BACKGROUND:Cerebral small vessel disease and alterations in retinal vascular calibre (RVC) are recognised precursors of stroke, dementia, and cognitive decline. We aimed to assess the effect of low-dose aspirin on white matter hyperintensity (WMH), a marker of cerebral small vessel disease, and changes in RVC. METHODS:We conducted a prospectively planned exploratory neurovascular substudy (ENVIS-ion) of the Aspirin in Reducing Events in the Elderly (ASPREE) double-blinded randomised clinical trial of 19 114 older adults (aged ≥70 years), who had no previous cardiovascular disease, stroke, or cognitive impairment at baseline. Participants were allocated to daily enteric-coated aspirin 100 mg or matching placebo using computer-generated randomisation and underwent MRI of the brain and fundus photography at two clinical trials sites in Australia at baseline and after 3 years. WMH and RVC measures were assessed by graders blinded to study treatment allocation. The effects of aspirin on total and regional WMH volumes (as a percentage of total brain volume) and RVC over time were analysed using linear models. ASPREE is registered with ClinicalTrials.gov, NCT01038583, and the International Standard Randomised Controlled Trial Number Registry, ISRCTN83772183. FINDINGS:Between April, 2010, and April, 2012, 610 participants from the eligible ASPREE cohort of 2346 individuals were enrolled in the ENVIS-ion substudy. Of the 610 participants (mean age 75·2 years [SD 4·1], 289 [47%] male and 321 [53%] female), 312 were assigned to receive aspirin and 298 to placebo. Over 3 years, the aspirin group had a greater increase in the percentage of deep WMH (β 0·14 [95% CI 0·01 to 0·27]) but there was no difference between aspirin and placebo groups in changes from baseline to 3 years in total brain WMH (0·05 [-0·02 to 0·11]) or periventricular WMH (0·03 [-0·03 to 0·09]). There was no evidence of an aspirin effect on RVC. The rate of major haemorrhage was higher in the aspirin arm for the ASPREE study (hazard ratio 1·38, 95% CI 1·18 to 1·62). INTERPRETATION:In this exploratory study, there was no evidence that low-dose aspirin in healthy older adults had any effect on RVC or attenuated the progression of WMH during a 3-year period. FUNDING:National Health and Medical Research Council of Australia.

Objective:Exercise-assistance strategies are useful in allowing mobility-impaired patients to access the benefits of exercise. This trial is the first of the Reviver device, which facilitates exercise via a novel strength and balance training mechanism. The objective was to examine the effect of a 12-week Reviver intervention on symptoms of Parkinsonism, and to pilot the randomised controlled trial design, including randomisation and acceptance of the exercise intervention. Methods:This was a pilot, parallel-arm randomised controlled trial with assessor blinding. Participants (n=30: 22 with Parkinson's disease (PD) and 8 with atypical Parkinsonism conditions (AP)) were allocated to either experimental or control group. The experimental group received 24 sessions of 30 min on the Reviver over 12 weeks, the control group received their standard care. The Movement Disorders Society Unified Parkinson's Disease Rating Scale, and secondary outcomes (balance, gait, mobility, lower-body strength/coordination, tremor and grip strength) were acquired at endpoints the week prior to intervention commencement and the week after intervention termination. Recruitment progress, adherence to intervention, acceptability of intervention and adverse effects were also recorded. Results:For the PD cohort, lower-body strength/coordination (5× Sit-To-Stand; b(95% CI)=-3.02 (-5.16 to -0.89), p=0.013), gait (self-selected walking speed; b=12.48 (2.18 to 22.78), p=0.029, stride length; b=9.75 (0.99 to 18.52), p=0.043) and backward walking speed (b=14.25 (1.93 to 26.57), p=0.038) were improved by the intervention. No significant effect of intervention on the outcome variables was found in the AP cohort. No serious adverse events were recorded. Median adherence to treatment was 95.8%. Interpretation:This pilot trial indicates that the Reviver is a safe and well-tolerated exercise-assistance intervention. The Reviver showed some indications of benefit in our secondary measures for PD participants, but not in our primary outcome. This was a small sample, short duration pilot study, and further studies with larger samples and higher exercise volume are warranted to fully assess the safety and efficacy of the device.

Dysarthria is a motor speech disorder that is a common symptom of cerebellar dysfunction in people with multiple sclerosis (pwMS). Despite its prevalence, little is known regarding changes in brain functioning associated with dysarthria in this cohort. Management strategies for cerebellar symptoms such as dysarthria are also limited. Fifty-five pwMS and 14 healthy controls participated in this study. We used fMRI to assess changes in speech related functional activation associated with MS, and split our MS cohort into people with and without dysarthria, and with and without cerebellar dysfunction clinically evident as upper limb action tremor. We found that pwMS performed worse on speech production tasks and had overall lower functional activation while preparing for speech than controls. Furthermore, pwMS require additional recruitment of the left Brodmann areas 45 and 46, key motor speech regions, during speech production compared to healthy controls. MS participants presenting with both dysarthria and action tremor performed worst on speech production tasks. These participants had lower functional activation during speech production compared to other MS participants. People with multiple sclerosis display altered functional activation of motor speech areas during speech production, either due to MS injury or reduced activity during preparation. Compensatory activation is reduced in those with both clinical dysarthria and action tremor compared to MS controls and those with tremor only, likely due to more advanced MS.

Visual snow syndrome (VSS) is a neurological disorder that is predominantly characterized by persistent, dynamic visual disturbances, experienced across the entire visual field. Earlier research highlighted the significance of distinct brain regions, exhibiting alterations in both anatomical structure and functional characteristics. To further investigate the functional role of these regions, we examined the resting-state connectivity between these areas in individuals with VSS and the relation with VSS symptoms and oculomotor measures of visual processing. Forty patients with VSS (53% females; age = 33.2 ± 10.1 years; 22 with migraine) and 60 healthy controls (58% females; age = 32.0 ± 9.2 years) were scanned using 7 Tesla MRI system. High spatial and temporal resting-state (RS) functional (TR = 800 ms, 1.6 mm isotropic) and anatomical (MP2RAGE, 0.75 mm isotropic) images were acquired. Resting-state data were pre-processed (motion correction, temporal filtering and spatial smoothing), functional connectivity was calculated between regions of interest and compared between groups. Significant metrics were compared with VSS patients with and without migraine and correlated with oculomotor measures (prosaccade and anti-saccade latencies), number of VSS symptoms, self-rated VSS intensity and perceived disruptiveness. Compared to healthy controls, VSS patients demonstrated significantly higher connectivity between the supramarginal gyrus and lateral occipital cortex (P = 0.016) and fusiform (P = 0.007), lower connectivity between the supramarginal gyrus and pallidum (P = 0.032), as well as between the parahippocampal gyrus and lateral occipital cortex (P = 0.007), which related to higher perceived disruptiveness (P = 0.002, r = -0.489). No differences were found between VSS with and without migraine. This study revealed altered functional connectivity strength in individuals with VSS, suggesting stronger connectivity between cortical areas, particularly centred around the supramarginal gyrus, and disconnections with deep grey matter and temporal cortices, which associated with perceived disruptiveness of VSS.

Background Remote objective tests may supplement in-clinic examination to better inform treatment decisions. Previous cross-sectional studies presented objective speech metrics as potential markers of Multiple Sclerosis (MS) disease progression. Objective To examine the short-term stability and long-term sensitivity of speech metrics to MS progression. Methods We prospectively recorded speech from people with MS at baseline, six, twelve weeks, and at ten months or longer after baseline (1y+). Only people with a definite diagnosis of MS and without other potential causes of dysarthria were included. Speech tasks comprehended 1) a sustained vowel /a/, 2) saying the days of the week, 3) repeating the non-word pa-ta-ka multiple times as fast as possible, 4) reading the Grandfather Passage, and 5) telling a personal story. We selected speech metrics of interest according to their association with MS presence, correlation with general disability, and short-term metric stability in the absence of disease progression. Selected speech metrics were analysed for short- versus long-term changes in the whole MS cohort and in the clinically stable versus progression subgroups at 1y+. Results Sixty-nine people with MS participated (76.8% female, age mean 47.5±11.1 SD, EDSS median 3.5, interquartile range 3.5). Twenty-six unique speech metrics satisfied the suitability criteria. On average, reading rate improved 3.5% for all people with MS and 6.5% for slow readers with MS from baseline to the six-week, driven by a reduction in pauses. At 1y+, participants showed a 3.1% average reduction in vocalization time during the reading task, which was similar in the progression (n=29) and non-progression (n=40) groups and thus unrelated to disease progression. Both findings are in the opposite direction of what would be generally expected for deterioration in speech performance and might be attributable to familiarity and training effects. Other speech metrics showed either negligible change or a similar variability between short-term and long-term differences. Conclusion Most individual long-term changes were small and within short-term variability intervals, irrespective of clinical disease progression. Familiarity and practice effects might have blunted the measurement of change. The present lack of longitudinal sensitivity of speech in MS contradicts previous cross-sectional findings and requires further investigation.

Study Objectives Obstructive sleep apnea (OSA) may increase the risk of dementia. A potential pathway for this risk is through cerebral small vessel disease (CSVD). In the context of an existing randomized trial of aspirin for primary prevention, we aimed to investigate OSA's impact on CSVD imaging measures and explore whether aspirin effects these measures over 3 years that differ in the presence or absence of OSA.Methods A substudy of the aspirin in reducing events in the elderly (ASPREE) randomized placebo-controlled trial of low-dose aspirin. Community-dwelling participants aged 70 years and above, without cognitive impairment, cardiovascular disease, or known OSA completed an unattended limited-channel sleep study that calculated the oxygen desaturation index and apnea-hypopnea index. At baseline and 3 years later, volumes of white matter hyperintensities (WMH) and silent brain infarctions (SBI) were measured on 1.5 Tesla brain magnetic resonance imaging, and retinal vessel calibers were calculated from retinal vascular imaging.Results Mild and moderate/severe OSA was detected in 48.9% and 29.9%, respectively, of the 311 participants, who had a mean age of 73.7 years (SD 3.4 years), 38.6% female. OSA of any severity was not associated with WMH volumes, SBI, nor retinal vessel calibers at baseline, nor with change in these measures in the 277 participants with repeated measures acquired after 3 years. OSA of any severity did not interact with aspirin on change in these measures over 3 years.Conclusions In healthy older adults undiagnosed OSA was not associated with retinal vascular calibers and neuroimaging measures of CSVD.Clinical Trial Information ASPREE trial has registration with the International Standard Randomized Controlled Trial Number (ISRCTN) www.isrctn.com, ISRCTN83772183 and with www.clinicaltrials.gov, NCT01038583. SNORE-ASA has registration with the Australian New Zealand Clinical Trials Registry (ANZCTR) at www.anzctr.org.au, ACTRN12612000891820. Graphical Abstract

IntroductionFunctional magnetic resonance imaging (fMRI) can improve our understanding of neural processes subserving motor speech function. Yet its reproducibility remains unclear. This study aimed to evaluate the reproducibility of fMRI using a word repetition task across two time points.MethodsImaging data from 14 healthy controls were analysed using a multi-level general linear model.ResultsSignificant activation was observed during the task in the right hemispheric cerebellar lobules IV-V, right putamen, and bilateral sensorimotor cortices. Activation between timepoints was found to be moderately reproducible across time in the cerebellum but not in other brain regions.DiscussionPreliminary findings highlight the involvement of the cerebellum and connected cerebral regions during a motor speech task. More work is needed to determine the degree of reproducibility of speech fMRI before this could be used as a reliable marker of changes in brain activity.

Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear. In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca's area, Wernicke's area, the corpus callosum, thalamus and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness-a perceptual measure of dysarthria-and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared with controls, although no brain volumetrics correlated with measures of dysarthria. These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis.

ABSTRACTINTRODUCTIONSmart devices are widely available and capable of quickly recording and uploading speech segments for health-related analysis. The switch from laboratory recordings with professional-grade microphone set ups to remote, smart device-based recordings offers immense potential for the scalability of voice assessment. Yet, a growing body of literature points to a wide heterogeneity among acoustic metrics for their robustness to variation in recording devices. The addition of consumer-grade plug-and-play microphones has been proposed as a possible solution. The aim of our study was to assess if the addition of consumer-grade plug-and-play microphones increases the acoustic measurement agreement between ultra-portable devices and a reference microphone.METHODSSpeech was simultaneously recorded by a reference high-quality microphone commonly used in research, and by two configurations with plug-and-play microphones. Twelve speech-acoustic features were calculated using recordings from each microphone to determine the agreement intervals in measurements between microphones. Agreement intervals were then compared to expected deviations in speech in various neurological conditions. Additionally, each microphone’s response to speech and to silence were characterized through acoustic analysis to explore possible reasons for differences in acoustic measurements between microphones. Lastly, the statistical differentiation of two groups, neurotypical and people with Multiple Sclerosis, using metrics from each tested microphone was compared to that of the reference microphone.RESULTSThe two consumer-grade plug-and-play microphones favoured high frequencies (mean centre of gravity difference ≥ +175.3Hz) and recorded more noise (mean difference in signal-to-noise ≤ -4.2dB) when compared to the reference microphone. Between consumer-grade microphones, differences in relative noise were closely related to distance between the microphone and the speaker’s mouth. Agreement intervals between the reference and consumer-grade microphones remained under disease-expected deviations only for fundamental frequency (f0, agreement interval ≤0.06Hz),f0instability (f0CoV, agreement interval ≤0.05%) and for tracking of second formant movement (agreement interval ≤1.4Hz/millisecond). Agreement between microphones was poor for other metrics, particularly for fine timing metrics (mean pause length and pause length variability for various tasks). The statistical difference between the two groups of speakers was smaller with the plug-and-play than with the reference microphone.CONCLUSIONMeasurement off0and F2 slope were robust to variation in recording equipment while other acoustic metrics were not. Thus, the tested plug-and-play microphones should not be used interchangeably with professional-grade microphones for speech analysis. Plug-and-play microphones may assist in equipment standardization within speech studies, including remote or self-recording, possibly with small loss in accuracy and statistical power as observed in the current study.

Objectives: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs). Methods: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison. Results: CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI). Interpretation: Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

Identifying when recovery from a sports-related concussion (SRC) has occurred remains a challenge in clinical practice. This study investigated the utility of ocular motor (OM) assessment to monitor recovery post-SRC between sexes and compared to common clinical measures. From 139 preseason baseline assessments (i.e. before they sustained an SRC), 18 (12 males, 6 females) consequent SRCs were sustained and the longitudinal follow-ups were collected at 2, 6, and 13 days post-SRC. Participants completed visually guided, antisaccade (AS), and memory-guided saccade tasks requiring a saccade toward, away from, and to a remembered target, respectively. Changes in latency (processing speed), visual-spatial accuracy, and errors were measured. Clinical measures included The Sports Concussion Assessment Tool, King-Devick test, Stroop task, and Digit span. AS latency was significantly longer at 2 days and returned to baseline by 13-days post-SRC in females only (P < 0.001). Symptom numbers recovered from 2 to 6 days and 13 days (P < 0.05). Persistently poorer AS visual-spatial accuracy was identified at 2, 6 and 13 days post-SRC (P < 0.05) in both males and females but with differing trajectories. Clinical measures demonstrated consistent improvement reminiscent of practice effects. OM saccade assessment may have improved utility in tracking recovery compared to conventional measures and between sexes.

An eddy current correction algorithm is proposed that exploits the spatially distributed nature of the receive coil array with signal acquisition immediately preceding image readout in PGSE-EPI diffusion-weighted imaging. The array coil phase for each diffusion gradient direction is expanded using spherical harmonics to yield an estimate of the eddy current-induced field shift in the FOV, and the resultant eddy current-induced pixel shift maps. Distortion corrected diffusion-weighted images are subsequently produced using the estimated pixel shift maps for each diffusion direction, with the method demonstrated in phantom and in-vivo 7T experimental data.

Visual snow syndrome (VSS) is a neurological disorder characterized by a range of continuous visual disturbances. Little is known about the functional pathological mechanisms underlying VSS and their effect on brain network topology, studied using high-resolution resting-state (RS) 7 T MRI. Forty VSS patients and 60 healthy controls underwent RS MRI. Functional connectivity matrices were calculated, and global efficiency (network integration), modularity (network segregation), local efficiency (LE, connectedness neighbors) and eigenvector centrality (significance node in network) were derived using a dynamic approach (temporal fluctuations during acquisition). Network measures were compared between groups, with regions of significant difference correlated with known aberrant ocular motor VSS metrics (shortened latencies and higher number of inhibitory errors) in VSS patients. Lastly, nodal co-modularity, a binary measure of node pairs belonging to the same module, was studied. VSS patients had lower modularity, supramarginal centrality and LE dynamics of multiple (sub)cortical regions, centered around occipital and parietal lobules. In VSS patients, lateral occipital cortex LE dynamics correlated positively with shortened prosaccade latencies (p = .041, r = .353). In VSS patients, occipital, parietal, and motor nodes belonged more often to the same module and demonstrated lower nodal co-modularity with temporal and frontal regions. This study revealed reduced dynamic variation in modularity and local efficiency strength in the VSS brain, suggesting that brain network dynamics are less variable in terms of segregation and local clustering. Further investigation of these changes could inform our understanding of the pathogenesis of the disorder and potentially lead to treatment strategies.

Background: Upper and lower limb disabilities are hypothesized to have partially independent underlying (network) disturbances in multiple sclerosis (MS). Objective: This study investigated functional network predictors and longitudinal network changes related to upper and lower limb progression in MS. Methods: Two-hundred fourteen MS patients and 58 controls underwent functional magnetic resonance imaging (fMRI), dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) measurements (baseline and 5 years). Patients were stratified into progressors (>20% decline) or non-progressors. Functional network efficiency was calculated using static (over entire scan) and dynamic (fluctuations during scan) approaches. Baseline measurements were used to predict progression; significant predictors were explored over time. Results: In both limbs, progression was related to supplementary motor area and caudate efficiency (dynamic and static, respectively). Upper limb progression showed additional specific predictors; cortical grey matter volume, putamen static efficiency and posterior associative sensory (PAS) cortex, putamen, primary somatosensory cortex and thalamus dynamic efficiency. Additional lower limb predictors included motor network grey matter volume, caudate (dynamic) and PAS (static). Only the caudate showed a decline in efficiency over time in one group (non-progressors). Conclusion: Disability progression can be predicted using sensorimotor network measures. Upper and lower limb progression showed unique predictors, possibly indicating different network disturbances underlying these types of progression in MS.

OBJECTIVE:To investigate the factors influencing enlarged perivascular space (EPVS) characteristics at the onset of acute ischemic stroke (AIS), and whether the PVS characteristics can predict later post-stroke epilepsy (PSE). METHODS:A total of 312 patients with AIS were identified, of whom 58/312 (18.6%) developed PSE. Twenty healthy participants were included as the control group. The number of PVS in the basal ganglia (BG), centrum semiovale (CS), and midbrain (MB) was manually calculated on T2 -weighted MRI. The scores and asymmetry index (AI) of EPVS in each region were compared among the enrolled participants. Other potential risk factors for PSE were also analyzed, including NIHSS at admission and stroke etiologies. RESULTS:The EPVS scores were significantly higher in the bilateral BG and CS of AIS patients compared to those of the control group (both p < 0.01). No statistical differences in EPVS scores in BG, CS, and MB were obtained between the PSE group and the nonepilepsy AIS group (all p > 0.01). However, markedly different AI scores in CS were found between the PSE group and the nonepilepsy AIS group (p = 0.004). Multivariable analysis showed that high asymmetry index of EPVS (AI≥0.2) in CS was an independent predictor for PSE (OR = 3.7, 95% confidence interval 1.5-9.1, p = 0.004). CONCLUSIONS:Asymmetric distribution of EPVS in CS may be an independent risk factor and a novel imaging biomarker for the development of PSE. Further studies to understand the mechanisms of this association and confirmation with larger patient populations are warranted.

The prodromal phase of Parkinson's disease (PD) is characterised by many non-motor symptoms, and these have recently been posited to be predictive of later diagnosis. Genetic rodent models can develop non-motor phenotypes, providing tools to identify mechanisms underlying the early development of PD. However, it is not yet clear how reproducible non-motor phenotypes are amongst genetic PD rodent models, whether phenotypes are age-dependent, and the translatability of these phenotypes has yet to be explored. A systematic literature search was conducted on studies using genetic PD rodent models to investigate non-motor phenotypes; cognition, anxiety/depressive-like behaviour, gastrointestinal (GI) function, olfaction, circadian rhythm, cardiovascular and urinary function. In total, 51 genetic models of PD across 150 studies were identified. We found outcomes of most phenotypes were inconclusive due to inadequate studies, assessment at different ages, or variation in experimental and environmental factors. GI dysfunction was the most reproducible phenotype across all genetic rodent models. The mouse model harbouring mutant A53T, and the wild-type hα-syn overexpression (OE) model recapitulated the majority of phenotypes, albeit did not reliably produce concurrent motor deficits and nigral cell loss. Furthermore, animal models displayed different phenotypic profiles, reflecting the distinct genetic risk factors and heterogeneity of disease mechanisms. Currently, the inconsistent phenotypes within rodent models pose a challenge in the translatability and usefulness for further biomechanistic investigations. This review highlights opportunities to improve phenotype reproducibility with an emphasis on phenotypic assay choice and robust experimental design.