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IntroductionShort-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15–20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear.MethodsA multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3–6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized.DiscussionLong-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease.Study registrationclinicaltrials.gov (MOIST late cross-sectional study; NCT04525404).

Abstract Objective Typical aging is associated with gradual cognitive decline and changes in brain structure. The observation that cognitive performance in mesial temporal lobe epilepsy (TLE) patients diverges from controls early in life with subsequent decline running in parallel would suggest an initial insult but does not support accelerated decline secondary to seizures. Whether TLE patients demonstrate similar trajectories of age‐related gray (GM) and white matter (WM) changes as compared to healthy controls remains uncertain. Methods 3D T1‐weighted and diffusion tensor images were acquired at a single site in 170 TLE patients (aged 23–74 years) with MRI signs of unilateral hippocampal sclerosis (HS, 77 right) and 111 healthy controls (aged 26–80 years). Global brain (GM, WM, total brain, and cerebrospinal fluid) and regional volumes (ipsi‐ and contralateral hippocampi), and fractional anisotropy (FA) of 10 tracts (three portions of corpus callosum, inferior longitudinal, inferior fronto‐occipital and uncinate fasciculi, body of fornix, dorsal and parahippocampal‐cingulum, and corticospinal tract) were compared between groups as a function of age. Results There were significant reductions of global brain and hippocampi volumes (greatest ipsilateral to HS), and FA of all 10 tracts in TLE versus controls. For TLE patients, regression lines run in parallel to those from controls for brain volumes and FA (for all tracts except the parahippocampal‐cingulum and corticospinal tract) versus age across the adult lifespan. Interpretation These results imply a developmental hindrance occurring earlier in life (likely in childhood/neurodevelopmental stages) rather than accelerated atrophy/degeneration of most brain structures herein analyzed in patients with TLE.

Objective: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. Methods: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. Results: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. Conclusions: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

Abstract Objective High‐resolution (1 mm isotropic) diffusion tensor imaging (DTI) of the hippocampus in temporal lobe epilepsy (TLE) patients has shown patterns of hippocampal subfield diffusion abnormalities, which were consistent with hippocampal sclerosis (HS) subtype on surgical histology. The objectives of this longitudinal imaging study were to determine the stability of focal hippocampus diffusion changes over time in TLE patients, compare diffusion and quantitative T2 abnormalities of the sclerotic hippocampus, and correlate presurgical mean diffusivity (MD) and T2 maps with postsurgical histology. Methods Nineteen TLE patients and 19 controls underwent two high‐resolution (1 mm isotropic) DTI and 1.1 × 1.1 × 1 mm3 T2 relaxometry scans (in a subset of 16 TLE patients and 9 controls) of the hippocampus at 3T, with a 2.6 ± 0.8 year inter‐scan interval. Within‐participant hippocampal volume, MD and T2 were compared between the scans. Contralateral hippocampal changes 2.3 ± 1.0 years after surgery and ipsilateral preoperative MD maps versus postoperative subfield histopathology were evaluated in eight patients who underwent surgical resection of the hippocampus. Results Reduced volume and elevated MD and T2 of sclerotic hippocampi remained unchanged between longitudinal scans. Focal regions of elevated MD and T2 in bilateral hippocampi of HS TLE were detected consistently at both scans. Regions of high MD and T2 correlated and remained consistent over time. Volume, MD, and T2 remained unchanged in postoperative contralateral hippocampus. Regional elevations of MD identified subfield neuron loss on postsurgical histology with 88% sensitivity and 88% specificity. Focal T2 elevations identified subfield neuron loss with 75% sensitivity and 88% specificity. Significance Diffusion and T2 abnormalities in ipsilateral and contralateral hippocampi remained unchanged between the scans suggesting permanent microstructural alterations. MD and T2 demonstrated good sensitivity and specificity to detect hippocampal subfield neuron loss on postsurgical histology, supporting the potential that high‐resolution hippocampal DTI and T2 could be used to diagnose HS subtype before surgery.

Abstract Background To evaluate the degeneration of the corticospinal tract (CST) and corpus callosum (CC) in patients with motor neuron disease and upper motor neuron (UMN) dysfunction using diffusion kurtosis imaging (DKI). Methods Twenty‐seven patients and 33 healthy controls underwent magnetic resonance imaging along with clinical and neuropsychological testing. Tractography of diffusion tensor images was performed to extract tracts of the bilateral CST and CC. Group mean differences both across the entire averaged tract and along each tract were assessed, including correlations between diffusion metrics and clinical measures. Tract‐based spatial statistics (TBSS) was performed to evaluate the spatial distribution of whole‐brain microstructural abnormalities in patients. Results In comparison to controls, patients had significantly higher mean and radial diffusivity and lower fractional anisotropy (FA), kurtosis anisotropy, mean kurtosis (MK), and radial kurtosis (RK) in the CST and CC (p

ObjectiveTo determine differences in diffusion metrics in key white matter (WM) tracts between women with chronic temporomandibular disorders (TMDs) and age- and sex-matched healthy controls.DesignCross sectional study compared diffusion metrics between groups and explored their associations with clinical variables in subjects with TMDs.MethodsIn a total of 33 subjects with TMDs and 33 healthy controls, we performed tractography to obtain diffusion metrics (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) from the cingulum near the cingulate gyrus (CGC), the cingulum near the hippocampus (CGH), the fornix, the anterior limb of the internal capsule (ALIC), the posterior limb of the internal capsule (PLIC), and the uncinate fasciculus (UF). We compared diffusion metrics across groups and explored the relationships between diffusion metrics and clinical measures (pain chronicity and intensity, central sensitization, somatization, depression, orofacial behavior severity, jaw function limitations, disability, and interference due to pain) in subjects with TMDs.ResultsWe observed differences in diffusion metrics between groups, primarily in the right side of the brain, with the right CGC having lower FA and the right UF having lower FA and higher MD and RD in subjects with TMDs compared to healthy controls. No clinical measures were consistently associated with diffusion metrics in subjects with TMDs.ConclusionThe UF showed potential microstructural damage in subjects with TMDs, but further studies are needed to confirm any associations between diffusion changes and clinical measures.

The analysis of large, multisite neuroimaging datasets provides a promising means for robust characterization of brain networks that can reduce false positives and improve reproducibility. However, the use of different MRI scanners introduces variability to the data. Managing those sources of variability is increasingly important for the generation of accurate group-level inferences. ComBat is one of the most promising tools for multisite (multiscanner) harmonization of structural neuroimaging data, but no study has examined its application to graph theory metrics derived from the structural brain connectome. The present work evaluates the use of ComBat for multisite harmonization in the context of structural network analysis of diffusion-weighted scans from the Advancing Concussion Assessment in Pediatrics (A-CAP) study. Scans were acquired on six different scanners from 484 children aged 8.00–16.99 years [Mean = 12.37 ± 2.34 years; 289 (59.7%) Male] ~10 days following mild traumatic brain injury (n = 313) or orthopedic injury (n = 171). Whole brain deterministic diffusion tensor tractography was conducted and used to construct a 90 x 90 weighted (average fractional anisotropy) adjacency matrix for each scan. ComBat harmonization was applied separately at one of two different stages during data processing, either on the (i) weighted adjacency matrices (matrix harmonization) or (ii) global network metrics derived using unharmonized weighted adjacency matrices (parameter harmonization). Global network metrics based on unharmonized adjacency matrices and each harmonization approach were derived. Robust scanner effects were found for unharmonized metrics. Some scanner effects remained significant for matrix harmonized metrics, but effect sizes were less robust. Parameter harmonized metrics did not differ by scanner. Intraclass correlations (ICC) indicated good to excellent within-scanner consistency between metrics calculated before and after both harmonization approaches. Age correlated with unharmonized network metrics, but was more strongly correlated with network metrics based on both harmonization approaches. Parameter harmonization successfully controlled for scanner variability while preserving network topology and connectivity weights, indicating that harmonization of global network parameters based on unharmonized adjacency matrices may provide optimal results. The current work supports the use of ComBat for removing multiscanner effects on global network topology.

Multi–site imaging consortiums strive to increase participant numbers by pooling data across sites, but scanner related differences can bias results. This study combines data from three research MRI centers, including three different scanner models from two vendors, to examine non–harmonized T1–weighted brain imaging protocols in two cohorts. First, 23 human traveling phantoms were scanned twice each at all three sites (six scans per person; 138 scans total) to quantify within–participant variability of brain volumes (total brain, white matter, gray matter, lateral ventricles, thalamus, caudate, putamen and globus pallidus), and to calculate site–specific correction factors for each structure. Sample size calculations were used to determine the number of traveling phantoms needed to achieve effect sizes for observed differences to help guide future studies. Next, cross–sectional lifespan volume trajectories were examined in 856 healthy participants (5—91 years of age) scanned at these sites. Cross–sectional trajectories of volume versus age for each structure were then compared before and after application of traveling phantom based site–specific correction factors, as well as correction using the open–source method ComBat. Although small systematic differences between sites were observed in the traveling phantom analysis, correction for site using either method had little impact on the lifespan trajectories. Only white matter had small but significant differences in the intercept parameter after ComBat correction (but not traveling phantom based correction), while no other fits differed. This suggests that age–related changes over the lifespan outweigh systematic differences between scanners for volumetric analysis. This work will help guide pooling of multisite datasets as well as meta–analyses of data from non–harmonized protocols.

Purpose: Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and clinical entity that occurs independently and with co-existent Alzheimer’s disease (AD) and small vessel disease. We compared diffusion tensor imaging (DTI) metrics of the fornix, the primary efferent tract of the hippocampus between CAA, AD and Mild Cognitive Impairment (MCI) and healthy controls. Methods: Sixty-eight healthy controls, 32 CAA, 21 AD, and 26 MCI patients were recruited at two centers. Diffusion tensor images were acquired at 3 T with high spatial resolution and fluid-attenuated inversion recovery (FLAIR) to suppress cerebrospinal fluid (CSF) and minimize partial volume effects on the fornix. The fornix was delineated with deterministic tractography to yield mean diffusivity (MD), axial diffusivity (AXD), radial diffusivity (RD), fractional anisotropy (FA) and tract volume. Volumetric measurements of the hippocampus, thalamus, and lateral ventricles were obtained using T1-weighted MRI. Results: Diffusivity (MD, AXD, and RD) of the fornix was highest in AD followed by CAA compared to controls; the MCI group was not significantly different from controls. FA was similar between groups. Fornix tract volume was ∼ 30% lower for all three patient groups compared to controls, but not significantly different between the patient groups. Thalamic and hippocampal volumes were preserved in CAA, but lower in AD and MCI compared to controls. Lateral ventricular volumes were increased in CAA, AD and MCI. Global cognition, memory, and executive function all correlated negatively with fornix diffusivity across the combined clinical group. Conclusion: There were significant diffusion changes of the fornix in CAA, AD and MCI compared to controls, despite relatively intact thalamic and hippocampal volumes in CAA, suggesting the mechanisms for fornix diffusion abnormalities may differ in CAA compared to AD and MCI.

Abstract Objective Hippocampal sclerosis (HS) is the most common pathology and best predictor of surgical outcome for medically refractory patients with temporal lobe epilepsy (TLE). Current clinical MRI methods can detect HS, but subfield pathology is poorly characterized, limiting accurate prediction of seizure‐free outcomes after surgery. Diffusion tensor imaging (DTI) can probe regional microstructural changes associated with focal hippocampal pathology, but is typically limited by low‐resolution whole‐brain acquisitions. Methods High‐resolution (1 × 1 × 1 mm3) DTI, T1, and quantitative T2 of the hippocampus was acquired in 18 preoperative TLE patients and 19 healthy controls. Diffusion images were qualitatively assessed for loss of internal architecture, and whole‐hippocampus diffusion, volume, and quantitative T2 were compared across groups. Regional hippocampal diffusion abnormalities were examined in all subjects and compared to histology in four subjects who underwent anterior temporal lobectomy. Results High‐resolution mean diffusion‐weighted images enabled visualization of internal hippocampal architecture, used to visually identify HS with 86% specificity and 93% sensitivity. Mean diffusivity (MD) elevations were regionally heterogenous within the hippocampus and varied across TLE patients. The spatial location of diffusion abnormalities corresponded with the location of focal subfield neuron loss, gliosis, and reduced myelin staining abnormalities identified with postsurgical histology in four subjects who underwent anterior temporal lobectomy. Whole‐hippocampus MD and T2 relaxation times were higher, and fractional anisotropy (FA) and volumes were lower in TLE patients relative to controls. Left hippocampus MD correlated with verbal memory in the TLE group. Significance Visualization of internal architecture and focal diffusion abnormalities on high‐resolution diffusion imaging suggests potential clinical utility of diffusion imaging in TLE and may have significant implications for surgical planning and prediction of seizure‐free outcomes in individual patients.

To extract Diffusion Tensor Imaging (DTI) parameters from the human cortex, the inner and outer boundaries of the cortex are usually defined on 3D-T1-weighted images and then applied to the co-registered DTI. However, this analysis requires the acquisition of an additional high-resolution structural image that may not be practical in various imaging studies. Here an automatic cortical boundary segmentation method was developed to work directly only on the native DTI images by using fractional anisotropy (FA) maps and mean diffusion weighted images (DWI), the latter with acceptable gray-white matter image contrast. This new method was compared to the conventional cortical segmentations generated from high-resolution T1 structural images in 5 participants. In addition, the proposed method was applied to 15 healthy young adults (10 cross-sectional, 5 test-retest) to measure FA, MD, and radiality of the primary eigenvector across the cortex on whole-brain 1.5 mm isotropic images acquired in 3.5 min at 3T. The proposed method generated reasonable segmentations of the cortical boundaries for all individuals and large proportions of the proposed method segmentations (more than 85%) were within ±1 mm from those generated with the conventional approach on higher resolution T1 structural images. Both FA (~0.15) and MD (~0.77 × 10−3 mm2/s) extracted halfway between the cortical boundaries were relatively stable across the cortex, although focal regions such as the posterior bank of the central sulcus, anterior insula, and medial temporal lobe showed higher FA. The primary eigenvectors were primarily oriented radially to the middle cortical surface, but there were tangential orientations in the sulcal fundi as well as in the posterior bank of the central sulcus. The proposed method demonstrates the feasibility and accuracy of cortical analysis in native DTI space while avoiding the acquisition of other imaging contrasts like 3D T1-weighted scans.

Introduction: The source of Tissue Sodium Concentration (TSC) increase in Multiple Sclerosis (MS) remains unclear, and could be attributed to altered intracellular sodium concentration or tissue microstructure. This paper investigates sodium in MS using three new MRI sequences.Methods: Three sodium scans were acquired at 4.7 T from 30 patients (11 relapsing-remitting, 10 secondary-progressive, 9 primary-progressive) and 9 healthy controls including: Density-Weighted (NaDW), with very short 30° excitation for more accurate TSC measurement; Projection Acquisition with Coherent MAgNetization (NaPACMAN), designed for enhanced relaxation-based contrast; and Soft Inversion Recovery FLuid Attenuation (NaSIRFLA), developed to reduce fluid space contribution. Signal was measured in both lesions (n = 397) and normal appearing white matter (NAWM) relative to controls in the splenium of corpus callosum and the anterior and posterior limbs of internal capsule. Correlations with clinical and cognitive evaluations were tested over all MS patients.Results: Sodium intensity in MS lesions was elevated over control WM by a greater amount for NaPACMAN (75%) than NaDW (35%), the latter representing TSC. In contrast, NaSIRFLA exhibited lower intensity, but only for region specific analysis in the SCC (−7%). Sodium intensity in average MS NAWM was not significantly different than control WM for either of the three scans. NaSIRFLA in the average NAWM and specifically the posterior limb of internal capsules positively correlated with the Paced Auditory Serial Addition Test (PASAT).Discussion: Lower NaSIRFLA signal in lesions and ~2× greater NaPACMAN signal elevation over control WM than NaDW can be explained with a demyelination model that also includes edema. A NAWM demyelination model that includes tissue atrophy suggests no signal change for NaSIRFLA, and only slightly greater NAWM signal than control WM for both NaDW and NaPACMAN, reflecting experimental results. Models were derived from previous total and myelin water fraction study in MS with T2-relaxometry, and for the first time include sodium within the myelin water space. Reduced auditory processing association with lower signal on NaSIRFLA cannot be explained by greater demyelination and its modeled impact on the three sodium MRI sequences. Alternative explanations include intra- or extracellular sodium concentration change. Relaxation-weighted sodium MRI in combination with sodium-density MRI may help elucidate microstructural and metabolic changes in MS.

Introduction Fetal alcohol spectrum disorder (FASD), which is caused by prenatal alcohol exposure (PAE), affects an estimated 4% of North Americans, and is the most common preventable cause of intellectual disability. Mental health problems, including anxiety and depression, are experienced by nearly all individuals with FASD. However, there is very limited knowledge about effective mental health treatments for individuals with FASD; effective treatments are hindered in part due to a lack of understanding of the basic neurobiology underlying internalising disorders in youth with FASD.Methods and analysis The Prenatal Exposure And Child brain and mental Health (PEACH) study includes children aged 7–18 years. We will use longitudinal neuroimaging (anatomical T1-weighted, diffusion and passive viewing function MRI) and mental health assessments (Behaviour Assessment Scale for Children, Multi-dimensional Anxiety Scale for Children, Children’s Depression Inventory (CDI-2), Kiddie Scale of Affective Disorders) to: (1) characterise brain development trajectories in youth with FASD, (2) determine whether brain alterations mediate increased anxiety and depression in youth with FASD and (3) identify baseline brain features that predict changes of anxiety and depression symptoms over the next 2 years. All of this will be done while considering sex and adverse postnatal experiences, which can significantly impact mental health and brain outcomes. This project will forge new understanding of FASD and mental health from a neurobiological perspective, highlighting key time periods (ie, sensitive windows) and brain regions (ie, that may be susceptible to neurostimulation), while identifying factors that predict individual trajectories of anxiety and depression symptoms.Ethics and dissemination This study was approved by the University of Calgary Conjoint Health Research Ethics Board and the University of Alberta Health Research Ethics Board. Study results will be disseminated in peer-reviewed journals, at relevant conferences and in conjunction with our knowledge mobilisation partners.

Noninvasive estimation of mean axon diameter presents a new opportunity to explore white matter plasticity, development, and pathology. Several diffusion-weighted MRI (DW-MRI) methods have been proposed to measure the average axon diameter in white matter, but they typically require many diffusion encoding measurements and complicated mathematical models to fit the signal to multiple tissue compartments, including intra- and extra-axonal spaces. Here, Monte Carlo simulations uncovered a straightforward DW-MRI metric of axon diameter: the change in radial apparent diffusion coefficient estimated at different effective diffusion times, ΔD⊥. Simulations indicated that this metric increases monotonically within a relevant range of effective mean axon diameter while being insensitive to changes in extra-axonal volume fraction, axon diameter distribution, g-ratio, and influence of myelin water. Also, a monotonic relationship was found to exist for signals coming from both intra- and extra-axonal compartments. The slope in ΔD⊥ with effective axon diameter increased with the difference in diffusion time of both oscillating and pulsed gradient diffusion sequences.

Background: Pediatric mild traumatic brain injury (mTBI) affects millions of children annually. Diffusion tensor imaging (DTI) is sensitive to axonal injuries and white matter microstructure and has been used to characterize the brain changes associated with mild traumatic brain injury (mTBI). Neurite orientation dispersion and density imaging (NODDI) is a diffusion model that can provide additional insight beyond traditional DTI metrics, but has not been examined in pediatric mTBI. The goal of this study was to employ DTI and NODDI to gain added insight into white matter alterations in children with mTBI compared to children with mild orthopedic injury (OI). Methods: Children (mTBI n = 320, OI n = 176) aged 8–16.99 years (12.39 ± 2.32 years) were recruited from emergency departments at five hospitals across Canada and underwent 3 T MRI on average 11 days post-injury. DTI and NODDI metrics were calculated for seven major white matter tracts and compared between groups using univariate analysis of covariance controlling for age, sex, and scanner type. False discovery rate (FDR) was used to correct for multiple comparisons. Results: Univariate analysis revealed no significant group main effects or interactions in DTI or NODDI metrics. Fractional anisotropy and neurite density index in all tracts exhibited a significant positive association with age and mean diffusivity in all tracts exhibited a significant negative association with age in the whole sample. Conclusions: Overall, there were no significant differences between mTBI and OI groups in brain white matter microstructure from either DTI or NODDI in the seven tracts. This indicates that mTBI is associated with relatively minor white matter differences, if any, at the post-acute stage. Brain differences may evolve at later stages of injury, so longitudinal studies with long-term follow-up are needed.

Magnetic resonance imaging (MRI) provides a means to non-invasively investigate the neurological links with dyslexia, a learning disability that affects one’s ability to read. Most previous brain MRI studies of dyslexia and reading skill have used structural or diffusion imaging to reveal regional brain abnormalities. However, volumetric and diffusion MRI lack specificity in their interpretation at the microstructural level. Myelin is a critical neural component for brain function and plasticity, and as such, deficits in myelin may impact reading ability. MRI can estimate myelin using myelin water fraction (MWF) imaging, which is based on evaluation of the proportion of short T2 myelin-associated water from multi-exponential T2 relaxation analysis, but has not yet been applied to the study of reading or dyslexia. In this study, MWF MRI, intelligence, and reading assessments were acquired in 20 participants aged 10–18 years with a wide range of reading ability to investigate the relationship between reading ability and myelination. Group comparisons showed markedly lower MWF by 16–69% in poor readers relative to good readers in the left and right thalamus, as well as the left posterior limb of the internal capsule, left/right anterior limb of the internal capsule, left/right centrum semiovale, and splenium of the corpus callosum. MWF over the entire group also correlated positively with three different reading scores in the bilateral thalamus as well as white matter, including the splenium of the corpus callosum, left posterior limb of the internal capsule, left anterior limb of the internal capsule, and left centrum semiovale. MWF imaging from T2 relaxation suggests that myelination, particularly in the bilateral thalamus, splenium, and left hemisphere white matter, plays a role in reading abilities. Myelin water imaging thus provides a potentially valuable in vivo imaging tool for the study of dyslexia and its remediation.

Individuals with prenatal alcohol exposure (PAE) exhibit neurological deficits associated with brain injury including smaller brain volumes. Additional risk factors such as lower socioeconomic status (SES) may also have an impact on brain development for this population. This study examined how brain volumes are related to SES in both neurotypically developing children and adolescents, and those with PAE. 3D T1-weighted MPRAGE images were acquired from 69 participants with PAE (13.0 ± 3.2 years, range 7.1–18.8 years, 49% female) and 70 neurotypical controls (12.4 ± 2.9 years, range 7.0–18.5 years, 60% female) from four scanning sites in Canada. SES scores calculated using Hollingshead’s Four-Factor Index of Social Status from current caregiver placement were not significantly different between groups, though more children with PAE had lower SES scores compared to controls. Psychometric data comprised 14 cognitive measures, including executive functioning, attention and working memory, memory, math/numerical ability, and word reading. All cognitive scores were significantly worse in children with PAE compared to controls, though SES was not correlated with cognitive scores in either group after correction for multiple comparisons. All 13 brain volumes were smaller in children with PAE compared to children in the control group. Higher SES was associated with larger hippocampus and amygdala volumes in controls, but there were no such associations in children with PAE. Direct evaluation of the interaction between SES and diagnostic group did not show a significant differential impact of SES on these structures. These findings support previous links between SES and brain volumes in neurotypically developing children, but the lack of such a relationship with SES in children with PAE may be due to the markedly smaller brain volumes resulting from the initial brain injury and postpartum brain development, regardless of later SES.

Conventional diffusion imaging uses pulsed gradient spin echo (PGSE) waveforms with diffusion times of tens of milliseconds (ms) to infer differences of white matter microstructure. The combined use of these long diffusion times with short diffusion times (

Amyotrophic lateral sclerosis (ALS) is characterized primarily by motor neuron but also frontotemporal lobar degeneration. Although the cerebellum is involved in both motor and cognitive functions, little is known of its role in ALS. We targeted the dentate nucleus (DN) in the cerebellum and the associated white matter fibers tracts connecting the DN to the rest of the brain using multimodal imaging techniques to examine the cerebellar structural and functional connectivity patterns in ALS patients and hypothesized that the DN is implicated in the pathophysiology of ALS. A cohort of 127 participants (56 healthy subjects (HS); 71 ALS patients) were recruited across Canada through the Canadian ALS Neuroimaging Consortium (CALSNIC). Resting state functional MRI, diffusion tensor imaging (DTI), and 3D weighted T1 structural images were acquired on a 3-tesla scanner. The DN in the cerebellum was used as a seed to evaluate the whole brain cerebral resting-state functional connectivity (rsFC). The superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and inferior cerebellar peduncle (ICP) were used as a region of interest in DTI to evaluate the structural integrity of the DN with the cortex and brain stem. Cerebellar volumetric analysis was done to examine the lobular and DN grey matter (GM) changes in ALS patients. Lastly, an association between DN rsFC and structural alterations were explored. DN rsFC was reduced with cerebrum (supplementary motor area, precentral gyrus, frontal, posterior parietal, temporal), lobule IV, and brain stem, and increased with parieto-occipital region. DN rsFC and white matter (WM) diffusivity alterations at SCP, MCP, and ICP were accompanied by correlations with ALSFRS-R. There were no DN volumetric changes. Notably, DN rsFC correlated with WM abnormalities at superior cerebellar peduncle. The DN plays a pathophysiological role in ALS. Impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. This study demonstrates altered cerebellar rsFC connectivity with motor and extra-motor regions in ALS, and impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. The correlation between the altered DN connectivity, and the behavioral data support the hypothesis that the DN plays a pathophysiological role in ALS.

Abstract Introduction Diffusion tensor imaging (DTI) has shown abnormalities of the fornix and other limbic white matter tracts in multiple sclerosis (MS), mainly focusing on relapsing‐remitting MS. Methods The goal here was to evaluate the fornix, cingulum, and uncinate fasciculus with DTI tractography at 1.7 mm isotropic resolution in three MS subgroups (11 relapsing‐remitting (RRMS), nine secondary progressive (SPMS), eight primary progressive (PPMS)) versus 11 controls, and assess correlations with cognitive and clinical scores. Results The MS group overall showed extensive diffusion abnormalities of the fornix with less volume, lower fractional anisotropy (FA), and higher mean and radial diffusivities, which were similarly affected in all three MS subgroups. The uncinate fasciculus had lower FA only in the secondary progressive subgroup, and the cingulum had no DTI differences in any MS subgroup. The FA and/or volumes of these tracts correlated negatively with larger total lesion volume. The only DTI‐cognitive correlation was lower right cingulum FA and greater depression over the entire MS cohort. Conclusions Diffusion tractography identified abnormalities in the fornix that appears to be affected early and consistently across all three primary MS phenotypes of RRMS, SPMS, and PPMS regardless of Expanded Disability Status Scale, time since diagnosis, or cognitive scores.

Quantitative magnetic resonance imaging (MRI) has revealed abnormalities in brain volumes, cortical thickness and white matter microstructure in fetal alcohol spectrum disorders (FASD); however, no study has reported all three measures within the same cohort to assess the relative magnitude of deficits, and few studies have examined sex differences. Participants with FASD (n=70; 30 females; 5–32years) and healthy controls (n=74; 35 females; 5–32years) underwent cognitive testing and MRI to assess cortical thickness, regional brain volumes and fractional anisotropy (FA)/mean diffusivity (MD) of white matter tracts. A significant effect of group, age-by-group, or sex-by-group was found for 9/9 volumes, 7/39 cortical thickness regions, 3/9 white matter tracts, and 9/10 cognitive tests, indicating group differences that in some cases differ by age or sex. Volume reductions for several structures were larger in males than females, despite similar deficits of cognition in both sexes. Correlations between brain structure and cognitive scores were found in females of both groups, but were notably absent in males. Correlations within a given MRI modality (e.g. total brain volume and caudate volume) were prevalent in both the control and FASD groups, and were more numerous than correlations between measurement types (e.g. volumes and diffusion tensor imaging) in either cohort. This multi-modal MRI study finds widespread differences of brain structure in participants with prenatal alcohol exposure, and to a greater extent in males than females which may suggest attenuation of the expected process of sexual dimorphism of brain structure during typical development. Keywords: Gender, Prenatal alcohol exposure, Diffusion tensor imaging, Cortical thickness, Brain volume, Cognition

Background Subacute ischemic lesions in intracerebral hemorrhage (ICH) have been hypothesized to result from hypoperfusion. Although studies of cerebral blood flow (CBF) indicate modest hypoperfusion in ICH, these investigations have been limited to early time points. Arterial spin labeling (ASL), a magnetic resonance imaging technique, can be used to measure CBF without a contrast agent. We assessed CBF in patients with ICH using ASL and tested the hypothesis that CBF is related to systolic blood pressure (SBP). Methods and Results In this cross‐sectional study, patients with ICH were assessed with ASL at 48 hours, 7 days, and/or 30 days after onset. Relative CBF (rCBF; ratio of ipsilateral/contralateral perfusion) was measured in the perihematomal regions, hemispheres, border zones, and the perilesional area in patients with diffusion‐weighted imaging hyperintensities. Twenty‐patients (65% men; mean±SD age, 68.5±12.7 years) underwent imaging with ASL at 48 hours (N=12), day 7 (N=6), and day 30 (N=11). Median (interquartile range) hematoma volume was 13.1 (6.3–19.3) mL. Mean±SD baseline SBP was 185.4±25.5 mm Hg. Mean perihematomal rCBF was 0.9±0.2 at 48 hours at all time points. Baseline SBP and other SBP measurements were not associated with a decrease in rCBF in any of the regions of interest (P≥0.111). rCBF did not differ among time points in any of the regions of interest (P≥0.097). Mean perilesional rCBF was 1.04±0.65 and was unrelated to baseline SBP (P=0.105). Conclusions ASL can be used to measure rCBF in patients with acute and subacute ICH. Perihematomal CBF was not associated with SBP changes at any time point. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976.

For standard clinical applications, ASL images are typically acquired with 4-8 mm thick slices and 3-4 mm in-plane resolution. However, in this paper we demonstrate that high-resolution continuous arterial spin labeling (CASL) perfusion images can be acquired in a clinically relevant scan time using current MRI technology. CASL was implemented with a separate neck coil for labeling the arterial blood on a 4.7T MRI using standard axial 2D GE-EPI. Typical-resolution to high-resolution (voxels of 95, 60, 45, 27, or 7 mm3) images were compared for qualitative and quantitative cerebral blood flow analysis (CBF) in nine healthy volunteers (ages: 24-32 years). The highest resolution (1.5x1.5x3 = 7 mm3) CASL implementation yielded perfusion images with improved cortex depiction and increased cortical CBF measurements (53 ± 8 ml/100g/min), consistent with reduced partial volume averaging. The 7 mm3 voxel images were acquired with 6 cm brain coverage in a clinically relevant scan of 6 minutes. Improved spatial resolution facilitates CBF measurement with reduced partial volume averaging and may be valuable for the detection of perfusion deficits in small lesions and perfusion measurement in small brain regions.

Response inhibition is the ability to suppress irrelevant impulses to enable goal-directed behavior. The underlying neural mechanisms of inhibition deficits are not clearly understood, but may be related to white matter connectivity, which can be assessed using diffusion tensor imaging (DTI). The goal of this study was to investigate the relationship between response inhibition during the performance of saccadic eye movement tasks and DTI measures of the corpus callosum in children with or without Fetal Alcohol Spectrum Disorder (FASD). Participants included 43 children with an FASD diagnosis (12.3 ± 3.1 years old) and 35 typically developing children (12.5 ± 3.0 years old) both aged 7–18, assessed at three sites across Canada. Response inhibition was measured by direction errors in an antisaccade task and timing errors in a delayed memory-guided saccade task. Manual deterministic tractography was used to delineate six regions of the corpus callosum and calculate fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity, and perpendicular diffusivity. Group differences in saccade measures were assessed using t-tests, followed by partial correlations between eye movement inhibition scores and corpus callosum FA and MD, controlling for age. Children with FASD made more saccade direction errors and more timing errors, which indicates a deficit in response inhibition. The only group difference in DTI metrics was significantly higher MD of the splenium in FASD compared to controls. Notably, direction errors in the antisaccade task were correlated negatively to FA and positively to MD of the splenium in the control, but not the FASD group, which suggests that alterations in connectivity between the two hemispheres of the brain may contribute to inhibition deficits in children with FASD.

BACKGROUND/OBJECTIVE:The underlying mechanism of fatigue in multiple sclerosis (MS) remains poorly understood. Our study investigates the involvement of the ascending reticular activating system (ARAS), originating in the pontine brainstem, in MS patients with symptoms of fatigue. METHODS:Female relapsing-remitting MS patients (n = 17) and controls (n = 15) underwent a magnetic resonance spectroscopic imaging protocol at 1.5T. Fatigue was assessed in every subject using the Fatigue Severity Scale (FSS). Using an FSS cut-off of 36, patients were categorized into a low (n = 9, 22 ± 10) or high (n = 10, 52 ± 6) fatigue group. The brain metabolites N-acetylaspartate (NAA) and total creatine (tCr) were measured from sixteen 5x5x10 mm3 spectroscopic imaging voxels in the rostral pons. RESULTS:MS patients with high fatigue had lower NAA/tCr concentration in the tegmental pons compared to control subjects. By using NAA and Cr values in the cerebellum for comparison, these NAA/tCr changes in the pons were driven by higher tCr concentration, and that these changes were focused in the WM regions. DISCUSSION/CONCLUSION:Since there were no changes in NAA concentration, the increase in tCr may be suggestive of gliosis, or an imbalanced equilibrium of the creatine and phosphocreatine ratio in the pons of relapsing-remitting MS patients with fatigue.

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.