Search

Background/Objectives: The objective of this study was to investigate associations between the spatial distribution of brain lesions and clinical outcomes in a cohort of people followed up 20 years after presentation with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).Methods: Brain lesion probability maps (LPMs) of T1 and T2 lesions were generated from 74 people who underwent magnetic resonance imaging (MRI) and clinical assessment a mean of 19.9 years following a CIS. One-tailed t-test statistics were used to compare LPMs between the following groups: clinically definite (CD) MS and those who remained with CIS, with an abnormal MRI; people with MS and an Expanded Disability Status Scale (EDSS) ≤3 and >3; people with relapsing–remitting (RR) and secondary progressive (SP) MS. The probability of each voxel being lesional was analysed adjusting for age and gender using a multiple linear regression model.Results: People with CDMS were significantly more likely than those with CIS and abnormal scan 20 years after onset to have T1 and T2 lesions in the corona radiata, optic radiation, and splenium of the corpus callosum (periventricularly) and T2 lesions in the right fronto-occipital fasciculus. People with MS EDSS >3, compared with those with EDSS ≤3, were more likely to have optic radiation and left internal capsule T2 lesions. No significant difference in lesion distribution was noted between RRMS and SPMS.Conclusion: This work demonstrates that lesion location characteristics are associated with CDMS and disability after long-term follow-up following a CIS. The lack of lesion spatial distribution differences between RRMS and SPMS suggests focal pathology affects similar regions in both subgroups. [ABSTRACT FROM AUTHOR]

Many magnetic resonance test-object properties are temperature-dependent, with typical temperature coefficients of ∼2-3% K−1. Therefore, to achieve consistent quality assurance measurements to within 1%, test object temperatures should ideally be known to within 0.3 K. Proton magnetic resonance spectroscopy has previously been used to estimate accurately absolute tissue temperature in vivo, based on the linear temperature dependence of the chemical shift difference between water and temperature-stable reference metabolites such as N-acetylaspartate. In this study, this method of 'internal thermometry' in quality assurance test-objects was investigated, and in particular the value of sodium 3-(trimethylsilyl)propane-1-sulfonate (DSS) as a chemical shift reference was demonstrated. The relationship between the DSS-water chemical shift difference ( σ, expressed in ppm) and temperature τ (in K) was shown to be τ = 764.55 (±5.05) − 97.72 (±1.05) σ (286 ≤ τ ≤ 309 K). Internal thermometry in MRI test-objects is feasible and straightforward, using readily available 1H-MRS pulse sequences and standard spectroscopy evaluation packages, with a minimum detectable temperature difference of 100 (±20) mK. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background/purpose: Patients' considerations when choosing an orthodontist are influenced by many factors, including background, ethnicity, and location. Accordingly, this study aimed to identify factors influencing patients' considerations when selecting an orthodontist in both Malaysia and Taiwan., Materials and Methods: In total, 248 dental students from Taipei Medical University and 110 dental students from Manipal University College Malaysia were selected for this study. Participants' considerations when selecting an orthodontist were assessed using a questionnaire survey. The questionnaire collected data regarding participants' demographic characteristics and their preferences regarding clinical settings, orthodontist attributes, administrative systems, and the influence of social media. The gathered data were analyzed and compared using independent t -test, ANOVA, and chi-squared for both cohorts., Results: The present results revealed significant differences between the Malaysian and Taiwanese participants with several variables, including orthodontist experience, recommendations, pain-free treatment procedures, treatment duration, friendly reception, sources of information about orthodontists, and preferred social media platforms. Notably, among the Taiwanese participants, "person responsible for treatment costs," was significantly correlated with the orthodontist's age, the orthodontist's work experience, information sources, travel distance, and content posted by orthodontists on social media. By contrast, among the Malaysian participants, this variable was correlated with the work experience of orthodontists., Conclusion: Significant differences were observed between the Malaysian and Taiwanese participants in terms of their considerations when choosing an orthodontist. Participant's gender significantly influenced orthodontist preferences among the Malaysian participants, whereas the individual responsible for treatment costs was identified to be the most crucial factor influencing the Taiwanese participants., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: Successful endodontic treatment needs accurate determination of working length (WL). Electronic apex locators (EALs) were presented as an alternative to radiographic methods; and since then, they have evolved and gained popularity in the determination of WL. However, there is insufficient evidence on the post-operative pain, adequacy, and accuracy of EALs in determining WL., Objective: The systematic review and meta-analysis aims to gather evidence regarding the effectiveness of EALs for WL determination when compared to different imaging techniques along with postoperative pain associated with WL determination, the number of radiographs taken during the procedure, the time taken, and the adverse effects., Methods: For the review, clinical studies with cross-over and parallel-arm randomized controlled trials (RCTs) were searched in seven electronic databases, followed by cross-referencing of the selected studies and related research synthesis. Risk of bias (RoB) assessment was carried out with Cochrane's RoB tool and a random-effects model was used. The meta-analysis was performed with the RevMan software 5.4.1., Results: Eleven eligible RCTs were incorporated into the review and eight RCTs into the meta-analysis, of which five had high RoB and the remaining six had unclear RoB. Following meta-analysis, no significant difference in postoperative pain was found among the EAL and radiograph groups (SMD 0.00, CI .29 to .28, 354 participants; P value = 0.98). Radiograph group showed better WL accuracy (SMD 0.55, CI .11 to .99, 254 participants; P value = 0.02), while the EAL group had 10% better WL adequacy (RR 1.10, CI 1.03-1.18, 573 participants; P value = 0.006)., Conclusion: We found very low-certainty evidence to support the efficacy of different types of EAL compared to radiography for the outcomes tested. We were unable to reach any conclusions about the superiority of any type of EAL. Well-planned RCTs need to be conducted by standardizing the outcomes and outcome measurement methods., (© 2024. The Author(s).)

Background: We assessed the ability of a brain-and-cord-matched quantitative magnetic resonance imaging (qMRI) protocol to differentiate patients with progressive multiple sclerosis (PMS) from controls, in terms of normal-appearing (NA) tissue abnormalities, and explain disability., Methods: A total of 27 patients and 16 controls were assessed on the Expanded Disability Status Scale (EDSS), 25-foot timed walk (TWT), 9-hole peg (9HPT) and symbol digit modalities (SDMT) tests. All underwent 3T brain and (C2-C3) cord structural imaging and qMRI (relaxometry, quantitative magnetisation transfer, multi-shell diffusion-weighted imaging), using a fast brain-and-cord-matched protocol with brain-and-cord-unified imaging readouts. Lesion and NA-tissue volumes and qMRI metrics reflecting demyelination and axonal loss were obtained. Random forest analyses identified the most relevant volumetric/qMRI measures to clinical outcomes. Confounder-adjusted linear regression estimated the actual MRI-clinical associations., Results: Several qMRI/volumetric differences between patients and controls were observed ( p < 0.01). Higher NA-deep grey matter quantitative-T1 (EDSS: beta = 7.96, p = 0.006; 9HPT: beta = -0.09, p = 0.004), higher NA-white matter orientation dispersion index (TWT: beta = -3.21, p = 0.005; SDMT: beta = -847.10, p < 0.001), lower whole-cord bound pool fraction (9HPT: beta = 0.79, p = 0.001) and higher NA-cortical grey matter quantitative-T1 (SDMT = -94.31, p < 0.001) emerged as particularly relevant predictors of greater disability., Conclusion: Fast brain-and-cord-matched qMRI protocols are feasible and identify demyelination - combined with other mechanisms - as key for disability accumulation in PMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: The impact of generative artificial intelligence-based Chatbots on medical education, particularly in Southeast Asia, is understudied regarding healthcare students' perceptions of its academic utility. Sociodemographic profiles and educational strategies influence prospective healthcare practitioners' attitudes toward AI tools., Aim and Objectives: This study aimed to assess healthcare university students' knowledge, attitude, and practice regarding ChatGPT for academic purposes. It explored chatbot usage frequency, purposes, satisfaction levels, and associations between age, gender, and ChatGPT variables., Methodology: Four hundred forty-three undergraduate students at a Malaysian tertiary healthcare institute participated, revealing varying awareness levels of ChatGPT's academic utility. Despite concerns about accuracy, ethics, and dependency, participants generally held positive attitudes toward ChatGPT in academics., Results: Multiple logistic regression highlighted associations between demographics, knowledge, attitude, and academic ChatGPT use. MBBS students were significantly more likely to use ChatGPT for academics than BDS and FIS students. Final-year students exhibited the highest likelihood of academic ChatGPT use. Higher knowledge and positive attitudes correlated with increased academic usage. Most users (45.8%) employed ChatGPT to aid specific assignment sections while completing most work independently. Some did not use it (41.1%), while others heavily relied on it (9.3%). Users also employed it for various purposes, from generating questions to understanding concepts. Thematic analysis of responses showed students' concerns about data accuracy, plagiarism, ethical issues, and dependency on ChatGPT for academic tasks., Conclusion: This study aids in creating guidelines for implementing GAI chatbots in healthcare education, emphasizing benefits, and risks, and informing AI developers and educators about ChatGPT's potential in academia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, George Pallivathukal et al.)

The present study synthesised and characterised zinc oxide nanoparticles (ZnO NPs) using spinach tree, Cnidoscolus aconitifolius and investigated its potential use as nanofertilizer. The synthesised nanoparticles showed UV-Vis absorption peak at 378 nm which is a feature of ZnO NPs. FT-IR analysis further revealed the presence of O-H stretching, C = C bending, O-H bending and C-N stretching functional groups of the stabilising action of the plant extract on the surface of the nanoparticles. SEM images displayed the shape of NPs to be spherical whereas TEM images showed their distribution sizes to be 100 nm. Synthesised ZnO NPs were used as a nano fertilizer on Sorghum bicolour plant. An increase in the shoot leaf length with an average length of 16.13 ± 0.19 cm as compared to the control group of 15.13 ± 0.07 cm was observed. The rate of photosynthesis also showed a significant increase with total chlorophyll content of 0.2806 ± 0.006 mg/mL as compared with control of 0.2476 ± 0.002 mg/mL. The activity of antioxidative enzymes was measured with an increase in the specific activity of SOD in the plant when ZnO NPs were used over NPK whereas, the specific activities of CAT were similar in all cases.

Aim: The present research was conducted to assess the microleakage of stainless steel crowns along with pedo jacket crowns following cementation with different luting cements., Materials and Methods: A total of 60 deciduous teeth subjected to extraction were employed in this in vitro research. These 60 specimens were randomly divided into two groups: Group I: Stainless steel crowns and Group II: Pedo Jacket crowns. Both crowns were subjected to cementation using self-cure resin-modified glass ionomer (RMGI) cement as well as by means of self-adhesive universal resin cement (RelyX luting cement). The specimens were subjected to storage in distilled water at 37°C for 24 h and were subjected to 500 thermal cycles between 5°C and 55°C using a dwell span of 30 s. Individual surfaces were assessed for the amount of dye infiltration at the boundaries by the side of the tooth-cement border beneath a stereomicroscope under 50× magnifying power. At the mesial and distal surfaces, the amount of microleakage was measured in micrometers (μm), and the mean value was computed for each sample., Results: Stainless steel crowns subject to cementation with RelyX luting cement exhibited the lowest microleakage (0.88 ± 0.78) versus self-cure RMGI cement (0.94 ± 0.78). There was no statistically significant difference found between the groups. Pedo Jacket crowns subject to cementation with RelyX luting cement exhibited the lowest microleakage (0.96. ± 0.32) while self-cure RMGI cement (1.83 ± 0.16) depicted the maximum microleakage. There was an extremely statistically noteworthy dissimilarity noted among the groups., Conclusion: The current research concluded that Pedo Jacket crowns subjected to cementation with RelyX luting cement can be regarded as an esthetically pleasing restorative alternative for numerous young patients. Applying RelyX luting cement to Pedo Jacket crowns provides a strong bolstering by composite materials that ensures the success of the therapy provided., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Pharmacy and Bioallied Sciences.)

Aim: The aim of the current research was to assess the ability of different dental varnishes in averting enamel demineralization adjoining the orthodontic brackets., Materials and Methods: Seventy-five premolars devoid of dental caries that were subjected to extraction for orthodontic purposes were employed in this research. The surface of enamel was etched with 37% phosphoric acid and subjected to primer application. Individual brackets were placed on the midregion of the buccal surfaces of the premolars with Transbond™ XT adhesive. Postbracket bonding, the dry premolar tooth samples were set aside cautiously. The samples were then allocated to three groups: Group I: Duraphat Varnish, Group II: Clinpro XT Varnish, and Group III: Profluorid Varnish. Every sample was independently subjected to immersion in demineralizing solution for a period of 96 h at 37°C in an incubator. Areas of demineralization were evaluated by documenting the microhardness along the severed surface using a microhardness tester equipped with a Vickers diamond., Results: The highest surface microhardness was noted with Profluorid Varnish group at 328.48 ± 1.12 in pursuit by Clinpro XT Varnish group at 322.08 ± 0.04 as well as Duraphat Varnish group at 307.42 ± 0.28 with a statistically noteworthy dissimilarity amid the groups., Conclusion: In conclusion, the three varnishes employed had an influence on the prevention of enamel demineralization surrounding the orthodontic brackets. Profluorid varnish however exhibited maximum efficiency in avoiding enamel demineralization versus Clinpro XT varnish as well as Duraphat varnish group., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Pharmacy and Bioallied Sciences.)

Magnetic resonance neurography (MRN) has been used successfully over the years to investigate the peripheral nervous system (PNS) because it allows early detection and precise localisation of neural tissue damage. However, studies demonstrating the feasibility of combining MRN with multi-parametric quantitative magnetic resonance imaging (qMRI) methods, which provide more specific information related to nerve tissue composition and microstructural organisation, can be invaluable. The translation of emerging qMRI methods previously validated in the central nervous system to the PNS offers real potential to characterise in patients in vivo the underlying pathophysiological mechanisms involved in a plethora of conditions of the PNS. The aim of this study was to assess the feasibility of combining MRN with qMRI to measure diffusion, magnetisation transfer and relaxation properties of the healthy sciatic nerve in vivo using a unified signal readout protocol. The reproducibility of the multi-parametric qMRI protocol as well as normative qMRI measures in the healthy sciatic nerve are reported. The findings presented herein pave the way to the practical implementation of joint MRN-qMRI in future studies of pathological conditions affecting the PNS., (© 2023. The Author(s).)

Purpose: Spinal cord gray-matter imaging is valuable for a number of applications, but remains challenging. The purpose of this work was to compare various MRI protocols at 1.5 T, 3 T, and 7 T for visualizing the gray matter., Methods: In vivo data of the cervical spinal cord were collected from nine different imaging centers. Data processing consisted of automatically segmenting the spinal cord and its gray matter and co-registering back-to-back scans. We computed the SNR using two methods (SNR&#95;single using a single scan and SNR&#95;diff using the difference between back-to-back scans) and the white/gray matter contrast-to-noise ratio per unit time. Synthetic phantom data were generated to evaluate the metrics performance. Experienced radiologists qualitatively scored the images. We ran the same processing on an open-access multicenter data set of the spinal cord MRI (N = 267 participants)., Results: Qualitative assessments indicated comparable image quality for 3T and 7T scans. Spatial resolution was higher at higher field strength, and image quality at 1.5 T was found to be moderate to low. The proposed quantitative metrics were found to be robust to underlying changes to the SNR and contrast; however, the SNR&#95;single method lacked accuracy when there were excessive partial-volume effects., Conclusion: We propose quality assessment criteria and metrics for gray-matter visualization and apply them to different protocols. The proposed criteria and metrics, the analyzed protocols, and our open-source code can serve as a benchmark for future optimization of spinal cord gray-matter imaging protocols., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background and Objective: To explore the relationship between slowly expanding lesions (SELs) on MRI and disability in secondary progressive multiple sclerosis (SPMS)., Methods: We retrospectively studied 345 patients with SPMS enrolled in the MS-SMART trial. They underwent brain MRI at baseline and at 24 and 96 weeks. Definite SELs were defined as concentrically expanding T2 lesions, as assessed by nonlinear deformation of volumetric T1-weighted images. Associations of SEL volumes with other MRI metrics and disability were assessed through Pearson correlations and regression analyses., Results: Averaged across patients, 29% of T2 lesions were classified as being definite SELs. A greater volume of definite SELs correlated with a higher total baseline T2 lesion volume ( r = 0.55, p < 0.001) and percentage brain volume reduction ( r = -0.26, p < 0.001), a higher number of new persisting T1 black holes ( r = 0.19, p < 0.001), and, in a subset of 106 patients, with a greater reduction in magnetization transfer ratio (adjusted difference 0.52, p < 0.001). In regression analyses, a higher definite SEL volume was associated with increasing disability, as assessed by the Expanded Disability Status Scale (β = 0.23, p = 0.020), z scores of the Multiple Sclerosis Functional Composite (β = -0.47, p = 0.048), Timed 25-Foot Walk Test (β = -2.10, p = 0.001), and Paced Auditory Serial Addition Task (β = -0.27, p = 0.006), and increased risk of disability progression (odds ratio 1.92, p = 0.025)., Discussion: Definite SELs represent almost one-third of T2 lesions in SPMS. They are associated with neurodegenerative MRI markers and related to clinical worsening, suggesting that they may contribute to disease progression and be a new target for therapeutic interventions., (© 2022 American Academy of Neurology.)

Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms. Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS. Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS. Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS. Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted., Competing Interests: FG is supported by PREdICT, a study co-funded by AstraZeneca (Spain). TS is an employee of DeepSpin (Germany) and previously worked for Philips (United Kingdom). MB is an employee of ASG Superconductors. MY is employed by Philips (Japan). AstraZeneca, Philips, DeepSpin and Superconductors were not involved in the study design; collection, analysis, interpretation of data; manuscript writing and decision to submit the manuscript for publication; or any other aspect concerning this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boonsuth, Samson, Tur, Battiston, Grussu, Schneider, Yoneyama, Prados, Ttofalla, Collorone, Cortese, Ciccarelli, Gandini Wheeler-Kingshott and Yiannakas.)

This study aims to determine tissue-specific neurodegeneration across the spinal cord in patients with mild-moderate degenerative cervical myelopathy (DCM). Twenty-four mild-moderate DCM and 24 healthy subjects were recruited. In patients, a T2-weighted scan was acquired at the compression site, whereas in all participants a T2*-weighted and diffusion-weighted scan was acquired at the cervical level (C2-C3) and in the lumbar enlargement (i.e., rostral and caudal to the site of compression). We quantified intramedullary signal changes, maximal canal and cord compression, white (WM) and gray matter (GM) atrophy, and microstructural indices from diffusion-weighted scans. All patients underwent clinical (modified Japanese Orthopaedic Association; mJOA) and electrophysiological assessments. Regression analysis assessed associations between magnetic resonance imaging (MRI) readouts and electrophysiological and clinical outcomes. Twenty patients were classified with mild and 4 with moderate DCM using the mJOA scale. The most frequent site of compression was at the C5-C6 level, with maximum cord compression of 38.73% ± 11.57%. Ten patients showed imaging evidence of cervical myelopathy. In the cervical cord, WM and GM atrophy and WM microstructural changes were evident, whereas in the lumbar cord only WM showed atrophy and microstructural changes. Remote cervical cord WM microstructural changes were pronounced in patients with radiological myelopathy and associated with impaired electrophysiology. Lumbar cord WM atrophy was associated with lower limb sensory impairments. In conclusion, tissue-specific neurodegeneration revealed by quantitative MRI is already apparent across the spinal cord in mild-moderate DCM before the onset of severe clinical impairments. WM microstructural changes are particularly sensitive to remote pathologically and clinically eloquent changes in DCM.

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis., Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m 2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed., Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55)., Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies., Funding: Multiple Sclerosis Society of the United Kingdom., Competing Interests: Declaration of interests JWLB reports personal fees from Biogen for real-world evidence consultation, outside the submitted work. NGC reports grants from the Multiple Sclerosis Society of the United Kingdom, during the conduct of the study. JLJ reports grants and personal fees from Sanofi, outside the submitted work. DR reports grants from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, TG Therapeutics, and Mitsubishi, and personal fees from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, Janssen, and Celgene, outside the submitted work. ORP reports personal fees from Biogen, Genzyme, Merck, Novartis, Celegene, and Roche, outside the submitted work. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global, and Allergan, and employment from Hoffmann La-Roche, outside the submitted work, and is a shareholder of Hoffmann La-Roche. Cf-C reports grants from Roche, outside the submitted work. CM reports personal fees from Sanofi, AstraZeneca, and Apitope, and non-financial support from Sanofi and AstraZeneca, outside the submitted work. RJMF reports grants from Biogen, and personal fees from Biogen, Frequency Therapeutics, and Rewind Therapeutics, outside the submitted work. SC reports funding from Phenotherapeutics, outside the submitted work. DTC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study, and personal fees from Biogen and Hoffmann-La Roche, grants from the International Progressive MS Alliance and the Multiple Sclerosis Society of the United Kingdom, and infrastructure support from the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, outside the submitted work. AJC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord., (© 2021. The Author(s).)

Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

This study highlights the importance of looking beyond the main effect of movement to study alterations in functional response in the presence of central nervous system pathologies such as multiple sclerosis (MS). Data show that MS selectively affects regional BOLD (blood oxygenation level dependent) responses to variable grip forces (GF). It is known that the anterior and posterior BA 4 areas (BA 4a and BA 4p) are anatomically and functionally distinct. It has also been shown in healthy volunteers that there are linear (first order, typical of BA 4a) and nonlinear (second to fourth order, typical of BA 4p) BOLD responses to different levels of GF applied during a dynamic motor paradigm. After modeling the BOLD response with a polynomial expansion of the applied GFs, the particular case of BA 4a and BA 4p were investigated in healthy volunteers (HV) and MS subjects. The main effect of movement (zeroth order) analysis showed that the BOLD signal is greater in MS compared with healthy volunteers within both BA 4 subregions. At higher order, BOLD-GF responses were similar in BA 4a but showed a marked alteration in BA 4p of MS subjects, with those with greatest disability showing the greatest deviations from the healthy response profile. Therefore, the different behaviors in HV and MS could only be uncovered through a polynomial analysis looking beyond the main effect of movement into the two BA 4 subregions. Future studies will investigate the source of this pathophysiology, combining the present fMRI paradigm with blood perfusion and nonlinear neuronal response analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alahmadi, Pardini, Samson, D’Angelo, Friston, Toosy and Gandini Wheeler-Kingshott.)

Multicenter clinical and quantitative magnetic resonance imaging (qMRI) studies require a high degree of reproducibility across different sites and scanner manufacturers, as well as time points. We therefore implemented a multiparameter mapping (MPM) protocol based on vendor's product sequences and demonstrate its repeatability and reproducibility for whole-brain coverage. Within ~20 min, four MPM metrics (magnetization transfer saturation [MT], proton density [PD], longitudinal [R1], and effective transverse [R2*] relaxation rates) were measured using an optimized 1 mm isotropic resolution protocol on six 3 T MRI scanners from two different vendors. The same five healthy participants underwent two scanning sessions, on the same scanner, at each site. MPM metrics were calculated using the hMRI-toolbox. To account for different MT pulses used by each vendor, we linearly scaled the MT values to harmonize them across vendors. To determine longitudinal repeatability and inter-site comparability, the intra-site (i.e., scan-rescan experiment) coefficient of variation (CoV), inter-site CoV, and bias across sites were estimated. For MT, R1, and PD, the intra- and inter-site CoV was between 4 and 10% across sites and scan time points for intracranial gray and white matter. A higher intra-site CoV (16%) was observed in R2* maps. The inter-site bias was below 5% for all parameters. In conclusion, the MPM protocol yielded reliable quantitative maps at high resolution with a short acquisition time. The high reproducibility of MPM metrics across sites and scan time points combined with its tissue microstructure sensitivity facilitates longitudinal multicenter imaging studies targeting microstructural changes, for example, as a quantitative MRI biomarker for interventional clinical trials., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions., Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient's evolution, and whether baseline gradients predict on-treatment relapses., Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups' baseline gradients and evolution., Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (-0.045 pu/band/year, p  = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( p  = 0.568) nor brain parenchymal fraction ( p  = 0.187) between those who relapsed within 4 years ( n  = 4) and those who did not ( n  = 15). However, the baseline gradient was significantly different ( p  = 0.020)., Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients - but not lesion loads or brain volumes - may predict on-treatment relapses. Larger confirmatory studies are required.

Background: In relapse-onset multiple sclerosis (MS), tissue abnormality - as assessed with magnetisation transfer ratio (MTR) imaging - is greater in the outer cortical and inner periventricular layers. The cause of this remains unknown but meningeal inflammation has been implicated, particularly lymphoid follicles, which are seen in secondary progressive (SP) but not primary progressive (PP) MS. Cortical and periventricular MTR gradients might, therefore, differ in PPMS and SPMS if these follicles are responsible., Objective: We assessed cortical and periventricular MTR gradients in PPMS, and compared gradients between people with PPMS and SPMS., Methods: Using an optimised processing pipeline, periventricular normal-appearing white matter and cortical grey-matter MTR gradients were compared between 51 healthy controls and 63 people with progressive MS (28 PPMS, 35 SPMS)., Results: The periventricular gradient was significantly shallower in healthy controls (0.122 percentage units (pu)/band) compared to PPMS (0.952 pu/band, p  < 0.0001) and SPMS (1.360 pu/band, p  < 0.0001). The cortical gradient was also significantly shallower in healthy controls (-2.860 pu/band) compared to PPMS (-3.214 pu/band, p  = 0.038) and SPMS (-3.328 pu/band, p  = 0.016)., Conclusion: Abnormal periventricular and cortical MTR gradients occur in both PPMS and SPMS, suggesting comparable underlying pathological processes.

Purpose: To enable clinical applications of quantitative magnetization transfer (qMT) imaging by developing a fast method to map one of its fundamental model parameters, the bound pool fraction (BPF), in the human brain., Theory and Methods: The theory of steady-state MT in the fast-exchange approximation is used to provide measurements of BPF, and bound pool transverse relaxation time ( T 2 B ). A sequence that allows sampling of the signal during steady-state MT saturation is used to perform BPF mapping with a 10-min-long fully echo planar imaging-based MRI protocol, including inversion recovery T 1 mapping and B 1 error mapping. The approach is applied in 6 healthy subjects and 1 multiple sclerosis patient, and validated against a single-slice full qMT reference acquisition., Results: BPF measurements are in agreement with literature values using off-resonance MT, with average BPF of 0.114(0.100-0.128) in white matter and 0.068(0.054-0.085) in gray matter. Median voxel-wise percentage error compared with standard single slice qMT is 4.6%. Slope and intercept of linear regression between new and reference BPF are 0.83(0.81-0.85) and 0.013(0.11-0.16). Bland-Altman plot mean bias is 0.005. In the multiple sclerosis case, the BPF is sensitive to pathological changes in lesions., Conclusion: The method developed provides accurate BPF estimates and enables shorter scan time compared with currently available approaches, demonstrating the potential of bringing myelin sensitive measurement closer to the clinic., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a framework to fully characterize quantitative magnetization transfer indices in the human cervical cord in vivo within a clinically feasible time., Methods: A dedicated spinal cord imaging protocol for quantitative magnetization transfer was developed using a reduced field-of-view approach with echo planar imaging (EPI) readout. Sequence parameters were optimized based in the Cramer-Rao-lower bound. Quantitative model parameters (i.e., bound pool fraction, free and bound pool transverse relaxation times [ T2F, T2B], and forward exchange rate [k FB ]) were estimated implementing a numerical model capable of dealing with the novelties of the sequence adopted. The framework was tested on five healthy subjects., Results: Cramer-Rao-lower bound minimization produces optimal sampling schemes without requiring the establishment of a steady-state MT effect. The proposed framework allows quantitative voxel-wise estimation of model parameters at the resolution typically used for spinal cord imaging (i.e. 0.75 × 0.75 × 5 mm 3 ), with a protocol duration of ∼35 min. Quantitative magnetization transfer parametric maps agree with literature values. Whole-cord mean values are: bound pool fraction = 0.11(±0.01), T2F = 46.5(±1.6) ms, T2B = 11.0(±0.2) µs, and k FB  = 1.95(±0.06) Hz. Protocol optimization has a beneficial effect on reproducibility, especially for T2B and k FB ., Conclusion: The framework developed enables robust characterization of spinal cord microstructure in vivo using qMT. Magn Reson Med 79:2576-2588, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a fast and robust method for measuring T 1 in the whole cervical spinal cord in vivo, and to assess its reproducibility., Methods: A spatially nonselective adiabatic inversion pulse is combined with zonally oblique-magnified multislice echo-planar imaging to produce a reduced field-of-view inversion-recovery echo-planar imaging protocol. Multi- inversion time data are obtained by cycling slice order throughout sequence repetitions. Measurement of T 1 is performed using 12 inversion times for a total protocol duration of 7 min. Reproducibility of regional T 1 estimates is assessed in a scan-rescan experiment on five heathy subjects., Results: Regional mean (standard deviation) T 1 was: 1108.5 (±77.2) ms for left lateral column, 1110.1 (±83.2) ms for right lateral column, 1150.4 (±102.6) ms for dorsal column, and 1136.4 (±90.8) ms for gray matter. Regional T 1 estimates showed good correlation between sessions (Pearson correlation coefficient = 0.89 (P value < 0.01); mean difference = 2 ms, 95% confidence interval ± 20 ms); and high reproducibility (intersession coefficient of variation approximately 1% in all the regions considered, intraclass correlation coefficient = 0.88 (P value < 0.01, confidence interval 0.71-0.95))., Conclusions: T 1 estimates in the cervical spinal cord are reproducible using inversion-recovery zonally oblique-magnified multislice echo-planar imaging. The short acquisition time and large coverage of this method paves the way for accurate T 1 mapping for various spinal cord pathologies. Magn Reson Med 79:2142-2148, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Fixed orthodontic retainers must be well retained on the tooth surfaces, allow physiologic movement of teeth and exert minimal forces on the teeth to be retained. Previous studies analyzed the bond strength and amount of deflection caused due to the debonding force but not the magnitude of force needed for unit deformation., Aims: This study aims to evaluate and compare the bond strength and load deflection rate (LDR) of three different fixed retainer wires., Materials and Methods: The wires were divided into three Groups: A - three-stranded twisted ligature wire, B - Bond-A-Braid (Reliance Orthodontics), and C - three-stranded twisted lingual retainer wire (3M Unitek). Twenty models were prepared for each group with a passive 15 mm long lingual retainer wire bonded to two lower incisors. An occlusogingival force was applied to the wire until it debonded. For LDR, three-point bending test was done at 0.5 mm deflection. These forces were measured using a Universal Instron Testing Machine., Statistical Analysis: Mean bond strength/LDR and pairwise comparisons were analyzed with one-way ANOVA and Tukey's honest significant difference post hoc test, respectively., Results: Group C exhibited the highest mean bond strength and LDR of 101.17N and 1.84N, respectively. The intergroup comparisons were all statistically significant., Conclusion: Compared to the other two wire types, Group C might be better retained on the teeth due to its higher bond strength. With its relatively higher LDR value, it may resist deformation from occlusal forces, thereby reducing inadvertent tooth movement and yet remain flexible enough to allow physiologic tooth movements., Competing Interests: There are no conflicts of interest.

Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: None declared.

The relationship between the BOLD response and an applied force was quantified in the cerebellum using a power grip task. To investigate whether the cerebellum responds in an on/off way to motor demands or contributes to motor responses in a parametric fashion, similarly to the cortex, five grip force levels were investigated under visual feedback. Functional MRI data were acquired in 13 healthy volunteers and their responses were analyzed using a cerebellum-optimized pipeline. This allowed us to evaluate, within the cerebellum, voxelwise linear and non-linear associations between cerebellar activations and forces. We showed extensive non-linear activations (with a parametric design), covering the anterior and posterior lobes of the cerebellum with a BOLD-force relationship that is region-dependent. Linear responses were mainly located in the anterior lobe, similarly to the cortex, where linear responses are localized in M1. Complex responses were localized in the posterior lobe, reflecting its key role in attention and executive processing, required during visually guided movement. Given the highly organized responses in the cerebellar cortex, a key question is whether deep cerebellar nuclei show similar parametric effects. We found positive correlations with force in the ipsilateral dentate nucleus and negative correlations on the contralateral side, suggesting a somatotopic organization of the dentate nucleus in line with cerebellar and cortical areas. Our results confirm that there is cerebellar organization involving all grey matter structures that reflect functional segregation in the cortex, where cerebellar lobules and dentate nuclei contribute to complex motor tasks with different BOLD response profiles in relation to the forces. Hum Brain Mapp 38:2566-2579, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

In established multiple sclerosis, tissue abnormality-as assessed using magnetization transfer ratio-increases close to the lateral ventricles. We aimed to determine whether or not (i) these changes are present from the earliest clinical stages of multiple sclerosis; (ii) they occur independent of white matter lesions; and (iii) they are associated with subsequent conversion to clinically definite multiple sclerosis and disability. Seventy-one subjects had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (49 females, mean age 33.5 years) and were followed up clinically 2 and 5 years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter, magnetization transfer ratio gradients were measured 1-5 mm and 6-10 mm from the lateral ventricles. In control subjects, magnetization transfer ratio was highest adjacent to the ventricles and decreased with distance from them; in optic neuritis, normal-appearing white matter magnetization transfer ratio was lowest adjacent to the ventricles, increased over the first 5 mm, and then paralleled control values. The magnetization transfer ratio gradient over 1-5 mm differed significantly between the optic neuritis and control groups [+0.059 percentage units/mm (pu/mm) versus -0.033 pu/mm, P = 0.010], and was significantly steeper in those developing clinically definite multiple sclerosis within 2 years compared to those who did not (0.132 pu/mm versus 0.016 pu/mm, P = 0.020). In multivariate binary logistic regression the magnetization transfer ratio gradient was independently associated with the development of clinically definite multiple sclerosis within 2 years (magnetization transfer ratio gradient odds ratio 61.708, P = 0.023; presence of T 2 lesions odds ratio 8.500, P = 0.071). At 5 years, lesional measures overtook magnetization transfer ratio gradients as significant predictors of conversion to multiple sclerosis. The magnetization transfer ratio gradient was not significantly affected by the presence of brain lesions [T 2 lesions (P = 0.918), periventricular T 2 lesions (P = 0.580) or gadolinium-enhancing T 1 lesions (P = 0.724)]. The magnetization transfer ratio gradient also correlated with Expanded Disability Status Scale score 5 years later (Spearman r = 0.313, P = 0.027). An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis, is clinically relevant, and may arise from one or more mechanisms that are at least partly independent of lesion formation., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess the association between proximity to the inner (ventricular and aqueductal) and outer (pial) surfaces of the brain and the distribution of normal appearing white matter (NAWM) and grey matter (GM) abnormalities, and white matter (WM) lesions, in multiple sclerosis (MS)., Methods: 67 people with relapse-onset MS and 30 healthy controls were included in the study. Volumetric T1 images and high-resolution (1 mm 3 ) magnetisation transfer ratio (MTR) images were acquired and segmented into 12 bands between the inner and outer surfaces of the brain. The first and last bands were discarded to limit partial volume effects with cerebrospinal fluid. MTR values were computed for all bands in supratentorial NAWM, cerebellar NAWM and brainstem NA tissue, and deep and cortical GM. Band WM lesion volumes were also measured., Results: Proximity to the ventricular surfaces was associated with progressively lower MTR values in the MS group but not in controls in supratentorial and cerebellar NAWM, brainstem NA and in deep and cortical GM. The density of WM lesions was associated with proximity to the ventricles only in the supratentorial compartment, and no link was found with distance from the pial surfaces., Conclusions: In MS, MTR abnormalities in NAWM and GM are related to distance from the inner and outer surfaces of the brain, and this suggests that there is a common factor underlying their spatial distribution. A similar pattern was not found for WM lesions, raising the possibility that different factors promote their formation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Diffusion tensor imaging (DTI) has recently started to be adopted into clinical investigations of spinal cord (SC) diseases. However, DTI applications to the lower SC are limited due to a number of technical challenges, related mainly to the even smaller size of the SC structure at this level, its position relative to the receiver coil elements and the effects of motion during data acquisition. Developing methods to overcome these problems would offer new means to gain further insights into microstructural changes of neurological conditions involving the lower SC, and in turn could help explain symptoms such as bladder and sexual dysfunction. In this work, the feasibility of obtaining grey and white matter (GM/WM) DTI indices such as axial/radial/mean diffusivity (AD/RD/MD) and fractional anisotropy (FA) within the lumbosacral enlargement (LSE) was investigated using a reduced field-of-view (rFOV) single-shot echo-planar imaging (ss-EPI) acquisition in 14 healthy participants using a clinical 3T MR system. The scan-rescan reproducibility of the measurements was assessed by calculating the percentage coefficient of variation (%COV). Mean FA was higher in WM compared to GM (0.58 and 0.4 in WM and GM respectively), AD and MD were higher in WM compared to GM (1.66 μm2ms-1 and 0.94 μm2ms-1 in WM and 1.2 μm2ms-1 and 0.82 μm2ms-1 in GM for AD and MD respectively) and RD was lower in WM compared to GM (0.58 μm2ms-1 and 0.63 μm2ms-1 respectively). The scan-rescan %COV was lower than 10% in all cases with the highest values observed for FA and the lowest for MD. This pilot study demonstrates that it is possible to obtain reliable tissue-specific estimation of DTI indices within the LSE using a rFOV ss-EPI acquisition. The DTI acquisition and analysis protocol presented here is clinically feasible and may be used in future investigations of neurological conditions implicating the lower SC., Competing Interests: The authors have declared that no competing interests exist.

Unlabelled: Previous studies have used fMRI to address the relationship between grip force (GF) applied to an object and BOLD response. However, whilst the majority of these studies showed a linear relationship between GF and neural activity in the contralateral M1 and ipsilateral cerebellum, animal studies have suggested the presence of non-linear components in the GF-neural activity relationship. Here, we present a methodology for assessing non-linearities in the BOLD response to different GF levels, within primary motor as well as sensory and cognitive areas and the cerebellum. To be sensitive to complex forms, we designed a feasible grip task with five GF targets using an event-related visually guided paradigm and studied a cohort of 13 healthy volunteers. Polynomial functions of increasing order were fitted to the data., Major Findings: (1) activated motor areas irrespective of GF; (2) positive higher-order responses in and outside M1, involving premotor, sensory and visual areas and cerebellum; (3) negative correlations with GF, predominantly involving the visual domain. Overall, our results suggest that there are physiologically consistent behaviour patterns in cerebral and cerebellar cortices; for example, we observed the presence of a second-order effect in sensorimotor areas, consistent with an optimum metabolic response at intermediate GF levels, while higher-order behaviour was found in associative and cognitive areas. At higher GF levels, sensory-related cortical areas showed reduced activation, interpretable as a redistribution of the neural activity for more demanding tasks. These results have the potential of opening new avenues for investigating pathological mechanisms of neurological diseases.

The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imaging (DTI) protocols, implemented at multiple sites (using scanners from two different manufacturers), one available on any clinical scanner, and one using more advanced options currently available in the research setting, and to use an automated processing method for unbiased quantification. DTI parameters are sensitive to changes in the diseased SC. However, imaging the cord can be technically challenging due to various factors including its small size, patient-related and physiological motion, and field inhomogeneities. Rapid acquisition sequences such as Echo Planar Imaging (EPI) are desirable but may suffer from image distortions. We present a multi-centre comparison of two acquisition protocols implemented on scanners from two different vendors (Siemens and Philips), one using a reduced field-of-view (rFOV) EPI sequence, and one only using options available on standard clinical scanners such as outer volume suppression (OVS). Automatic analysis was performed with the Spinal Cord Toolbox for unbiased and reproducible quantification of DTI metrics in the white matter. Images acquired using the rFOV sequence appear less distorted than those acquired using OVS alone. SC DTI parameter values obtained using both sequences at all sites were consistent with previous measurements made at 3T. For the same scanner manufacturer, DTI parameter inter-site SDs were smaller for the rFOV sequence compared to the OVS sequence. The higher inter-site reproducibility (for the same manufacturer and acquisition details, i.e. ZOOM data acquired at the two Philips sites) of rFOV compared to the OVS sequence supports the idea that making research options such as rFOV more widely available would improve accuracy of measurements obtained in multi-centre clinical trials. Future multi-centre studies should also aim to match the rFOV technique and signal-to-noise ratios in all sequences from different manufacturers/sites in order to avoid any bias in measured DTI parameters and ensure similar sensitivity to pathological changes.

Background: The HLA-DRB*1501 haplotype influences the risk of developing multiple sclerosis (MS), but it is not known how it affects grey matter pathology., Aim: To assess HLA-DRB(*)1501 effects on magnetic resonance imaging (MRI) cortical grey matter pathology., Methods: Whole and lesional cortical grey matter volumes, lesional and normal-appearing grey matter magnetization transfer ratio were measured in 85 people with MS and 36 healthy control subjects. HLA-DRB(*)1501 haplotype was determined by genotyping (rs3135388)., Results: No significant differences were observed in MRI measures between the HLA-DRB(*)1501 subgroups., Conclusions: The HLA-DRB(*)1501 haplotype is not strongly associated with MRI-visible grey matter pathology., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed., Objective: To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS., Methods: Seventy-two people with MS (46 relapsing-remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter., Results: Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability., Conclusion: Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability., (© The Author(s), 2015.)

Motor fMRI studies, comparing dominant (DH) and nondominant (NDH) hand activations have reported mixed findings, especially for the extent of ipsilateral (IL) activations and their relationship with task complexity. To date, no study has directly compared DH and NDH activations using an event-related visually guided dynamic power-grip paradigm with parametric (three) forces (GF) in healthy right-handed subjects. We implemented a hierarchical statistical approach aimed to: (i) identify the main effect networks engaged when using either hand; (ii) characterise DH/NDH responses at different GFs; (iii) assess contralateral (CL)/IL-specific and hemisphere-specific activations. Beyond confirming previously reported results, this study demonstrated that increasing GF has an effect on motor response that is contextualised also by the use of DH or NDH. Linear analysis revealed increased activations in sensorimotor areas, with additional increased recruitments of subcortical and cerebellar areas when using the NDH. When looking at CL/IL-specific activations, CL sensorimotor areas and IL cerebellum were activated with both hands. When performing the task with the NDH, several areas were also recruited including the CL cerebellum. Finally, there were hand-side-independent activations of nonmotor-specific areas in the right and left hemispheres, with the right hemisphere being involved more extensively in sensori-motor integration through associative areas while the left hemisphere showing greater activation at higher GF. This study shows that the functional networks subtending DH/NDH power-grip visuomotor functions are qualitatively and quantitatively distinct and this should be taken into consideration when performing fMRI studies, particularly when planning interventions in patients with specific impairments., (© 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.)

Objective: To develop a composite MRI-based measure of motor network integrity, and determine if it explains disability better than conventional MRI measures in patients with multiple sclerosis (MS)., Methods: Tract density imaging and constrained spherical deconvolution tractography were used to identify motor network connections in 22 controls. Fractional anisotropy (FA), magnetization transfer ratio (MTR), and normalized volume were computed in each tract in 71 people with relapse onset MS. Principal component analysis was used to distill the FA, MTR, and tract volume data into a single metric for each tract, which in turn was used to compute a composite measure of motor network efficiency (composite NE) using graph theory. Associations were investigated between the Expanded Disability Status Scale (EDSS) and the following MRI measures: composite motor NE, NE calculated using FA alone, FA averaged in the combined motor network tracts, brain T2 lesion volume, brain parenchymal fraction, normal-appearing white matter MTR, and cervical cord cross-sectional area., Results: In univariable analysis, composite motor NE explained 58% of the variation in EDSS in the whole MS group, more than twice that of the other MRI measures investigated. In a multivariable regression model, only composite NE and disease duration were independently associated with EDSS., Conclusions: A composite MRI measure of motor NE was able to predict disability substantially better than conventional non-network-based MRI measures., (© 2015 American Academy of Neurology.)

Magnetisation transfer (MT) imaging of the central nervous system has provided further insight into the pathophysiology of neurological disease. However, the use of this method to study the lower spinal cord has been technically challenging, despite the important role of this region, not only for motor control of the lower limbs, but also for the neural control of lower urinary tract, sexual and bowel functions. In this study, the feasibility of obtaining reliable grey matter (GM) and white matter (WM) magnetisation transfer ratio (MTR) measurements within the lumbosacral enlargement (LSE) was investigated in ten healthy volunteers using a clinical 3T MRI system. The mean cross-sectional area of the LSE (LSE-CSA) and the mean GM area (LSE-GM-CSA) were first obtained by means of image segmentation and tissue-specific (i.e. WM and GM) MTR measurements within the LSE were subsequently obtained. The reproducibility of the segmentation method and MTR measurements was assessed from repeated measurements and their % coefficient of variation (%COV). Mean (± SD) LSE-CSA across 10 healthy subjects was 59.3 (± 8.4) mm2 and LSE-GM-CSA was 17.0 (± 3.1) mm2. The mean intra- and inter-rater % COV for measuring the LSE-CSA were 0.8% and 2.3%, respectively and for the LSE-GM-CSA were 3.8% and 5.4%, respectively. Mean (± SD) WM-MTR was 43.2 (± 4.4) and GM-MTR was 40.9 (± 4.3). The mean scan-rescan % COV for measuring WM-MTR was 4.6% and for GM-MTR was 3.8%. Using a paired t-test, a statistically significant difference was identified between WM-MTR and GM-MTR in the LSE (p<0.0001). This pilot study has shown that it is possible to obtain reliable tissue-specific MTR measurements within the LSE using a clinical MR system at 3T. The MTR acquisition and analysis protocol presented in this study can be used in future investigations of intrinsic spinal cord diseases that affect the LSE.

In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken. The present study investigates this relationship in vivo using quantitative magnetic resonance imaging and compares the abnormalities between secondary progressive and relapsing remitting multiple sclerosis. Forty-three patients with relapsing remitting and 28 with secondary progressive multiple sclerosis, and 38 healthy control subjects were included in this study. T1-weighted volumetric, magnetization transfer and proton density/T2-weighted scans were acquired for all subjects. From the magnetization transfer data, magnetization transfer ratio maps were prepared. White matter tissue masks were derived from SPM8 segmentations of the T1-weighted images. Normal-appearing white matter masks were generated by subtracting white matter lesions identified on the proton density/T2 scan, and a two-voxel perilesional ring, from the SPM8 derived white matter masks. White matter was divided in concentric bands, each ∼1-mm thick, radiating from the ventricles toward the cortex. The first periventricular band was excluded from analysis to mitigate partial volume effects, and normal-appearing white matter and lesion magnetization transfer ratio values were then computed for the 10 bands nearest to the ventricles. Compared with controls, magnetization transfer ratio in the normal-appearing white matter bands was significantly lower in patients with multiple sclerosis. In controls, magnetization transfer ratio was highest in the band adjacent to the ventricles and declined with increasing distance from the ventricles. In the multiple sclerosis groups, relative to controls, reductions in magnetization transfer ratio were greater in the secondary progressive multiple sclerosis compared with relapsing remitting multiple sclerosis group, and these reductions were greatest next to the ventricles and became smaller with distance from them. White matter lesion magnetization transfer ratio reductions were also more apparent adjacent to the ventricle and decreased with distance from the ventricles in both the relapsing remitting and secondary progressive multiple sclerosis groups. These findings suggest that in people with multiple sclerosis, and more so in secondary progressive than relapsing remitting multiple sclerosis, tissue structural abnormalities in normal-appearing white matter and white matter lesions are greatest near the ventricles. This would be consistent with a cerebrospinal fluid or ependymal mediated pathogenesis., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)., Methods: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping., Results: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation., Conclusions: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently., (© The Author(s), 2014.)