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Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on “Best Practices & Tools for Diffusion MR Spectroscopy” held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.

Background and objectives Reliable detection of white matter hyperintensities (WMH) is crucial for studying the impact of diffuse white-matter pathology on brain health and monitoring changes in WMH load over time. However, manual annotation of 3D high-dimensional neuroimages is laborious and can be prone to biases and errors in the annotation procedure. In this study, we evaluate the performance of deep learning (DL) segmentation tools and propose a novel volumetric segmentation model incorporating self-attention via a transformer-based architecture. Ultimately, we aim to evaluate diverse factors that influence WMH segmentation, aiming for a comprehensive analysis of the state-of-the-art algorithms in a broader context. Methods We trained state-of-the-art DL algorithms, and incorporated advanced attention mechanisms, using structural fluid-attenuated inversion recovery (FLAIR) image acquisitions. The anatomical MRI data utilized for model training was obtained from healthy individuals aged 62–70 years in the Live active Successful Aging (LISA) project. Given the potential sparsity of lesion volume among healthy aging individuals, we explored the impact of incorporating a weighted loss function and ensemble models. To assess the generalizability of the studied DL models, we applied the trained algorithm to an independent subset of data sourced from the MICCAI WMH challenge (MWSC). Notably, this subset had vastly different acquisition parameters compared to the LISA dataset used for training. Results Consistently, DL approaches exhibited commendable segmentation performance, achieving the level of inter-rater agreement comparable to expert performance, ensuring superior quality segmentation outcomes. On the out of sample dataset, the ensemble models exhibited the most outstanding performance. Conclusions DL methods generally surpassed conventional approaches in our study. While all DL methods performed comparably, incorporat, Background and objectives: Reliable detection of white matter hyperintensities (WMH) is crucial for studying the impact of diffuse white-matter pathology on brain health and monitoring changes in WMH load over time. However, manual annotation of 3D high-dimensional neuroimages is laborious and can be prone to biases and errors in the annotation procedure. In this study, we evaluate the performance of deep learning (DL) segmentation tools and propose a novel volumetric segmentation model incorporating self-attention via a transformer-based architecture. Ultimately, we aim to evaluate diverse factors that influence WMH segmentation, aiming for a comprehensive analysis of the state-of-the-art algorithms in a broader context. Methods: We trained state-of-the-art DL algorithms, and incorporated advanced attention mechanisms, using structural fluid-attenuated inversion recovery (FLAIR) image acquisitions. The anatomical MRI data utilized for model training was obtained from healthy individuals aged 62–70 years in the Live active Successful Aging (LISA) project. Given the potential sparsity of lesion volume among healthy aging individuals, we explored the impact of incorporating a weighted loss function and ensemble models. To assess the generalizability of the studied DL models, we applied the trained algorithm to an independent subset of data sourced from the MICCAI WMH challenge (MWSC). Notably, this subset had vastly different acquisition parameters compared to the LISA dataset used for training. Results: Consistently, DL approaches exhibited commendable segmentation performance, achieving the level of inter-rater agreement comparable to expert performance, ensuring superior quality segmentation outcomes. On the out of sample dataset, the ensemble models exhibited the most outstanding performance. Conclusions: DL methods generally surpassed conventional approaches in our study. While all DL methods performed comparably, incorporating attention mechanisms could prove

Diffusion magnetic resonance imaging (dMRI) is sensitive to the mobility of water in tissue and sensitive to cell geometry and organization in the central nervous system — providing unique insight into both local microstructure and white matter connectivity. Most dMRI methods were developed for studying cerebral white matter but can provide useful information about cerebellar white and gray matter. However, the small size and intricate structure of the cerebellum poses challenges for dMRI. In this review, we discuss these challenges, recent advancements in methodology, and insights from cerebellar applications of novel dMRI methods. While many limitations still remain and should be considered in conclusions regarding microstructure and connectivity, carefully designed experiments and analyses can provide new insight into behavioral and pathological aspects of cerebellar structure and function.

BACKGROUND AND OBJECTIVE: Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20+ T cells and the effect of dimethyl fumarate on CD20+ T cells in PPMS. METHODS: The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20+ T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume. RESULTS: Assessing CD20+ T cells in patients with PPMS and controls showed an increased percentage of CD20+ T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8+CD20+ T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8+CD20+ T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20+ T cells were unaffected. DISCUSSION: This study shows an association between intrathecal CD8+CD20+ T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8+CD20+ T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8+CD20+ T cells in CSF.

Background Many patients do not fully regain motor function after ischemic stroke. Transcranial direct current stimulation (TDCS) targeting the motor cortex may improve motor outcome as an add-on intervention to physical rehabilitation. However, beneficial effects on motor function vary largely among patients within and across TDCS trials. In addition to a large heterogeneity of study designs, this variability may be caused by the fact that TDCS was given as a one-size-fits-all protocol without accounting for anatomical differences between subjects. The efficacy and consistency of TDCS might be improved by a patient-tailored design that ensures precise targeting of a physiologically relevant area with an appropriate current strength. Methods In a randomized, double-blinded, sham-controlled trial, patients with subacute ischemic stroke and residual upper-extremity paresis will receive two times 20 min of focal TDCS of ipsilesional primary motor hand area (M1-HAND) during supervised rehabilitation training three times weekly for 4 weeks. Anticipated 60 patients will be randomly assigned to active or sham TDCS of ipsilesional M1-HAND, using a central anode and four equidistant cathodes. The placement of the electrode grid on the scalp and current strength at each cathode will be personalized based on individual electrical field models to induce an electrical current of 0.2 V/m in the cortical target region resulting in current strengths between 1 and 4 mA. Primary endpoint will be the difference in change of Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score between active TDCS and sham at the end of the intervention. Exploratory endpoints will include UE-FMA at 12 weeks. Effects of TDCS on motor network connectivity and interhemispheric inhibition will be assessed with functional MRI and transcranial magnetic stimulation. Discussion The study will show the feasibility and test the efficacy of personalized, multi-electrode ano

Introduction Dimethyl fumarate treatment is approved in Europe for patients with relapsing-remitting multiple sclerosis (MS) and in the US for relapsing forms of MS. We recently published the results of the first randomized placebo-controlled trial of 48 weeks of treatment with dimethyl fumarate or placebo in primary progressive MS (PPMS) (clinicaltrial.gov NCT02959658). The placebo-controlled phase of the trial did not meet its primary endpoint (reduction in cerebrospinal fluid concentrations of neurofilament light chain [NFL]). Aim To investigate the effects of dimethyl fumarate treatment in the open-label extension phase of the trial (week 48-96), where all patients were treated with DMF. Methods Reported data are from screening, week 48, and week 96 visits. Patients were clinically evaluated with Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, and Brief Visuospatial Memory-Revised. Serum NFL concentrations were measured by single-molecule array analysis. MRI was performed on a 3 tesla MRI scanner and included: new/enlarging lesions, volume of lesions, cortical grey matter, putamen, thalamus, and normal-appearing white matter, and additional diffusion tensor imaging and magnetization transfer ratio measures. Results Forty-two patients entered the open-label treatment phase, and 33 patients (61%) had complete data sets at week 96. The remaining 39% did not complete the trial and were not evaluated at week 96. We found no evidence of differences in clinical and MRI measures between patients initially treated with dimethyl fumarate and patients initially treated with placebo from baseline to week 48 and from week 48–96, where all patients were treated with dimethyl fumarate. Serum NFL concentrations remained stable in both groups over 96 weeks. Assessed with either EDSS, T25FW, or 9HPT at week 96, progress, Introduction: Dimethyl fumarate treatment is approved in Europe for patients with relapsing-remitting multiple sclerosis (MS) and in the US for relapsing forms of MS. We recently published the results of the first randomized placebo-controlled trial of 48 weeks of treatment with dimethyl fumarate or placebo in primary progressive MS (PPMS) (clinicaltrial.gov NCT02959658). The placebo-controlled phase of the trial did not meet its primary endpoint (reduction in cerebrospinal fluid concentrations of neurofilament light chain [NFL]).Aim: To investigate the effects of dimethyl fumarate treatment in the open-label extension phase of the trial (week 48-96), where all patients were treated with DMF.Methods: Reported data are from screening, week 48, and week 96 visits. Patients were clinically evaluated with Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, and Brief Visuospatial Memory-Revised. Serum NFL concentrations were measured by single-molecule array analysis. MRI was performed on a 3 tesla MRI scanner and included: new/enlarging lesions, volume of lesions, cortical grey matter, putamen, thalamus, and normal-appearing white matter, and additional diffusion tensor imaging and magnetization transfer ratio measures.Results: Forty-two patients entered the open-label treatment phase, and 33 patients (61%) had complete data sets at week 96. The remaining 39% did not complete the trial and were not evaluated at week 96. We found no evidence of differences in clinical and MRI measures between patients initially treated with dimethyl fumarate and patients initially treated with placebo from baseline to week 48 and from week 48-96, where all patients were treated with dimethyl fumarate. Serum NFL concentrations remained stable in both groups over 96 weeks. Assessed with either EDSS, T25FW, or 9HPT at week 96, progression was observed for 14 patients (45%).

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sec

Background: Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multiple neurotransmitter systems. In patients with chronic schizophrenia, memantine, a non-competitive glutamatergic NMDA receptor antagonist, shows promise for ameliorating negative symptoms and improving cognition. Yet, it is unknown how memantine modulates glutamate levels, and memantine has not been investigated in patients with first-episode psychosis. Aims: This investigator-initiated double-blinded randomized controlled trial is designed to (1) test the clinical effects on negative symptoms of add-on memantine to antipsychotic medication, and (2) neurobiologically characterize the responders to add-on memantine. Materials and Equipment: Antipsychotic-naïve patients with first-episode psychosis will be randomized to 12 weeks treatment with [amisulpride + memantine] or [amisulpride + placebo]. We aim for a minimum of 18 patients in each treatment arm to complete the trial. Brain mapping will be performed before and after 12 weeks focusing on glutamate and neuromelanin in predefined regions. Regional glutamate levels will be probed with proton magnetic resonance spectroscopy (MRS), while neuromelanin signal will be mapped with neuromelanin-sensitive magnetic resonance imaging (MRI). We will also perform structural and diffusion weighted, whole-brain MRI. MRS and MRI will be performed at an ultra-high field strength (7 Tesla). Alongside, participants undergo clinical and neuropsychological assessments. Twenty matched healthy controls will undergo similar baseline- and 12-week examinations, but without receiving treatment. Outcome Measures: The primary endpoint is negative symptom severity. Secondary outcomes comprise: (i) clinical endpoints related to cognitio

Background: Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multiple neurotransmitter systems. In patients with chronic schizophrenia, memantine, a non-competitive glutamatergic NMDA receptor antagonist, shows promise for ameliorating negative symptoms and improving cognition. Yet, it is unknown how memantine modulates glutamate levels, and memantine has not been investigated in patients with first-episode psychosis. Aims: This investigator-initiated double-blinded randomized controlled trial is designed to (1) test the clinical effects on negative symptoms of add-on memantine to antipsychotic medication, and (2) neurobiologically characterize the responders to add-on memantine. Materials and Equipment: Antipsychotic-naïve patients with first-episode psychosis will be randomized to 12 weeks treatment with [amisulpride + memantine] or [amisulpride + placebo]. We aim for a minimum of 18 patients in each treatment arm to complete the trial. Brain mapping will be performed before and after 12 weeks focusing on glutamate and neuromelanin in predefined regions. Regional glutamate levels will be probed with proton magnetic resonance spectroscopy (MRS), while neuromelanin signal will be mapped with neuromelanin-sensitive magnetic resonance imaging (MRI). We will also perform structural and diffusion weighted, whole-brain MRI. MRS and MRI will be performed at an ultra-high field strength (7 Tesla). Alongside, participants undergo clinical and neuropsychological assessments. Twenty matched healthy controls will undergo similar baseline- and 12-week examinations, but without receiving treatment. Outcome Measures: The primary endpoint is negative symptom severity. Secondary outcomes com

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectio

Post-traumatic stress disorder (PTSD) is a heterogenous condition and the underlying neurobiology is still poorly understood. In this study, we tested the hypothesis that PTSD is associated with microstructural changes in white matter (WM) fibre tracts that connect regions involved in emotional processing, memory, attention, and language. Furthermore, we examined how different response patterns to individualized trauma-provoking stimuli related to underlying WM microstructure. Sixty-nine trauma-affected male refugees with PTSD (N = 38) or without PTSD (N = 31) underwent clinical assessments and diffusion-weighted magnetic resonance imaging (DWI) of the whole brain at 3 Tesla. Diffusion tensor metrics were computed from DWI data and used to characterize regional white-matter microstructure. An automated tract segmentation method was used to extract diffusion tensor metrics from subject-based reconstructions of tract segments (ROI), including uncinate fasciculus (UF), cingulum bundle (CB), superior longitudinal fasciculus (SLF) in three subdivisions (SLF I - III), and fibre bundles connecting orbito-frontal cortex to striatum (OF-ST). Outside the scanner we obtained measures of immediate (state) arousal, avoidance and dissociation symptoms assessed in response to auditory exposure to a personal traumatic memory. Using mean FA of the middle part of each ROI, mixed ANOVA revealed a significant interaction between group, ROI and hemisphere. Post-hoc comparisons showed that, relative to refugees without PTSD, refugees with PTSD had lower FA in right CB, left SLF-I, bilateral OF-ST and bilateral SLF-II. Mean FA scaled negatively with avoidance in right CB while mean FA in bilateral UF scaled positively with individual scores reflecting dissociation symptoms. The results support a pathophysiological model of PTSD that implicates limbic structures, prefrontal cortex and striatum. The results also emphasize the need to consider PTSD's multifaceted manifestations when searc

Metabolite diffusion measurable in humans in vivo with diffusion-weighted spectroscopy (DW-MRS) provides a window into the intracellular morphology and state of specific cell types. Anisotropic diffusion in white matter is governed by the microscopic properties of the individual cell types and their structural units (axons, soma, dendrites). However, anisotropy is also markedly affected by the macroscopic orientational distribution over the imaging voxel, particularly in DW-MRS, where the dimensions of the volume of interest (VOI) are much larger than those typically used in diffusion-weighted imaging. One way to address the confound of macroscopic structural features is to average the measurements acquired with uniformly distributed gradient directions to mimic a situation where fibers present in the VOI are orientationally uniformly distributed. This situation allows the extraction of relevant microstructural features such as transverse and longitudinal diffusivities within axons and the related microscopic fractional anisotropy. We present human DW-MRS data acquired at 7 T in two different white matter regions, processed and analyzed as described above, and find that intra-axonal diffusion of the neuronal metabolite N-acetyl aspartate is in good correspondence to simple model interpretations, such as multi-Gaussian diffusion from disperse fibers where the transverse diffusivity can be neglected. We also discuss the implications of our approach for current and future applications of DW-MRS for cell-specific measurements.

Background: Smoking, cardiovascular risk factors, and genetic factors can have adverse effects in MS. Objective: To determine if smoking after disease onset, cardiovascular risk factors, and genetic variants influence primary progressive MS (PPMS). Method: In this cross-sectional study, smoking habits, Framingham Risk Score (FRS), genetic variants, including the low-density lipoprotein receptor-related protein 2 (LRP2) SNP rs12988804 and MRI were collected in 60 PPMS trial participants. Disability and cognition were assessed with the Age-Related Multiple Sclerosis Severity (ARMSS) score, the Progressive-Onset MS Multiple Sclerosis Severity Score, and the Brief International Cognitive Assessment for MS. Results: Smoking after PPMS onset was significantly associated with higher ARMSS (95% CI 0.8–2.4, p = 0.00016) statistically significant after Bonferroni correction. Lower magnetization transfer ratio in lesions was also significantly associated with smoking after onset of PPMS after correction (95% CI -0.9–-4.4, p = 0.0035). Pack-years in people who smoked after onset was likewise significantly associated with higher ARMSS score (b = 0.06 95% CI 0.02–0.09, p = 0.0021) as well as lower Symbol Digit Modalities Test scores (b = -0.40; 95% CI -0.66–-0.13, p = 0.0037), both statistically significant after Bonferroni correction. The LRP2 risk allele was associated with decreased performance on the California Verbal Learning Test 2 after correction (CC vs. CT+TT 95% CI -14.2–-3.4, p = 0.0018). Conclusion: If validated, these findings suggest that intervention regarding smoking may be beneficial in PPMS. If confirmed, assessment of the LRP2 gene variant may aid in the understanding of underlying pathological mechanisms in PPMS.

BACKGROUND AND OBJECTIVE: To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). METHODS: In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. RESULTS: Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more fr

Purpose: MRI can be utilized for quantitative characterization of tissue. To assess e.g. water fractions or diffusion coefficients for compartments in the brain, a decomposition of the signal is necessary. Imposing standard models carries the risk of estimating biased parameters if model assumptions are violated. This work introduces a data-driven multicomponent analysis, the monotonous slope non-negative matrix factorization (msNMF), tailored to extract data features expected in MR signals. Methods: The msNMF was implemented by extending the standard NMF with monotonicity constraints on the signal profiles and their first derivatives. The method was validated using simulated data, and subsequently applied to both ex vivo DWI data and in vivo relaxometry data. Reproducibility of the method was tested using the latter. Results: The msNMF recovered the multi-exponential signals in the simulated data and showed superiority to standard NMF (based on the explained variance, area under the ROC curve, and coefficient of variation). Diffusion components extracted from the DWI data reflected the cell density of the underlying tissue. The relaxometry analysis resulted in estimates of edema water fractions (EWF) highly correlated with published results, and demonstrated acceptable reproducibility. Conclusion: The msNMF can robustly separate MR signals into components with relation to the underlying tissue composition, and may potentially be useful for e.g. tumor tissue characterization.

Evaluation of the structural connectivity (SC) of the brain based on tractography has mainly focused on the choice of diffusion model, tractography algorithm, and their respective parameter settings. Here, we systematically validate SC derived from a post mortem monkey brain, while varying key acquisition parameters such as the b-value, gradient angular resolution and image resolution. As gold standard we use the connectivity matrix obtained invasively with histological tracers by Markov et al. (2014). As performance metric, we use cross entropy as a measure that enables comparison of the relative tracer labeled neuron counts to the streamline counts from tractography. We find that high angular resolution and high signal-to-noise ratio are important to estimate SC, and that SC derived from low image resolution (1.03 mm3) are in better agreement with the tracer network, than those derived from high image resolution (0.53 mm3) or at an even lower image resolution (2.03 mm3). In contradiction, sensitivity and specificity analyses suggest that if the angular resolution is sufficient, the balanced compromise in which sensitivity and specificity are identical remains 60–64% regardless of the other scanning parameters. Interestingly, the tracer graph is assumed to be the gold standard but by thresholding, the balanced compromise increases to 70–75%. Hence, by using performance metrics based on binarized tracer graphs, one risks losing important information, changing the performance of SC graphs derived by tractography and their dependence of different scanning parameters.

Multiple sclerosis leads to diffuse damage of the central nervous system, affecting also the normal-appearing white matter. Demyelination and axonal degeneration reduce regional fractional anisotropy in normal-appearing white matter, which can be routinely mapped with diffusion tensor imaging. However, the standard fractional anisotropy metric is also sensitive to physiological variations in orientation dispersion of white matter fibres. This complicates the detection of disease-related damage in large parts of cerebral white matter where microstructure physiologically displays a high degree of fibre dispersion. To resolve this ambiguity, we employed a novel tensor-valued encoding method for diffusion MRI, which yields a microscopic fractional anisotropy metric that is unaffected by regional variations in orientation dispersion. In 26 patients with relapsing-remitting multiple sclerosis, 14 patients with primary-progressive multiple sclerosis and 27 age-matched healthy controls, we compared standard fractional anisotropy mapping with the novel microscopic fractional anisotropy mapping method, focusing on normal-appearing white matter. Mean microscopic fractional anisotropy and standard fractional anisotropy of normal-appearing white matter were significantly reduced in both patient groups relative to healthy controls, but microscopic fractional anisotropy yielded a better reflection of disease-related white-matter alterations. The reduction in mean microscopic fractional anisotropy showed a significant positive linear relationship with physical disability, as reflected by the expanded disability status scale. Mean reduction of microscopic fractional anisotropy in normal-appearing white matter also scaled positively with individual cognitive dysfunction, as measured with the symbol digit modality test. Mean microscopic fractional anisotropy reduction in normal-appearing white matter also showed a positive relationship with total white-matter lesion load as well as

Extracting microanatomical information beyond the image resolution of MRI would provide valuable tools for diagnostics and neuroscientific research. A number of mathematical models already suggest microstructural interpretations of diffusion MRI (dMRI) data. Examples of such microstructural features could be cell bodies and neurites, e.g. the axon's diameter or their orientational distribution for global connectivity analysis using tractography, and have previously only been possible to access through conventional histology of post mortem tissue or invasive biopsies. The prospect of gaining the same knowledge non-invasively from the whole living human brain could push the frontiers for the diagnosis of neurological and psychiatric diseases. It could also provide a general understanding of the development and natural variability in the healthy brain across a population. However, due to a limited image resolution, most of the dMRI measures are indirect estimations and may depend on the whole chain from experimental parameter settings to model assumptions and implementation. Here, we review current literature in this field and highlight the integrative work across anatomical length scales that is needed to validate and trust a new dMRI method. We encourage interdisciplinary collaborations and data sharing in regards to applying and developing new validation techniques to improve the specificity of future dMRI methods.

Molecular diffusion measured with diffusion weighted MRI (DWI) offers a probe for tissue microstructure. However, inferring microstructural properties from conventional DWI data is a complex inverse problem and has to account for heterogeneity in sizes, shapes and orientations of the tissue compartments contained within an imaging voxel. Alternative experimental means for disentangling the signal signatures of such features could provide a stronger link between the data and its interpretation. Double diffusion encoding (DDE) offers the possibility to factor out variation in compartment shapes from orientational dispersion of anisotropic domains by measuring the correlation between diffusivity in multiple directions. Time dependence of the diffusion is another effect reflecting the dimensions and distributions of barriers. In this paper we extend on DDE with a modified version of the oscillating gradient spin echo (OGSE) experiment, giving a basic contrast mechanism closely linked to both the temporal diffusion spectrum and the compartment anisotropy. We demonstrate our new method on post mortem brain tissue and show that we retrieve the correct temporal diffusion tensor spectrum in synthetic data from Monte Carlo simulations of random walks in a range of disordered geometries of different sizes and shapes.

Magnetic resonance imaging is today the most versatile imaging method for characterization of multiple sclerosis (MS) in vivo, but clinical examinations lack sensitivity to capture changes in the tissue microstructure. Using a multi-dimensional microstructural imaging approach, we demonstrate how it is possible to obtain more specific and broader microstructural insights about the underlying pathology of MS. For this we use a comprehensive battery of conventional and novel diffusion weighted imaging and quantitative MRI sequences each capable of explaining different and complementary microstructural properties. This allows us to explore the underlying pathology of MS, which is normally only accessible with histology.

Purpose: To illustrate the potential bias caused by imaging gradients in correlation MRI sequences using longitudinal magnetization storage (LS) and examine the case of filter exchange imaging (FEXI) yielding maps of the apparent exchange rate (AXR). Methods: The effects of imaging gradients in FEXI were observed on yeast cells. To analyze the AXR bias, signal evolution was calculated by applying matrix exponential operators. Results: A sharp threshold for the slice thickness was identified, below which the AXR is increasingly underestimated. The bias can be understood in terms of an extended low-pass diffusion filtering during the LS interval, which is more pronounced at lower exchange rates. For a total exchange rate constant larger than 1 s-1, the AXR bias is expected to be negligible when slices thicker than 2.5mm are used. Conclusion: In correlation experiments like FEXI, relying on LS with variable duration, imaging gradients may cause disrupting effects that cannot be easily mitigated and should be carefully considered for unbiased results. In typical clinical applications of FEXI, the imaging gradients are expected to cause a negligible AXR bias. However, the AXR bias may be significant in preclinical settings or whenever thin imaging slices are used.

Human bipedal gait requires supraspinal control and gait is consequently severely impaired in most persons with spinal cord injury (SCI). Little is known of the contribution of lesion of specific descending pathways to the clinical manifestations of gait deficits. Here, we assessed transmission in descending pathways using imaging and electrophysiological techniques and correlated them with clinical measures of impaired gait in persons with SCI. Twenty-five persons with SCI participated in the study. Functional assessment of gait included the Walking Index for Spinal Cord Injury (WISCI), the Timed-Up and Go (TUG), the 6-Min Walking Test (6MWT), and the maximal treadmill gait speed. Balance was evaluated clinically by the Berg Balance Scale (BBS). The amplitude of tibialis anterior (TA) motor-evoked potentials (MEPs) at rest elicited by transcranial magnetic stimulation as a measure of corticospinal transmission showed a moderately good correlation with all clinical measures (r(2)~0.5), whereas the latency of the MEPs showed less good correlation (r(2)~0.35). Interestingly, the MEP amplitude was correlated to atrophy in the ventrolateral rather than the dorsolateral section of the spinal cord where the main part of the corticospinal tract is located. TA intramuscular coherence in the beta and gamma frequency range has been suggested to reflect corticospinal transmission and was, consistent with this, found to be correlated to atrophy in the dorsolateral and ventrolateral sections of the spinal cord. Coherence was found to correlate to all clinical measures to the same extent as the MEP amplitude. The latency and duration of medium-latency responses in the soleus muscle to galvanic stimulation as measures of vestibulospinal transmission showed very good correlation to BBS (r(2)=-0.8) and moderately good correlation to the assessments of gait function (r(2)~0.4). 6MWT and gait speed were correlated to atrophy of the lateral sections of the spinal cord bilaterally, w

Diffusion weighted imaging (DWI) is used to study white-matter fibre organisation, orientation and structural connectivity by means of fibre reconstruction algorithms and tractography. For clinical settings, limited scan time compromises the possibilities to achieve high image resolution for finer anatomical details and signal-to-noise-ratio for reliable fibre reconstruction. We assessed the potential benefits of interpolating DWI datasets to a higher image resolution before fibre reconstruction using a diffusion tensor model. Simulations of straight and curved crossing tracts smaller than or equal to the voxel size showed that conventional higher-order interpolation methods improved the geometrical representation of white-matter tracts with reduced partial-volume-effect (PVE), except at tract boundaries. Simulations and interpolation of ex-vivo monkey brain DWI datasets revealed that conventional interpolation methods fail to disentangle fine anatomical details if PVE is too pronounced in the original data. As for validation we used ex-vivo DWI datasets acquired at various image resolutions as well as Nissl-stained sections. Increasing the image resolution by a factor of eight yielded finer geometrical resolution and more anatomical details in complex regions such as tract boundaries and cortical layers, which are normally only visualized at higher image resolutions. Similar results were found with typical clinical human DWI dataset. However, a possible bias in quantitative values imposed by the interpolation method used should be considered. The results indicate that conventional interpolation methods can be successfully applied to DWI datasets for mining anatomical details that are normally seen only at higher resolutions, which will aid in tractography and microstructural mapping of tissue compartments.