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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. [ABSTRACT FROM AUTHOR]

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 anodal TDCS of M1-HAND in patients with subacute stroke patients with upper-extremity paresis. Concurrent multimodal brain mapping will shed light into the mechanisms of action of therapeutic personalized TDCS of M1-HAND. Together, the results from this trial may inform future personalized TDCS studies in patients with focal neurological deficits after stroke. [ABSTRACT FROM AUTHOR]

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-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially. [ABSTRACT FROM AUTHOR]

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 cognition, psychotic symptoms, side effects, and (ii) neurobiological endpoints related to regional glutamate- and neuromelanin levels, and structural brain changes. Anticipated Results: We hypothesize that add-on memantine to amisulpride will be superior to amisulpride monotherapy in reducing negative symptoms, and that this effect will correlate with thalamic glutamate levels. Moreover, we anticipate that add-on memantine will restore regional white matter integrity and improve cognitive functioning. Perspectives: By combining two licensed, off-patent drugs, AMEND aims to optimize treatment of psychosis while investigating the memantine response. Alongside, AMEND will provide neurobiological insights to effects of dual receptor modulation, which may enable future stratification of patients with first-episode psychosis before initial antipsychotic treatment. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04789915]. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An increasing number of studies supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes functional recovery in humans with spinal cord injury (SCI). However, the neural mechanisms contributing to these effects remain poorly understood. Here we examined motor-evoked potentials in arm muscles elicited by cortical and subcortical stimulation of corticospinal axons before and after 20 min of TESS (30 Hz pulses with a 5 kHz carrier frequency) and sham-TESS applied between C5 and C6 spinous processes in males and females with and without chronic incomplete cervical SCI. The amplitude of subcortical, but not cortical, motorevoked potentials increased in proximal and distal arm muscles for 75 min after TESS, but not sham-TESS, in control subjects and SCI participants, suggesting a subcortical origin for these effects. Intracortical inhibition, elicited by paired stimuli, increased after TESS in both groups. When TESS was applied without the 5 kHz carrier frequency both subcortical and cortical motor-evoked potentials were facilitated without changing intracortical inhibition, suggesting that the 5 kHz carrier frequency contributed to the cortical inhibitory effects. Hand and arm function improved largely when TESS was used with, compared with without, the 5 kHz carrier frequency. These novel observations demonstrate that TESS influences cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. We hypothesized that these parallel effects contribute to further the recovery of limb function following SCI. [ABSTRACT FROM AUTHOR]

Objective: Spasticity is one of the most common symptoms manifested in humans with spinal cord injury (SCI). The neural mechanisms contributing to its development are not yet understood. Using neurophysiological and imaging techniques, we examined the influence of residual descending motor pathways on spasticity in humans with SCI.Methods: We measured spasticity in 33 individuals with motor complete SCI (determined by clinical examination) without preservation of voluntary motor output in the quadriceps femoris muscle. To examine residual descending motor pathways, we used magnetic and electrical stimulation over the leg motor cortex to elicit motor evoked potentials (MEPs) in the quadriceps femoris muscle and structural magnetic resonance imaging to measure spinal cord atrophy.Results: We found that 60% of participants showed symptoms of spasticity, whereas the other 40% showed no spasticity, demonstrating the presence of 2 clear subgroups of humans with motor complete SCI. MEPs were only present in individuals who had spasticity, and MEP size correlated with the severity of spasticity. Spinal cord atrophy was greater in nonspastic compared with spastic subjects. Notably, the degree of spared tissue in the lateral regions of the spinal cord was positively correlated with the severity of spasticity, indicating preservation of white matter related to motor tracts when spasticity was present.Interpretation: These results support the hypothesis that preservation of descending motor pathways influences spasticity in humans with motor complete SCI; this knowledge might help the rehabilitation and assessment of people with SCI. ANN NEUROL 2019. [ABSTRACT FROM AUTHOR]

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 2.5 mm 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. [ABSTRACT FROM AUTHOR]

Stejskal and Tanner's ingenious pulsed field gradient design from 1965 has made diffusion NMR and MRI the mainstay of most studies seeking to resolve microstructural information in porous systems in general and biological systems in particular. Methods extending beyond Stejskal and Tanner's design, such as double diffusion encoding (DDE) NMR and MRI, may provide novel quantifiable metrics that are less easily inferred from conventional diffusion acquisitions. Despite the growing interest on the topic, the terminology for the pulse sequences, their parameters, and the metrics that can be derived from them remains inconsistent and disparate among groups active in DDE. Here, we present a consensus of those groups on terminology for DDE sequences and associated concepts. Furthermore, the regimes in which DDE metrics appear to provide microstructural information that cannot be achieved using more conventional counterparts (in a model-free fashion) are elucidated. We highlight in particular DDE's potential for determining microscopic diffusion anisotropy and microscopic fractional anisotropy, which offer metrics of microscopic features independent of orientation dispersion and thus provide information complementary to the standard, macroscopic, fractional anisotropy conventionally obtained by diffusion MR. Finally, we discuss future vistas and perspectives for DDE. [ABSTRACT FROM AUTHOR]

Purpose The short diffusion time regime provides an interesting probe for tissue microstructure and can be investigated with oscillating gradient spin echo (OGSE) experiments. Several studies report new contrasts in preclinical settings and the first in vivo human experiments have recently been presented. One major hurdle in practical implementation is the low effective diffusion weighting provided at high frequency with limited gradient strength. Theory As a solution to the low diffusion weighting of OGSE, circularly polarized OGSE (CP-OGSE) is introduced. CP-OGSE gives a twofold increase in diffusion weighting with encoding in a plane rather than in one direction. CP-OGSE can be used for rotationally invariant acquisitions on anisotropic tissues. Methods Experiments with a 4.7 T preclinical scanner on a postmortem monkey brain as well as simulations were performed using conventional OGSE and CP-OGSE. Results Simulations and experiments show that CP-OGSE provides the same microstructural information as OGSE but provides more robust parameter estimates with limited gradient strength. Conclusions CP-OGSE can be an important contribution for making OGSE imaging more effective in clinical imaging settings with limited gradient strength. Furthermore, the improved diffusion weighting can also be used to expand the investigated frequency range. Magn Reson Med 73:1171-1176, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose Double-wave diffusion experiments offer the possibility of probing correlation between molecular diffusion at multiple time points. It has recently been shown that this technique is capable of measuring the exchange of water across cellular membranes. The aim of this study was to investigate the effect of macroscopic tissue anisotropy on the measurement of the apparent exchange rate (AXR) in multicompartment systems. Methods AXR data were collected from yeast and perfusion-fixated brain tissue at high angular resolution on a preclinical imaging system. The AXR was expanded for anisotropic systems by calculating scalar AXR values along the principal directions of the diffusion tensor. Results In yeast, both the AXR and diffusivity were rotational invariant, whereas in fixated brain tissue, the measured AXR was sensitive to the orientation of anisotropic structures. AXR, especially in white matter, was robustly estimated along the first and second principal directions of the diffusion tensor, but increasing noise was seen in the AXR estimates along the third principal direction of the diffusion tensor. Conclusion Our results indicate that tissue anisotropy must be considered for AXR estimates in complex biological systems. Magn Reson Med 72:756-762, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Stimulated echo acquisition mode (STEAM) diffusion MRI can be advantageous over pulsed-gradient spin-echo (PGSE) for diffusion times that are long compared with T2. It therefore has potential for biomedical diffusion imaging applications at 7T and above where T2 is short. However, gradient pulses other than the diffusion gradients in the STEAM sequence contribute much greater diffusion weighting than in PGSE and lead to a disrupted experimental design. Here, we introduce a simple compensation to the STEAM acquisition that avoids the orientational bias and disrupted experiment design that these gradient pulses can otherwise produce. The compensation is simple to implement by adjusting the gradient vectors in the diffusion pulses of the STEAM sequence, so that the net effective gradient vector including contributions from diffusion and other gradient pulses is as the experiment intends. High angular resolution diffusion imaging (HARDI) data were acquired with and without the proposed compensation. The data were processed to derive standard diffusion tensor imaging (DTI) maps, which highlight the need for the compensation. Ignoring the other gradient pulses, a bias in DTI parameters from STEAM acquisition is found, due both to confounds in the analysis and the experiment design. Retrospectively correcting the analysis with a calculation of the full B matrix can partly correct for these confounds, but an acquisition that is compensated as proposed is needed to remove the effect entirely. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pulsed field gradient diffusion sequences (PFG) with multiple diffusion encoding blocks have been indicated to offer new microstructural tissue information, such as the ability to detect nonspherical compartment shapes in macroscopically isotropic samples, i.e. samples with negligible directional signal dependence on diffusion gradients in standard diffusion experiments. However, current acquisition schemes are not rotationally invariant in the sense that the derived metrics depend on the orientation of the sample, and are affected by the interplay of sampling directions and compartment orientation dispersion when applied to macroscopically anisotropic systems. Here we propose a new framework, the d-PFG 5-design, to enable rotationally invariant estimation of double wave vector diffusion metrics (d-PFG). The method is based on the idea that an appropriate orientational average of the signal emulates the signal from a powder preparation of the same sample, where macroscopic anisotropy is absent by construction. Our approach exploits the theory of exact numerical integration (quadrature) of polynomials on the rotation group, and we exemplify the general procedure with a set consisting of 60 pairs of diffusion wave vectors (the d-PFG 5-design) facilitating a theoretically exact determination of the fourth order Taylor or cumulant expansion of the orientationally averaged signal. The d-PFG 5-design is evaluated with numerical simulations and ex vivo high field diffusion MRI experiments in a nonhuman primate brain. Specifically, we demonstrate rotational invariance when estimating compartment eccentricity, which we show offers new microstructural information, complementary to that of fractional anisotropy (FA) from diffusion tensor imaging (DTI). The imaging observations are supported by a new theoretical result, directly relating compartment eccentricity to FA of individual pores. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging has been used in a number of spinal cord studies, but severe distortions caused by susceptibility induced field inhomogeneities limit its applicability to investigate small volumes within acceptable acquisition times. A way to evaluate image distortions is to map the point spread function of the voxel intensity in a reference scan. In this study, the point spread function was mapped for an echo-planar imaging sequence in the human cervical spinal cord with isotropic resolution and large field of view. Correction with the point spread function map improved anatomical consistency, and full cervical tractography was thereby possible from a C1 seed region in healthy controls and one individual with spinal cord injury. It is suggested that point spread function mapping of the spinal cord can be used in combination with sequence-based methods for reduction of susceptibility artifacts or in high-field imaging settings where off-resonance effects are pronounced. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]