I see your effort: Force-Related BOLD effects in an extended action execution-observation network involving the cerebellum

Action observation (AO) is crucial for motor planning, imitation learning, and social interaction, but it is not clear whether and how an action execution-observation network (AEON) processes the effort of others engaged in performing actions. In this functional magnetic resonance imaging (fMRI) study, we used a "squeeze ball" task involving different grip forces to investigate whether AEON activation showed similar patterns when executing the task or observing others performing it. Both in action execution, AE (subjects performed the visuomotor task) and action observation, AO (subjects watched a video of the task being performed by someone else), the fMRI signal was detected in cerebral and cerebellar regions. These responses showed various relationships with force mapping onto specific areas of the sensorimotor and cognitive systems. Conjunction analysis of AE and AO was repeated for the "0th" order and linear and nonlinear responses, and revealed multiple AEON nodes remapping the detection of actions, and also effort, of another person onto the observer's own cerebrocerebellar system. This result implies that the AEON exploits the cerebellum, which is known to process sensorimotor predictions and simulations, performing an internal assessment of forces and integrating information into high-level schemes, providing a crucial substrate for action imitation

Thalamocortical connectivity in experimentally-induced migraine attacks: A pilot study

In this study we used nitroglycerin (NTG)-induced migraine attacks as a translational human disease model. Static and dynamic functional connectivity (FC) analyses were applied to study the associated functional brain changes. A spontaneous migraine-like attack was induced in five episodic migraine (EM) patients using a NTG challenge. Four task-free functional magnetic resonance imaging (fMRI) scans were acquired over the study: baseline, prodromal, full-blown, and recovery. Seed-based correlation analysis (SCA) was applied to fMRI data to assess static FC changes between the thalamus and the rest of the brain. Wavelet coherence analysis (WCA) was applied to test time-varying phase-coherence changes between the thalamus and salience networks (SNs). SCA results showed significantly FC changes between the right thalamus and areas involved in the pain circuits (insula, pons, cerebellum) during the prodromal phase, reaching its maximal alteration during the full-blown phase. WCA showed instead a loss of synchronisation between thalami and SN, mainly occurring during the prodrome and full-blown phases. These findings further support the idea that a temporal change in thalamic function occurs over the experimentally induced phases of NTG-induced headache in migraine patients. Correlation of FC changes with true clinical phases in spontaneous migraine would validate the utility of this model

Substantia Nigra Volumetry with 3-T MRI in De Novo and Advanced Parkinson Disease

Background: Magnetization transfer–prepared T1-weighted MRI can depict a hyperintense subregion of the substantia nigra involved in the degeneration process of Parkinson disease. / Purpose: To evaluate quantitative measurement of substantia nigra volume by using MRI to support clinical diagnosis and staging of Parkinson disease. / Materials and Methods: In this prospective study, a high-spatial-resolution magnetization transfer–prepared T1-weighted volumetric sequence was performed with a 3-T MRI machine between January 2014 and October 2015 for participants with de novo Parkinson disease, advanced Parkinson disease, and healthy control participants. A reproducible semiautomatic quantification analysis method that entailed mesencephalic intensity as an internal reference was used for hyperintense substantia nigra volumetry normalized to intracranial volume. A general linear model with age and sex as covariates was used to compare the three groups. / Results: Eighty participants were evaluated: 20 healthy control participants (mean age ± standard deviation, 56 years ± 11; 11 women), 29 participants with de novo Parkinson disease (64 years ± 10; 19 men), and 31 participants with advanced Parkinson disease (60 years ± 9; 16 women). Volumetric measurement of hyperintense substantia nigra from magnetization transfer–prepared T1-weighted MRI helped differentiate healthy control participants from participants with advanced Parkinson disease (mean difference for ipsilateral side, 64 mm3 ± 14, P < .001; mean difference for contralateral side, 109 mm3 ± 14, P < .001) and helped distinguish healthy control participants from participants with de novo Parkinson disease (mean difference for ipsilateral side, 45 mm3 ± 15, P < .01; mean difference for contralateral side, 66 mm3 ± 15, P < .001) and participants with de novo Parkinson disease from those with advanced Parkinson disease (mean difference for ipsilateral side, 20 mm3 ± 13, P = .40; mean difference for contralateral side, 43 mm3 ± 13, P = .004). / Conclusion: Magnetization transfer–prepared T1-weighted MRI volumetry of the substantia nigra helped differentiate the stages of Parkinson disease

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA. Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally. Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content. Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort

Normative values of the topological metrics of the structural connectome: A multi-site reproducibility study across the Italian Neuroscience network

Purpose: The use of topological metrics to derive quantitative descriptors from structural connectomes is receiving increasing attention but deserves specific studies to investigate their reproducibility and variability in the clinical context. This work exploits the harmonization of diffusion-weighted acquisition for neuroimaging data performed by the Italian Neuroscience and Neurorehabilitation Network initiative to obtain normative values of topological metrics and to investigate their reproducibility and variability across centers. / Methods: Different topological metrics, at global and local level, were calculated on multishell diffusion-weighted data acquired at high-field (e.g. 3 T) Magnetic Resonance Imaging scanners in 13 different centers, following the harmonization of the acquisition protocol, on young and healthy adults. A “traveling brains” dataset acquired on a subgroup of subjects at 3 different centers was also analyzed as reference data. All data were processed following a common processing pipeline that includes data pre-processing, tractography, generation of structural connectomes and calculation of graph-based metrics. The results were evaluated both with statistical analysis of variability and consistency among sites with the traveling brains range. In addition, inter-site reproducibility was assessed in terms of intra-class correlation variability. / Results: The results show an inter-center and inter-subject variability of <10%, except for “clustering coefficient” (variability of 30%). Statistical analysis identifies significant differences among sites, as expected given the wide range of scanners’ hardware. / Conclusions: The results show low variability of connectivity topological metrics across sites running a harmonised protocol

Quantitative MRI Harmonization to Maximize Clinical Impact: The RIN–Neuroimaging Network

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures

Mechanisms of Cognitive Impairment in Cerebral Small Vessel Disease: Multimodal MRI Results from the St George's Cognition and Neuroimaging in Stroke (SCANS) Study.

Cerebral small vessel disease (SVD) is a common cause of vascular cognitive impairment. A number of disease features can be assessed on MRI including lacunar infarcts, T2 lesion volume, brain atrophy, and cerebral microbleeds. In addition, diffusion tensor imaging (DTI) is sensitive to disruption of white matter ultrastructure, and recently it has been suggested that additional information on the pattern of damage may be obtained from axial diffusivity, a proposed marker of axonal damage, and radial diffusivity, an indicator of demyelination. We determined the contribution of these whole brain MRI markers to cognitive impairment in SVD. Consecutive patients with lacunar stroke and confluent leukoaraiosis were recruited into the ongoing SCANS study of cognitive impairment in SVD (n = 115), and underwent neuropsychological assessment and multimodal MRI. SVD subjects displayed poor performance on tests of executive function and processing speed. In the SVD group brain volume was lower, white matter hyperintensity volume higher and all diffusion characteristics differed significantly from control subjects (n = 50). On multi-predictor analysis independent predictors of executive function in SVD were lacunar infarct count and diffusivity of normal appearing white matter on DTI. Independent predictors of processing speed were lacunar infarct count and brain atrophy. Radial diffusivity was a stronger DTI predictor than axial diffusivity, suggesting ischaemic demyelination, seen neuropathologically in SVD, may be an important predictor of cognitive impairment in SVD. Our study provides information on the mechanism of cognitive impairment in SVD

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

Background: Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives: To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design: A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size was 440 patients. Setting: Thirteen UK clinical neuroscience centres. Participants: Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan; had a relapse or steroids in the previous 3 months; or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Interventions: Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. Main outcome measures: The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Results: Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [n = 111 (99)], fluoxetine [n = 111 (96)], riluzole [n = 111 (99)] or placebo [n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%); riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. Limitations: There was a lower than expected uptake in the cerebrospinal fluid substudy. Conclusions: A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. Future work: To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Trial registration: Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society

Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART):a phase 2b, multiarm, double-blind, randomised placebo-controlled trial

Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259

Spinal cord grey matter segmentation challenge

An important image processing step in spinal cord magnetic resonance imaging is the ability to reliably and accurately segment grey and white matter for tissue specific analysis. There are several semi- or fully-automated segmentation methods for cervical cord cross-sectional area measurement with an excellent performance close or equal to the manual segmentation. However, grey matter segmentation is still challenging due to small cross-sectional size and shape, and active research is being conducted by several groups around the world in this field. Therefore a grey matter spinal cord segmentation challenge was organised to test different capabilities of various methods using the same multi-centre and multi-vendor dataset acquired with distinct 3D gradient-echo sequences. This challenge aimed to characterize the state-of-the-art in the field as well as identifying new opportunities for future improvements. Six different spinal cord grey matter segmentation methods developed independently by various research groups across the world and their performance were compared to manual segmentation outcomes, the present gold-standard. All algorithms provided good overall results for detecting the grey matter butterfly, albeit with variable performance in certain quality-of-segmentation metrics. The data have been made publicly available and the challenge web site remains open to new submissions. No modifications were introduced to any of the presented methods as a result of this challenge for the purposes of this publication