue of detecting diffuse brain tissue damage beyond the apparent T2-hyperintense lesions continues to spark considerable interest. Motivated by the notion that rotating frame MRI methods are sensitive to slow motional regimes critical for tissue characterization, here we utilized novel imaging protocols of rotating frame MRI on a clinical 3 Tesla platform, including adiabatic longitudinal, T1ρ, and transverse, T2ρ, relaxation methods, and Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank 4 (RAFF4), in 10 relapsing-remitting multiple sclerosis patients and 10 sex- and age-matched healthy controls. T1ρ, T2ρ and RAFF4 relaxograms extracted from the whole white matter exhibited a significant shift towards longer relaxation time constants in MS patients as compared to controls. T1ρ and RAFF4 detected alterations even when considering only regions of normally appearing white matter (NAWM), while other MRI metrics such as T1w/T2w ratio and diffusion tensor imaging measures failed to find group differences. In addition, RAFF4, T2ρ and, to a lesser extent, T1ρ showed differences in subcortical grey matter structures, mainly hippocampus, whereas no functional changes in this region were detected in resting-state functional MRI metrics. We conclude that rotating frame MRI techniques are exceptionally sensitive methods for the detection of subtle abnormalities not only in NAWM, but also in deep grey matter in MS, where they surpass even highly sensitive measures of functional changes, which are often suggested to precede detectable structural alterations. Such abnormalities are consistent with a wide spectrum of different, but interconnected pathological features of MS, including the loss of neuronal cells and their axons, decreased levels of myelin even in NAWM, and altered iron content.

Highlights • Limbic and caudal motor cortico-striatal tracts appear to be selectively vulnerable to degeneration in the early premanifest Huntington’s disease (preHD), approximately 11 years from predicted onset. • Similarly of cortico-thalamic connections, pre-motor and primary motor-thalamic connections appear selectively vulnerable to early degeneration. • However these connections appear preserved in a preHD cohort 25 years from predicted onset. • This highlights vulnerable subregions of the striatum and thalamus that may be important targets for future therapies that seek to prevent early neurodegeneration in preHD., Objectives To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington’s disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. Methods We performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. Results We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington’s disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. Conclusions Our findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS., Highlights • Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors. • Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed. • Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.

Objective To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS., Highlights • This study evaluates the relationship between 1H-MRS and [11C]-PBR28 PET-MR measures in people with ALS. • Myo-inositol/Creatine correlates positively with glial activation measured by [11C]-PBR28 PET, and negatively with fractional anisotropy. • N-acetyl-aspartate/Creatine correlates negatively with [11C]-PBR28 PET, and positively with fractional anisotropy. • Myo-inositol/Creatine and N-acetyl-aspartate/Creatine correlate with ALS-functional rating scale and upper motor neuron burden. • 1H-MRS and PET-MR measures provide complementary information to better understand brain pathology in people with ALS.

Objective To investigate the rich-club organization in clinically isolated syndrome (CIS) and multiple sclerosis (MS), and to characterize its relationships with physical disabilities and cognitive impairments. Methods We constructed high-resolution white matter (WM) structural networks in 41 CIS, 32 MS and 35 healthy controls (HCs) using diffusion MRI and deterministic tractography. Group differences in rich-club organization, global and local network metrics were investigated. The relationship between the altered network metrics, brain lesions and clinical variables including EDSS, MMSE, PASAT, disease duration were calculated. Additionally, reproducibility analysis was performed using different parcellation schemes. Results Compared with HCs, MS patients exhibited a decreased strength in all types of connections (rich-club: p, Highlights • The rich-club organization was disrupted in MS patients and preserved in CIS. • The disrupted rich-club connectivity correlated with cognitive impairment in MS. • The rich-club results are reproducible across data analysis methods.

Objective Isolated adult-onset focal dystonia is considered a network disorder with disturbances to the motor basal ganglia and cerebellar circuits playing a pathophysiological role, but why specific body regions become affected remains unknown. We aimed to use diffusion tensor imaging to determine if the two most common phenotypes of focal dystonia are associated with distinguishing microstructural changes affecting the motor network. Methods Fifteen blepharospasm patients, 20 cervical dystonia patients, and 30 age- and sex-matched healthy controls were recruited. Maps of fractional anisotropy and mean diffusivity were analyzed using a voxel-based approach and an automated region-of-interest technique to evaluate deep gray matter nuclei. Correlations between diffusion measures and dystonia severity were tested, and post hoc discriminant analyses were conducted. Results Voxel-based analyses revealed significantly reduced fractional anisotropy in the right cerebellum and increased mean diffusivity in the left caudate of cervical dystonia patients compared to controls, as well as lower fractional anisotropy in the right cerebellum in cervical dystonia patients relative to blepharospasm patients. In addition to reduced fractional anisotropy in the bilateral caudate nucleus of cervical dystonia patients relative to controls and blepharospasm patients, region-of-interest analyses revealed significantly reduced fractional anisotropy in the right globus pallidus internus and left red nucleus of blepharospasm patients compared to both controls and cervical dystonia patients. Diffusivity measures in the red nucleus of blepharospasm patients correlated with disease severity. In a three-group discriminant analysis, participants were correctly classified with only modest reliability (67–75%), but in a two-group discriminant analysis, patients could be distinguished from each other with high reliability (83–100%). Conclusions Different focal dystonia phenotypes are associated with distinct patterns of altered microstructure within constituent regions of basal ganglia and cerebellar circuits., Highlights • Globus pallidus and red nucleus microstructure is altered in blepharospasm. • Caudate and cerebellar microstructure is altered in cervical dystonia. • Disease severity in blepharospasm correlates with diffusivity in the red nucleus. • Diffusivity differences can differentiate blepharospasm from cervical dystonia. • Basal ganglia and cerebellar network disruptions may differ in dystonia phenotypes.

Locus of control (LOC) is an important personality trait. LOC over cognitive competency reflects an individual's perceived control of desired cognitive outcomes, which is critical for maintaining successful cognitive aging. It is important to understand the neural substrates of LOC over cognitive competency in older adults, especially for individuals at high risk of dementia. Here, we characterized a cohesive functional and structural connectivity profile underlying LOC among 55 older adults with amnestic mild cognitive impairment (aMCI), combining resting-state functional magnetic resonance imaging and diffusion tensor imaging. The results showed that both functional and structural connectivity between the medial prefrontal cortex and amygdala were significantly correlated with external LOC. The functional connectivity mediated the correlation between structural connectivity and external LOC. In addition, aging-associated neurodegeneration moderated the relationship between structural connectivity and external LOC, showing that the structural connectivity was positively correlated with external LOC in low, but not high neurodegeneration. Our results suggest a critical role of the functional amygdala-frontal network, which may serve as a bridge between its white matter tract and LOC over cognitive competency in groups at high risk for dementia., Highlights • Amygdala connectivity is associated with external locus of control (eLOC). • Functional connectivity mediates the relationship of structural connectivity and eLOC. • Neurodegeneration disrupts the relationship between structural connectivity and eLOC.

The symptoms of idiopathic normal pressure hydrocephalus (iNPH) can be improved by shunt surgery, but prediction of treatment outcome is not established. We investigated changes of the corticospinal tract (CST) in iNPH before and after shunt surgery by using diffusion microstructural imaging, which infers more specific tissue properties than conventional diffusion tensor imaging. Two biophysical models were used: neurite orientation dispersion and density imaging (NODDI) and white matter tract integrity (WMTI). In both methods, the orientational coherence within the CSTs was higher in patients than in controls, and some normalization occurred after the surgery in patients, indicating axon stretching and recovery. The estimated axon density was lower in patients than in controls but remained unchanged after the surgery, suggesting its potential as a marker for irreversible neuronal damage. In a Monte-Carlo simulation that represented model axons as undulating cylinders, both NODDI and WMTI separated the effects of axon density and undulation. Thus, diffusion MRI may distinguish between reversible and irreversible microstructural changes in iNPH. Our findings constitute a step towards a quantitative image biomarker that reflects pathological process and treatment outcomes of iNPH., Highlights • NODDI and WMTI provide markers of reversible and irreversible changes in iNPH. • Measures of axon orientation indicated recovery from stretching after surgery. • Axon density remained low after surgery, suggesting chronic neuronal damage. • Axon stretching in simulations differentially affected diffusion metrics.

Highlights • Diffusion MRI method reveals heterogeneity within white matter hyperintensities. • Lesion classes can be differentiated by their multi-tissue diffusion profiles. • Variability within lesion classes was identified based on microstructural features. • Offers in vivo method to probe relevance of lesion types to Alzheimer’s disease., White matter hyperintensities (WMH) are regions of high signal intensity typically identified on fluid attenuated inversion recovery (FLAIR). Although commonly observed in elderly individuals, they are more prevalent in Alzheimer’s disease (AD) patients. Given that WMH appear relatively homogeneous on FLAIR, they are commonly partitioned into location- or distance-based classes when investigating their relevance to disease. Since pathology indicates that such lesions are often heterogeneous, probing their microstructure in vivo may provide greater insight than relying on such arbitrary classification schemes. In this study, we investigated WMH in vivo using an advanced diffusion MRI method known as single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), which models white matter microstructure while accounting for grey matter and CSF compartments. Diffusion MRI data and FLAIR images were obtained from AD (n = 48) and healthy elderly control (n = 94) subjects. WMH were automatically segmented, and classified: (1) as either periventricular or deep; or (2) into three distance-based contours from the ventricles. The 3-tissue profile of WMH enabled their characterisation in terms of white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our SS3T-CSD findings revealed substantial heterogeneity in the 3-tissue profile of WMH, both within lesions and across the various classes. Moreover, this heterogeneity information indicated that the use of different commonly used WMH classification schemes can result in different disease-based conclusions. We conclude that future studies of WMH in AD would benefit from inclusion of microstructural information when characterising lesions, which we demonstrate can be performed in vivo using SS3T-CSD.

Highlights • Deep brain stimulation (DBS) benefits from precise targeting of white matter tracts. • Better to increase spatial vs. angular resolution for separating parallel tracts. • Scanning time trade-off between angular & spatial resolution depends on local anatomy. • We recommend increased spatial resolution dMRI for tract-guided internal capsule DBS., Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b = 2200s/mm2). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization.

Highlights • Diffusion MRI measures provide insight into gray matter microstructure in PTSD. • Amygdala-hippocampal and cingulate microstructure is associated with PTSD severity. • Mild TBI may exacerbate the impact of limbic microstructure on PTSD severity. • Neural contributors to psychiatric disorder severity may be affected by brain injury., Background Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships. Methods Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI. Results Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex. Conclusions These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.

Highlights • Fractionating insight into objects aids its neuroanatomical exploration in dementia. • Distinctive neural correlates seem to underpin different insight objects in FTD. • Altered insight into disease/health condition mostly involves right frontal areas. • Altered insight into social cognition implicates frontal, temporal and limbic areas. • Frontal, medial temporal and parietal areas underpin insight into memory problems., Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

Background: Diffusion tensor imaging (DTI) is widely used; however, most of the prior studies have resulted in presurgical decreased fractional anisotropy (FA) values in patients with cervical spondylotic myelopathy (CSM). We used ZOOM DTI and could acquire highly accurate FA values during perioperative periods, which indicated different insights than preceding studies. The objective of this study was to assess the perioperative FA change in patients with CSM and determine the prognostic factor. Methods: Twenty-eight patients with CSM and healthy control subjects were enrolled in this study. Twenty patients (71%) had intracordal high intensity before surgery. All patients underwent decompressive surgery. ZOOM DTI and the Japanese Orthopaedic Association (JOA) assessment were performed before and after surgery. The region of interest was manually contoured to omit the surrounding cerebrospinal fluid. The axial plane of the most stenotic cervical level was assessed. Results: FA values before surgery and at 1 week after surgery, and FA values at 1 week after surgery and at 6 months after surgery differed significantly as determined. The FA values of patients with intracordal high intensity significantly decreased after surgery and significantly increased from 1 week to 6 months, whereas those of patients without intracordal high intensity did not significantly change. JOA scores at 6 months after surgery (13.1) improved significantly compared with JOA scores before surgery (10.8). Only FA values at 1 week after surgery had a significant positive relationship with JOA scores presurgery and at 6 months after surgery. Conclusions: The presurgical FA value in patients with CSM did not differ from that of normal control subjects, but significantly decreased after surgery, and significantly increased 6 months after surgery. We concluded that the postsurgical FA value approximates the proper state of the damaged cord and the presurgical FA value includes a masked effect as an aligned fiber effect because of compression by degenerative construction. Only the FA value at 1 week had a significant positive relationship with the JOA score presugery and at 6 months, which established that the postsurgical FA value may be a more accurate prognostic factor than the presurgical FA value. Key words: Cervical degenerative spondylosis, Diffusion tensor imaging, Fractional anisotropy, Prognostic factor, Tractography

Background Mild Cognitive Impairment (MCI) is an intermediate state between normal cognition and dementia that is associated with twice the risk of falls. It is unknown whether white matter integrity (WMI) is associated with increased risk of falls in MCI. The purpose of this study was to evaluate if early changes in WMI were associated with gait impairment and falls. Methods Forty-three participants with MCI from the Gait and Brain Study underwent standardized assessment of cognition, gait performance under single and dual-task conditions (walking while talking), and WMI using 3 Tesla diffusion tensor imaging (DTI). Macro-structural imaging characteristics (white and grey matter morphology) as well as microstructural WMI parameters were examined for associations with falls and gait performance. Significantly associated WM tracts were then used to test the interplay between WMI and history of falls, after adjusting for other important covariates. Results Multiple WM tracts (corpus callosum, forceps minor, and the left inferior fronto-occipital fasciculus) were significantly associated with history of falls and lower dual-task gait performance. A multivariable regression model showed that fall history was associated with the radial diffusivity in the forceps minor, even after adjusting for education, sex, BMI, MMSE scores, comorbidities, gait velocity and WMH volume as covariates. Conclusions Multiple WM tracts that are known to be involved in executive and visuospatial functions were preferentially affected in MCI individuals with history of falls. Our preliminary findings support the notion that WMI in key brain regions may increase risk of falls in older adults with MCI., Highlights • 43 older adults with MCI were assessed for falls, gait, and WMI using 3 T DTI. • Multiple WM tracts were associated with falls and lower dual-task gait performance. • Tracts affected are known to be involved in executive and visuospatial functions.

Introduction The underlying microstructural properties of white matter differences in children born very preterm (, Highlights • Children born VPT have lower FA and higher MD, RD, and ODI in white matter regions. • Higher ODI in the corona radiata was associated with perinatal white matter lesions. • Associations were found between FA and NDI with outcomes in the children born VPT. • NODDI metrics aid interpretation of white matter differences in children born VPT.

Connectome-based lesion symptom mapping (CLSM) can be used to relate disruptions of brain network connectivity with clinical measures. We present a novel method that extends current CLSM approaches by introducing a fast reliable and accurate way for computing disconnectomes, i.e. identifying damaged or lesioned connections. We introduce a new algorithm that finds the maximally disconnected subgraph containing regions and region pairs with the greatest shared connectivity loss. After normalizing a stroke patient's segmented MRI lesion into template space, probability weighted structural connectivity matrices are constructed from shortest paths found in white matter voxel graphs of 210 subjects from the Human Connectome Project. Percent connectivity loss matrices are constructed by measuring the proportion of shortest-path probability weighted connections that are lost because of an intersection with the patient's lesion. Maximally disconnected subgraphs of the overall connectivity loss matrix are then derived using a computationally fast greedy algorithm that closely approximates the exact solution. We illustrate the approach in eleven stroke patients with hemiparesis by identifying expected disconnections of the corticospinal tract (CST) with cortical sensorimotor regions. Major disconnections are found in the thalamus, basal ganglia, and inferior parietal cortex. Moreover, the size of the maximally disconnected subgraph quantifies the extent of cortical disconnection and strongly correlates with multiple clinical measures. The methods provide a fast, reliable approach for both visualizing and quantifying the disconnected portion of a patient's structural connectome based on their routine clinical MRI, without reliance on concomitant diffusion weighted imaging. The method can be extended to large databases of stroke patients, multiple sclerosis or other diseases causing focal white matter injuries helping to better characterize clinically relevant white matter lesions and to identify biomarkers for the recovery potential of individual patients., Highlights • Significantly accelerated shortest path tractography approach for constructing connectomes and disconnectomes. • New algorithm extracts the subnetwork containing cortical connections and regions with maximal shared connectivity loss. • The size of the maximally disconnected subnetwork quantifies the extent of disconnection and correlates with stroke measures. • Fast and accurate approach for visualizing and analyzing the disconnected portion of a patient's structural connectome.

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current avenues of AD research focus on pre-symptomatic biomarkers that will assist with early diagnosis of AD. The majority of magnetic resonance imaging (MRI) based biomarker research to date has focused on neuronal loss in grey matter and there is a paucity of research on white matter. Methods Longitudinal DTI data from the Alzheimer's Disease Neuroimaging Initiative 2 database were used to examine 1) the within-group microstructural white matter changes in individuals with AD and healthy controls at baseline and year one; and 2) the between-group microstructural differences in individuals with AD and healthy controls at both time points. Results 1) Within-group: longitudinal Tract-Based Spatial Statistics revealed that individuals with AD and healthy controls both had widespread reduced fractional anisotropy (FA) and increased mean diffusivity (MD) with changes in the hippocampal cingulum exclusive to the AD group. 2) Between-group: relative to healthy controls, individuals with AD had lower FA and higher MD in the hippocampal cingulum, as well as the corpus callosum, internal and external capsule; corona radiata; posterior thalamic radiation; superior and inferior longitudinal fasciculus; fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; and tapetum. Conclusion The current results indicate that sensitivity to white matter microstructure is a promising avenue for AD biomarker research. Additional longitudinal studies on both white and grey matter are warranted to further evaluate potential clinical utility., Highlights • Longitudinal white matter research in Alzheimer's disease. • Diffusion tensor imaging used to assess microstructural white matter changes. • Decreased fractional anisotropy and increased mean diffusivity over one year. • Widespread changes in Alzheimer's disease include the hippocampal cingulum. • DTI holds potential as Alzheimer's disease biomarker.

Antisocial behavior (AB), including aggression, violence, and theft, is thought be underpinned by abnormal functioning in networks of the brain critical to emotion processing, behavioral control, and reward-related learning. To better understand the abnormal functioning of these networks, research has begun to investigate the structural connections between brain regions implicated in AB using diffusion tensor imaging (DTI), which assesses white-matter tract microstructure. This systematic review integrates findings from 22 studies that examined the relationship between white-matter microstructure and AB across development. In contrast to a prior hypothesis that AB is associated with greater diffusivity specifically in the uncinate fasciculus, findings suggest that adult AB is associated with greater diffusivity across a range of white-matter tracts, including the uncinate fasciculus, inferior fronto-occipital fasciculus, cingulum, corticospinal tract, thalamic radiations, and corpus callosum. The pattern of findings among youth studies was inconclusive with both higher and lower diffusivity found across association, commissural, and projection and thalamic tracts., Highlights • Antisocial behavior (AB) is characterized by impaired emotion and reward processing. • These behaviors may develop from microstructural abnormalities of white-matter tracts. • We provide a systematic review of 22 diffusion tensor imaging studies of AB. • Adult AB was linked to greater diffusivity (“poorer integrity”) across a range of white-matter tracts. • For youth AB, there were mixed findings.

Current imaging diagnostic techniques are often insensitive to the underlying pathological changes following mild traumatic brain injury (TBI) or concussion so much so that the explicit definition of these uncomplicated mild brain injuries includes the absence of radiological findings. In the US military, this is complicated by the natural tendency of service members to down play symptoms for fear of removal from their unit particularly in combat making it challenging for clinicians to definitively diagnose and determine course of treatment. Questions remain regarding the long-term impact of these war-time brain injuries. The objective of the current study was to evaluate the long-term imaging sequelae of blast concussion in active-duty US military and leverage previous longitudinal data collected in these same patients to identify predictors of sustained DTI signal change indicative of chronic neurodegeneration. In total, 50 blast TBI and 44 combat-deployed controls were evaluated at this 5-year follow up by advanced neuroimaging techniques including diffusion tensor imaging and quantitative volumetry. While cross-sectional analysis of regions of white matter on DTI images did not reveal significant differences across groups after statistical correction, an approach flexible to the heterogeneity of brain injury at the single-subject level identified 74% of the concussive blast TBI cohort to have reductions in fractional anisotropy indicative of chronic brain injury. Logistic regression leveraging clinical and demographic data collected in the acute/sub-acute and 1-year follow up to determine predictors of these long-term imaging changes determined that brain injury diagnosis, older age, verbal memory and verbal fluency best predicted the presence of DTI abnormalities 5 years post injury with an AUC of 0.78 indicating good prediction strength. These results provide supporting evidence for the evolution not resolution of this brain injury pathology, adding to the growing body of literature describing imaging signatures of chronic neurodegeneration even after mild TBI and concussion., Highlights • Design: prospective, observational, longitudinal research study • Patients: concussive blast (n = 50), combat-deployed control (n = 44) • Diffusion tensor imaging analyzed 5 yr post-injury, highly predicted by 1 yr outcomes. • Imaging abnormalities appear to evolve from sub-acute, to 1-year, to 5-year scan. • Findings indicate chronic neurodegeneration in majority of blast concussion patients.

Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n = 109; Age: M = 47.2, SD = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologist's diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population., Highlights • We conducted ROC analyses using DTI data from veterans with and without traumatic brain injury. • For each participant, DTI analysis identified measures (FA, MD, RD, AD) from twenty fiber tracts. • ROC analyses determined which fiber tracts best predict TBI status for each measure.

The relationships between impairment, function, arm use and underlying brain structure following stroke remain unclear. Although diffusion weighted imaging is useful in broadly assessing white matter structure, it has limited utility in identifying specific underlying neurobiological components, such as myelin. The purpose of the present study was to explore relationships between myelination and impairment, function and activity in individuals with chronic stroke. Assessments of paretic upper-extremity impairment and function were administered, and 72-hour accelerometer based activity monitoring was conducted on 19 individuals with chronic stroke. Participants completed a magnetic resonance imaging protocol that included a high resolution T1 anatomical scan and a multi-component T2 relaxation imaging scan to quantify myelin water fraction (MWF). MWF was automatically parcellated from pre- and post-central subcortical regions of interest and quantified as an asymmetry ratio (contralesional/ipsilesional). Cluster analysis was used to group more and less impaired individuals based on Fugl-Meyer upper extremity scores. A significantly higher precentral MWF asymmetry ratio was found in the more impaired group compared to the less impaired group (p, Highlights • Identification of neurobiology that contributes to recovery after stroke is critical. • Human post-stroke myelination can be imaged in vivo using T2 relaxation imaging. • Impaired individuals demonstrate precentral myelin asymmetry between hemispheres. • Precentral myelin asymmetry is a predictor of motor function and impairment. • Myelination may be a specific marker of post-stroke neurobiological changes.

We sought to investigate white matter abnormalities in mild traumatic brain injury (mTBI) using diffusion-weighted magnetic resonance imaging (DW-MRI). We applied a global approach based on tract-based spatial statistics skeleton as well as constrained spherical deconvolution tractography. DW-MRI was performed on 102 patients with mTBI within two months post-injury and 30 control subjects. A robust global approach considering only the voxels with a single-fiber configuration was used in addition to global analysis of the tract skeleton and probabilistic whole-brain tractography. In addition, we assessed whether the microstructural parameters correlated with age, time from injury, patient's outcome and white matter MRI hyperintensities. We found that whole-brain global approach restricted to single-fiber voxels showed significantly decreased fractional anisotropy (FA) (p = 0.002) and increased radial diffusivity (p = 0.011) in patients with mTBI compared with controls. The results restricted to single-fiber voxels were more significant and reproducible than those with the complete tract skeleton or the whole-brain tractography. FA correlated with patient outcomes, white matter hyperintensities and age. No correlation was observed between FA and time of scan post-injury. In conclusion, the global approach could be a promising imaging biomarker to detect white matter abnormalities following traumatic brain injury., Highlights • Mild TBI is associated with microstructural changes in the white matter. • The global approach restricted to single-fiber voxels is robust and reliable. • Fractional anisotropy values are associated with neurological outcome.

Highlights • Maturation of specific WM tracts in preterm individuals differs from those of term controls. • The elastic net logistic regression model was used to identify altered white matter tracts in the preterm brain. • The alteration of the cingulum in the preterm at near-term correlate with neurodevelopmental scores at 18–22 months of age., Background Relative to full-term infants, very preterm infants exhibit disrupted white matter (WM) maturation and problems related to development, including motor, cognitive, social-emotional, and receptive and expressive language processing. Objective The present study aimed to determine whether regional abnormalities in the WM microstructure of very preterm infants, as defined relative to those of full-term infants at a near-term age, are associated with neurodevelopmental outcomes at the age of 18–22 months. Methods We prospectively enrolled 89 very preterm infants (birth weight

Graphical abstract, Highlights • Tractography was compared between two groups of tinnitus and control participants. • Diffusion was modeled with ss3t-CSD allowing apparent fiber density (AFD) calculation. • 27 bundles of interest were chosen for their link to the auditory and limbic systems. • AFD was significantly increased in the tinnitus group in the right frontal isthmus. • AFD in the acoustic radiations was not significantly different between the groups., Subjective tinnitus is a symptom characterized by the perception of sound with no external acoustic source, most often accompanied by co-morbidities. To date, the specific role of white matter abnormalities related to tinnitus reaches no consensus in the literature. The goal of this study was to explore the structural connectivity related to tinnitus percept per se, thus focusing on a specific population presenting chronic non-bothersome tinnitus of similar etiology (noise induced) without co-morbidities. We acquired diffusion-weighted images with high angular resolution in a homogeneous group of mildly impacted tinnitus participants (n = 19) and their matched controls (n = 19). We focused the study on two subsets of fiber bundles of interest: on one hand, we extracted the acoustic radiation and further included any intersecting fiber bundles; on the other hand, we explored the tracts related to the limbic system. We modeled the diffusion signal using constrained spherical deconvolution. We conducted a deep-learning based tractography segmentation and mapped Apparent Fiber Density (AFD) on the bundles of interest. C, as well as Fractional Anisotropy (FA) and FOD peak amplitude for comparison. Between group statistical comparison was performed along the 27 tracts of interest controlling for confounding hearing loss, tinnitus severity, and duration since onset. We tested a potential correlation with hearing loss, tinnitus duration and tinnitus handicap score along these tracts. In the tinnitus group, we observed increased AFD related to chronic tinnitus percept after acoustic trauma in two main white matter regions. First, in the right hemisphere, in the isthmus between inferior temporal and inferior frontal cortices, in the uncinate fasciculus (UF), and in the inferior fronto-occipital bundle (IFO). Second, in the left hemisphere, underneath the superior parietal region in the thalamo parietal tract and parieto-occipital pontine tract. Between-group differences in the acoustic radiations were not significant with AFD but were with FA. Furthermore, significant correlations with hearing loss were found in the left hemisphere in the inferior longitudinal fasciculus and in the fronto-pontine tract. No additional correlation was found with tinnitus duration nor with tinnitus handicap, as reflected by THI scores. The regions that displayed tinnitus related increased AFD also displayed increased FA. The isthmus of the UF and IFO in the right hemisphere appear to be involved with a number of neuropsychiatric and traumatic disorders confirming the involvement of the limbic system even in chronic non-bothersome tinnitus subjects, potentially suggesting a common pathway between these pathologies. White matter changes underneath the superior parietal cortex found here in tinnitus participants supports the implication of an auditory-somatosensory pathway in tinnitus perception.

Graphical abstract, Highlights • Ultrahigh-b DWI (UHb-DWI) method applied to MS spinal cords. • UHb-DWI provides quantitative measures of the MS lesions in the spinal cord. • High-b diffusion coefficient (DH) is theoretically sensitive for demyelination. • DH in MS lesion is significantly elevated compared to that of normal spinal cords., Purpose The purpose of this study was to investigate UHb-rDWI signal in white matter tracts of the cervical spinal cord (CSC) and compare quantitative values between healthy control WM with both MS NAWM and MS WM lesions. Methods UHb-rDWI experiments were performed on (a) 7 MS patients with recently active or chronic lesions in CSC and on (b) 7 healthy control of similar age range and gender distribution to MS subjects. All MRI data were acquired using clinical 3T MRI system. Axial high-b diffusion images were acquired using 2D single-shot DW stimulated EPI with reduced FOV and a CSC-dedicated 8 channel array coil. High-b diffusion coefficient DH was estimated by fitting the signal-b curve to a double or single-exponential function. Results The high-b diffusivity DH values were measured as (0.767 ± 0.297) × 10−3 mm2/s in the posterior column lesions, averaged over 6 MS patients, and 0.587 × 10−3 mm2/s in the corticospinal tract for another patient. The averaged DH values of the 7 healthy volunteers from the posterior and lateral column were (0.0312 ± 0.0306) × 10−3 and (0.0505 ± 0.0205) × 10−3 mm2/s, respectively. UHb-rDWI signal-b curves of the MS patients revealed to noticeably behave differently to that of the healthy controls. The patient signal-b curves decayed with greater high-b decay constants to reach lower signal intensities relative to signal-b curves of the healthy controls. Conclusion UHb-DWI of the CSC reveals a marked difference in signal-b-curves and DH values in MS lesions compared to NAWM and healthy control WM. Based on physical principles, we interpret these altered observations of quantitative diffusion values to be indicative of demyelination. Further studies in animal models will be required to fully interpret UHb-DWI quantitative diffusion values during demyelination and remyelination.

Highlights • Examining associations between physical activity, physical capability and brain health. • Higher global FA were observed in older adults with higher walking speed. • Lower subcortical brain age gap (BAG) were observed in more physically active women., Maintaining high levels of daily activity and physical capability have been proposed as important constituents to promote healthy brain and cognitive aging. Studies investigating the associations between brain health and physical activity in late life have, however, mainly been based on self-reported data or measures designed for clinical populations. In the current study, we examined cross-sectional associations between physical activity, recorded by an ankle-positioned accelerometer for seven days, physical capability (grip strength, postural control, and walking speed), and neuroimaging based surrogate markers of brain health in 122 healthy older adults aged 65–88 years. We used a multimodal brain imaging approach offering complementary structural MRI based indicators of brain health: global white matter fractional anisotropy (FA) and mean diffusivity (MD) based on diffusion tensor imaging, and subcortical and global brain age based on brain morphology inferred from T1-weighted MRI data. In addition, based on the results from the main analysis, follow-up regression analysis was performed to test for association between the volume of key subcortical regions of interest (hippocampus, caudate, thalamus and cerebellum) and daily steps, and a follow-up voxelwise analysis to test for associations between walking speed and FA across the white matter Tract-Based Spatial Statistics (TBSS) skeleton. The analyses revealed a significant association between global FA and walking speed, indicating higher white matter integrity in people with higher pace. Voxelwise analysis supported widespread significant associations. We also found a significant interaction between sex and subcortical brain age on number of daily steps, indicating younger-appearing brains in more physically active women, with no significant associations among men. These results provide insight into the intricate associations between different measures of brain and physical health in old age, and corroborate established public health advice promoting physical activity.

Introduction The effects of nusinersen in adults with SMA rely on neuromotor function scales and qualitative assessments. There are limited clinical or imaging data on muscle changes over time. Methods Two adult SMA patients underwent clinical assessments including measures of upper and lower limb function with Revised Upper Limb Module (RULM) and Hammersmith Function Motor Scale Expanded (HFMSE); both patients were also studied with whole-body muscle MRI (T1-weighted and Diffusion Tensor Imaging/DTI sequences), at baseline and after 10 and 24 months from the beginning of treatment with nusinersen. Results After two years of treatment, HFMSE and RULM scores were stable in both patients. DTI sequences revealed an increased number, length and organization of muscle fiber tracks, and Fractional Anisotropy (FA) values showed a significant reduction after 10 and 24 months from baseline, in their corresponding maps. Discussion Muscle DTI imaging seems to play an interesting role to monitor treatment effects over time in adult SMA patients., Highlights • Nusinersen treatment has created great expectations in older SMA patients having long-lasting muscular atrophy. • DTI is a very sensitive technique to identify small changes in muscle architecture. • DTI shows that nusinersen treatment may have a positive effect on size, length and organization of fiber tracts.

Children born very preterm (VPT, Highlights • Very preterm children have widespread decreased MTR in white matter. • T1-w/T2-w ratio measures showed consistent white matter alterations. • T1-w/T2-w ratio was also reduced in subcortical, occipital and temporal regions. • MTR and T1-w/T2-w were correlated throughout the brain. • MTR and T1-w/T2-w correlated with developmental assessments.

Objective Focused ultrasound thalamotomy is an emerging treatment for essential tremor, and it is ideal for studying reorganization in the human brain after acute injury because it creates a controlled thalamic ablation without breaching the cortex. However, there is not yet a metric capable of detecting microstructural changes in the presence of acute phase edema with good sensitivity in the chronic phase, when the lesion boundaries become inconspicuous. Methods We prospectively studied microstructural changes at the lesion site using generalized q-sampling imaging with restricted diffusion imaging. We obtained diffusion-weighted MRI scans preoperatively, 1 day after (n = 18), and 1 year after (n = 9) focused ultrasound thalamotomy. The restricted diffusion imaging maps were compared at the group level, controlling for improvement in contralateral hand tremor. Results The restricted diffusion imaging metric significantly increased in the 1 day post images, and the area with restricted diffusivity extended beyond the lesion boundaries identified on T2-weighted imaging. Two distinct zones of microstructural changes were identified, and the lesion area was identifiable at 1 year. The anterior and medial aspects of the lesion had a significant changes in RDI at 1 year, potentially signifying reorganization. The voxels with significant changes in restricted diffusion imaging values extend beyond the VIM into the surrounding white matter. Interpretation Correcting for free water contamination with restricted diffusion imaging allowed us to study microstructural changes after focused ultrasound thalamotomy. We observed statistically significant changes in RDI in the anterior and medial aspect of the lesion at 1 year. Whether these changes represent tissue reorganization remains to be confirmed in future studies. These findings may support performing additional ablations antero-medially for durable efficacy., Highlights • Focused ultrasound thalamotomy is an emerging treatment for essential tremor, but challenges remain in determining microstructural changes in the ablated tissue. • We prospectively studied microstructural changes at the lesion site using generalized q-sampling imaging with restrictyed diffusion imaging (RDI) in 18 patients with ET. • The RDI metric significantly increased after focused ultrasound, and the area with restricted diffusivity extended beyond the lesion boundaries identified on T2-weighted imaging. • Two distinct zones of microstructural changes were identified, and the lesion area was also identifiable at 1 year. The anterior and medial aspects of the lesion had a significant RDI change at 1 year, potentially signifying reorganization.

Background Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). Conclusions FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter., Highlights • MRI-based classification was performed on presymptomatic FTD gene carriers and controls. • Presymptomatic carriers were separated from controls significantly better than chance-level. • The best performing model was based on white matter features from structural and diffusion scans. • Multimodal MRI-based classification scores may be useful to aid earlier FTD diagnosis.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. Methods Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. Results In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. Conclusions Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation., Highlights • (SMA) type 3 and 4 is a lower motor neuron syndrome. Nevertheless, wider involvement of the nervous system might be possible. • 25 adults type 3 and 4 SMA patients were studied using brain and cervical spinal cord neuroimaging techniques. • Grey matter atrophy was observed in the spinal cord. No white matter degeneration was present at brain and spinal level. • Increased grey matter density was detected in cerebral motor regions and explained as compensatory mechanism.

Background Cerebral microbleeds (CMBs) are considered to be risk factors for cognitive dysfunction. The specific pathology and clinical manifestations of CMBs are different based on their locations. We investigated the association between CMBs at different locations and cognitive dysfunction and explored the potential underlying pathways in a rural Han Chinese population. Methods We used baseline data from 562 community-dwelling adults (55–65 years old) in the Taizhou Imaging Study between 2013 and 2015. All individuals underwent multimodal brain magnetic resonance imaging (MRI) and 444 subjects completed neuropsychological tests: the Mini-Mental Status Examination and the Montreal Cognitive Assessment. Multinomial logistic regression was used to estimate the association between CMBs and cognitive dysfunction. The volume of brain regions and white matter microstructure were analyzed using Freesurfer and tract-based spatial statistics, respectively. Results CMBs were detected in 104 individuals (18.5%) in our study. Multinomial logistic regression found deep/mixed CMBs were associated with global cognitive dysfunction (OR 3.52; 95% CI 1.21 to 10.26), whereas lobar CMBs (OR 1.76; 95% CI 0.56 to 5.53) were not. Quantification of multimodal brain MRI showed that deep/mixed CMBs were accompanied by decreased thalamic volume and loss of fractional anisotropy of bilateral anterior thalamic radiations. Conclusion Deep/mixed CMBs were associated with cognitive dysfunction in this Chinese cross-sectional study. Disruption of thalamocortical connectivity might be a potential pathway underlying this relationship., Highlights • Cerebral microbleeds (CMBs) are found in 18.5% of middle-aged Chinese population. • Deep/mixed CMBs, not lobar CMBs, are associated with cognitive dysfunction. • Atrophy and fiber connectivity disruption might be the underlying neural pathways.

Alzheimer's disease (AD), an irreversible neurodegenerative disease, is the most common type of dementia in elderly people. This present study incorporated multiple structural and functional connectivity metrics into a graph theoretical analysis framework and investigated alterations in brain network topology in patients with mild cognitive impairment (MCI) and AD. By using this multiparametric analysis, we expected different connectivity metrics may reflect additional or complementary information regarding the topological changes in brain networks in MCI or AD. In our study, a total of 73 subjects participated in this study and underwent the magnetic resonance imaging scans. For the structural network, we compared commonly used connectivity metrics, including fractional anisotropy and normalized streamline count, with multiple diffusivity-based metrics. We compared Pearson correlation and covariance by investigating their sensitivities to functional network topology. Significant disruption of structural network topology in MCI and AD was found predominantly in regions within the limbic system, prefrontal and occipital regions, in addition to widespread alterations of local efficiency. At a global scale, our results showed that the disruption of the structural network was consistent across different edge definitions and global network metrics from the MCI to AD stages. Significant changes in connectivity and tract-specific diffusivity were also found in several limbic connections. Our findings suggest that tract-specific metrics (e.g., fractional anisotropy and diffusivity) provide more sensitive and interpretable measurements than does metrics based on streamline count. Besides, the use of inversed radial diffusivity provided additional information for understanding alterations in network topology caused by AD progression and its possible origins. Use of this proposed multiparametric network analysis framework may facilitate early MCI diagnosis and AD prevention., Highlights • Alzheimer's disease alters structural network mainly in limbic and superior frontal regions. • Altered global network topology may occur in earlier stage during mild cognitive impairment. • The capability of proposed multiparametric network analysis has been demonstrated. • The potential of inversed radial diffusivity on network analysis has been shown.

Sensory-motor integration models have been proposed aiming to explain how the brain uses sensory information to guide and check the planning and execution of movements. Sensory neuronopathy (SN) is a peculiar disease characterized by exclusive, severe and widespread sensory loss. It is a valuable condition to investigate how sensory deafferentation impacts brain organization. We thus recruited patients with clinical and electrophysiological criteria for SN to perform structural and functional MRI analyses. We investigated volumetric changes in gray matter (GM) using anatomical images; the microstructure of WM within segmented regions of interest (ROI), via diffusion images; and brain activation related to a finger tapping task. All significant results were related to the long disease duration subgroup of patients. Structural analysis showed hypertrophy of the caudate nucleus, whereas the diffusion study identified reduction of fractional anisotropy values in ROIs located around the thalamus and the striatum. We also found differences regarding finger-tapping activation in the posterior parietal regions and in the medial areas of the cerebellum. Our results stress the role of the caudate nucleus over the other basal ganglia in the sensory-motor integration models, and suggest an inhibitory function of a recently discovered tract between the thalamus and the striatum. Overall, our findings confirm plasticity in the adult brain and open new avenues to design neurorehabilitation strategies., Highlights • Sensory deafferentation impacts basal ganglia circuitry. • Hypertrophy of the caudate nuclei seems to be a consequence of proprioceptive loss. • The caudate nucleus is a key structure in the sensory-motor integration system. • Activation of cerebellum and parietal regions is abnormal during finger-tapping.

Improved characterization of the microstructural brain changes occurring in the early stages of Alzheimer's disease may permit more timely disease detection. This study examined how longitudinal change in brain microstructure relates to cognitive decline in aging and prodromal Alzheimer's disease. At baseline and two-year follow-up, 29 healthy controls and 21 individuals with mild cognitive impairment or mild Alzheimer's disease underwent neuropsychological evaluation and restriction spectrum imaging (RSI). Microstructural change in the hippocampus, entorhinal cortex, and white matter tracts previously shown to be vulnerable to Alzheimer's disease, was compared between healthy controls and impaired participants. Partial correlations and stepwise linear regressions examined whether baseline RSI metrics predicted subsequent cognitive decline, or change in RSI metrics correlated with cognitive change. In medial temporal gray and white matter, restricted isotropic diffusion and crossing fibers were lower, and free water diffusion was higher, in impaired participants. Restricted isotropic diffusion in the hippocampus declined more rapidly for cognitively impaired participants. Baseline hippocampal restricted isotropic diffusion predicted cognitive decline, and change in hippocampal and entorhinal restricted isotropic diffusion correlated with cognitive decline. Within controls, changes in white matter restricted oriented diffusion and crossing fibers correlated with memory decline. In contrast, there were no correlations between rates of cortical atrophy and cognitive decline in the full sample or within controls. Changes in medial temporal lobe microarchitecture were associated with cognitive decline in prodromal Alzheimer's disease, and these changes were distinct from microstructural changes in normal cognitive aging. RSI metrics of brain microstructure may hold value for predicting cognitive decline in aging and for monitoring the course of Alzheimer's disease., Highlights • Longitudinal diffusion MRI was conducted in individuals with MCI/AD and controls. • Mean restricted diffusion in hippocampus declined more rapidly in MCI/AD. • Baseline hippocampal restricted diffusion predicted cognitive decline. • Change in medial temporal restricted diffusion correlated with cognitive decline. • In healthy controls, white matter microstructure correlated with memory decline.