Fixel-based Analysis of Diffusion MRI: Methods, Applications, Challenges and Opportunities.

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.

Effects of Smart Goggles Used Before Bed on Objectively Measured Sleep and Self-Reported Anxiety, Stress, and Relaxation: A Pilot Study.

BACKGROUND: Insufficient sleep is a problem affecting millions. Poor sleep can instigate or worsen anxiety and, conversely, anxiety can lead to or exacerbate poor sleep. Advances in innovative consumer products designed to promote relaxation and support healthy sleep are emerging and their effectiveness can be evaluated accurately using sleep measurement technologies in the home environment. OBJECTIVE: This pilot study examined the effects of smart goggles used before bed to deliver gentle, slow vibration to the eyes and temples. The hypothesis was that objective sleep, perceived sleep, and self-reported stress, anxiety, relaxation, and sleepiness would improve after using the smart goggles. METHODS: A within-subjects, pre-post design was implemented. Healthy adults with subclinical threshold sleep problems (N=20) tracked their sleep nightly using a PSG-validated non-contact biomotion device and completed daily questionnaires (3 weeks baseline, 3 weeks intervention). During the baseline period, participants slept at home as usual. During the intervention period, participants used Therabody SmartGoggles in Sleep mode before bed. This mode, designed for relaxation, delivers gentle eye and temple massage through the inflation of internal compartments to create a kneading sensation and vibrating motors. At night, participants completed questionnaires assessing relaxation, stress, anxiety, and sleepiness immediately before and after goggle use. Daily questionnaires assessed perceived sleep each morning, complementing the objective sleep measurement. RESULTS: Multilevel regression analysis of 676 nights of objective data showed improvements during nights when using the goggles, relative to baseline, in sleep duration (+12 minutes, P=.014); deep sleep, measured in duration (+6 minutes, P=.002), proportion of the night (7% relative increase, P=.020), and BodyScore, an age- and gender-normalized measure of deep sleep (4% increase, P=.002); number of nighttime awakenings (7% decrease, P=.021); total time awake at night after sleep onset (-6 minutes, P=.047); and SleepScore, a measure of overall sleep quality (3% increase, P=.020). Questionnaire data showed that, compared to baseline, participants felt they had better sleep quality (P<.001) and felt more well-rested upon waking (P<.001). Furthermore, immediately after using the goggles each night, compared to immediately before, participants reported feeling sleepier, less stressed, less anxious, and more relaxed (all Ps<.05). A standardized inventory administered before and after the 3-week intervention period indicated reduced anxiety, confirming the nightly analysis (P=.03). CONCLUSIONS: Objectively measured sleep quality and duration, as well as perceived sleep, improved when using the goggles before bed compared to baseline. Participants also reported increased feelings of relaxation along with reduced stress and anxiety. Future research expanding on this pilot study is warranted to confirm the preliminary evidence presented in this brief report.

Post-stroke sleep disturbance and recurrent cardiovascular and cerebrovascular events: A systematic review and meta-analysis.

Despite improvements in survival rates, risk of recurrent events following stroke remains high. Identifying intervention targets to reduce secondary cardiovascular risk in stroke survivors is a priority. The relationship between sleep and stroke is complex: sleep disturbances are likely both a contributor to, and consequence of, stroke. The current aim was to examine the association between sleep disturbance and recurrent major acute coronary events or all-cause mortality in the post-stroke population. Thirty-two studies were identified, including 22 observational studies and 10 randomized clinical trials (RCTs). Identified studies included the following as predictors of post-stroke recurrent events: obstructive sleep apnea (OSA, n = 15 studies), treatment of OSA with positive airway pressure (PAP, n = 13 studies), sleep quality and/or insomnia (n = 3 studies), sleep duration (n = 1 study), polysomnographic sleep/sleep architecture metrics (n = 1 study), and restless legs syndrome (n = 1 study). A positive relationship of OSA and/or OSA severity with recurrent events/mortality was seen. Findings on PAP treatment for OSA were mixed. Positive findings indicating a benefit of PAP for post-stroke risk came largely from observational studies (pooled RR [95% CI] for association between PAP and recurrent cardiovascular event: 0.37 [0.17-0.79], I2 = 0%). Negative findings came largely from RCTs (RR [95% CI] for association between PAP and recurrent cardiovascular event + death: 0.70 [0.43-1.13], I2 = 30%). From the limited number of studies conducted to date, insomnia symptoms/poor sleep quality and long sleep duration were associated with increased risk. Sleep, a modifiable behavior, may be a secondary prevention target to reduce the risk of recurrent event and death following stroke. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021266558.

Sleep architectural dysfunction and undiagnosed obstructive sleep apnea after chronic ischemic stroke.

OBJECTIVE/BACKGROUND: Sleep-wake dysfunction is bidirectionally associated with the incidence and evolution of acute stroke. It remains unclear whether sleep disturbances are transient post-stroke or are potentially enduring sequelae in chronic stroke. Here, we characterize sleep architectural dysfunction, sleep-respiratory parameters, and hemispheric sleep in ischemic stroke patients in the chronic recovery phase compared to healthy controls. PATIENTS/METHODS: Radiologically confirmed ischemic stroke patients (n = 28) and matched control participants (n = 16) were tested with ambulatory polysomnography, bi-hemispheric sleep EEG, and demographic, stroke-severity, mood, and sleep-circadian questionnaires. RESULTS: Twenty-eight stroke patients (22 men; mean age = 69.61 ± 7.4 years) were cross-sectionally evaluated 4.1 ± 0.9 years after mild-moderate ischemic stroke (baseline NIHSS: 3.0 ± 2.0). Fifty-seven percent of stroke patients (n = 16) exhibited undiagnosed moderate-to-severe obstructive sleep apnea (apnea-hypopnea index >15). Despite no difference in total sleep or wake after sleep onset, stroke patients had reduced slow-wave sleep time (66.25 min vs 99.26 min, p = 0.02), increased time in non-rapid-eye-movement (NREM) stages 1-2 (NREM-1: 48.43 vs 28.95, p = 0.03; NREM-2: 142.61 vs 115.87, p = 0.02), and a higher arousal index (21.46 vs 14.43, p = 0.03) when compared to controls. Controlling for sleep apnea severity did not attenuate the magnitude of sleep architectural differences between groups (NREM 1-3=ηp2 >0.07). We observed no differences in ipsilesionally versus contralesionally scored sleep architecture. CONCLUSIONS: Fifty-seven percent of chronic stroke patients had undiagnosed moderate-severe obstructive sleep apnea and reduced slow-wave sleep with potentially compensatory increases in NREM 1-2 sleep relative to controls. Formal sleep studies are warranted after stroke, even in the absence of self-reported history of sleep-wake pathology.

Sleep-wake parameters can be detected in patients with chronic stroke using a multisensor accelerometer: a validation study.

STUDY OBJECTIVES: Sleep-wake dysfunction is bidirectionally associated with the pathogenesis and evolution of stroke. Longitudinal and prospective measurement of sleep after chronic stroke remains poorly characterized because of a lack of validated objective and ambulatory sleep measurement tools in neurological populations. This study aimed to validate a multisensor sleep monitor, the SenseWear Armband (SWA), in patients with ischemic stroke and control patients using at-home polysomnography. METHODS: Twenty-eight radiologically confirmed patients with ischemic stroke (aged 69.61 ± 7.35 years; mean = 4.1 years poststroke) and 16 control patients (aged 73.75 ± 7.10 years) underwent overnight at-home polysomnography in tandem with the SWA. Lin's concordance correlation coefficient and reduced major axis regressions were employed to assess concordance of SWA vs polysomnography-measured total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset. Subsequently, data were converted to 30-second epochs to match at-home polysomnography. Epoch-by-epoch agreement between SWA and at-home polysomnography was estimated using crude agreement, Cohen's kappa, sensitivity, and specificity. RESULTS: Total sleep time was the most robustly quantified sleep-wake variable (concordance correlation coefficient = 0.49). The SWA performed poorest for sleep measures requiring discrimination of wakefulness (sleep onset latency; concordance correlation coefficient = 0.16). The sensitivity of the SWA was high (95.90%) for patients with stroke and for control patients (95.70%). The specificity of the SWA was fair-moderate for patients with stroke (40.45%) and moderate for control patients (45.60%). Epoch-by-epoch agreement rate was fair (78%) in patients with stroke and fair (74%) in controls. CONCLUSIONS: The SWA shows promise as an ambulatory tool to estimate macro parameters of sleep-wake; however, agreement at an epoch level is only moderate-fair. Use of the SWA warrants caution when it is used as a diagnostic tool or in populations with significant sleep-wake fragmentation.

Sleep and circadian rhythms: pillars of health-a Keystone Symposia report.

The human circadian system consists of the master clock in the suprachiasmatic nuclei of the hypothalamus as well as in peripheral molecular clocks located in organs throughout the body. This system plays a major role in the temporal organization of biological and physiological processes, such as body temperature, blood pressure, hormone secretion, gene expression, and immune functions, which all manifest consistent diurnal patterns. Many facets of modern life, such as work schedules, travel, and social activities, can lead to sleep/wake and eating schedules that are misaligned relative to the biological clock. This misalignment can disrupt and impair physiological and psychological parameters that may ultimately put people at higher risk for chronic diseases like cancer, cardiovascular disease, and other metabolic disorders. Understanding the mechanisms that regulate sleep circadian rhythms may ultimately lead to insights on behavioral interventions that can lower the risk of these diseases. On February 25, 2021, experts in sleep, circadian rhythms, and chronobiology met virtually for the Keystone eSymposium "Sleep & Circadian Rhythms: Pillars of Health" to discuss the latest research for understanding the bidirectional relationships between sleep, circadian rhythms, and health and disease.

Regional neurodegeneration correlates with sleep-wake dysfunction after stroke.

Sleep-wake disruption is a key modifiable risk factor and sequela of stroke. The pathogenesis of poststroke sleep dysfunction is unclear. It is not known whether poststroke sleep pathology is due to focal infarction to sleep-wake hubs or to accelerated poststroke neurodegeneration in subcortical structures after stroke. We characterize the first prospective poststroke regional brain volumetric and whole-brain, fiber-specific, white matter markers of objectively measured sleep-wake dysfunction. We hypothesized that excessively long sleep (>8 h) duration and poor sleep efficiency (<80%) measured using the SenseWear Armband 3-months poststroke (n = 112) would be associated with reduced regional brain volumes of a priori-selected sleep-wake regions of interest when compared to healthy controls with optimal sleep characteristics (n = 35). We utilized a novel technique known as a whole-brain fixel-based analysis to investigate the fiber-specific white matter differences in participants with long sleep duration. Stroke participants with long sleep (n = 24) duration exhibited reduced regional volumes of the ipsilesional thalamus and contralesional amygdala when compared with controls. Poor sleep efficiency after stroke (n = 29) was associated with reduced ipsilesional thalamus, contralesional hippocampus, and contralesional amygdala volumes. Whole-brain fixel-based analyses revealed widespread macrostructural degeneration to the corticopontocerebellar tract in stroke participants with long sleep duration, with fiber reductions of up to 40%. Neurodegeneration to subcortical structures, which appear to be vulnerable to accelerated brain volume loss after stroke, may drive sleep-wake deficiencies poststroke, independent of lesion characteristics and confounding comorbidities. We discuss these findings in the context of the clinicopathological implications of sleep-related neurodegeneration and attempt to corroborate previous mechanistic-neuroanatomical findings.

Choroid plexus volume after stroke.

BACKGROUND: Cerebrospinal fluid circulation is crucial for the functioning of the brain. Aging and brain pathologies such as Alzheimer's disease have been associated with a change in the morphology of the ventricles and the choroid plexus. Despite the evidence from animal models that the cerebrospinal fluid system plays an important role in neuroinflammation and the restoration of the brain after ischemic brain injury, little is known about changes to the choroid plexus after stroke in humans. AIMS: Our goal was to characterize structural choroid plexus changes poststroke. METHODS: We used an automatic segmentation tool to estimate the volumes of choroid plexus and lateral ventricles in stroke and control participants at three time points (at baseline, 3 and 12 months) over the first year after stroke. We assessed group differences cross-sectionally at each time point and longitudinally. For stroke participants, we specifically differentiated between ipsi- and contra-lesional volumes. Statistical analyses were conducted for each region separately and included covariates such as age, sex, total intracranial volume, and years of education. RESULTS: We observed significantly larger choroid plexus volumes in stroke participants compared to controls in both cross-sectional and longitudinal analyses. Choroid plexus volumes did not exhibit any change over the first year after stroke, with no difference between ipsi- and contra-lesional volumes. This was in contrast to the volume of lateral ventricles that we found to enlarge over time in all participants, with more accelerated expansion in stroke survivors ipsi-lesionally. CONCLUSIONS: Our results suggest that chronic stages of stroke are characterized by larger choroid plexus volumes, but the enlargement likely takes place prior to or very early after the stroke incident.

The bidirectional impact of sleep and circadian rhythm dysfunction in human ischaemic stroke: A systematic review.

Sleep and circadian rhythm disruption are potentially modifiable risk factors and consequences of ischaemic stroke. Pre-clinical evidence suggests a direct effect of sleep and endogenous circadian rhythm dysfunction on lesion volumes and post-stroke recovery. In humans, sleep and stroke literature has focused primarily on obstructive sleep apnoea. However, the bidirectional impact of non-apnoea related sleep disorders, sleep architecture, and endogenous circadian rhythm dysfunction in ischaemic stroke remains unclear. A systematic search of publications in three major databases from inception to August 7 2018 identified 67 studies meeting inclusion criteria. Long sleep duration or sleep disorders significantly increased the risk of ischaemic stroke. Inversely, ischaemic stroke was associated with sleep architectural and endogenous circadian rhythm disruption which were generally associated with post-stroke severity and functional outcome. Importantly, no studies examined direct measures of circadian rhythm dysfunction as a risk factor for ischaemic stroke. Most studies were moderate to high quality. However, methodology and stroke characteristics (e.g., stroke topography, stroke severity) were heterogenous thereby limiting generalisable conclusions. Furthermore, a priori neuroimaging outcomes in conjunction with sleep and circadian features were seldom assessed. The clinical pathogenic implications and methodological limitations of studies are discussed, and a research agenda for future studies is outlined.

APOE ɛ4 Carriers Show Delayed Recovery of Verbal Memory and Smaller Entorhinal Volume in the First Year After Ischemic Stroke.

BACKGROUND: The apolipoprotein E (APOE) gene ɛ4 allele is a risk factor for Alzheimer's disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear. OBJECTIVE: We compared cognition and medial temporal lobe volumes in APOEɛ4 carriers and non-carriers in the first year after ischemic stroke. METHODS: We sampled 20 APOEɛ4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (3, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood. RESULTS: APOEɛ4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at 3 months post-stroke (p = 0.046), but were better in executive function at 12 months (p = 0.035). Carriers demonstrated a significant improvement in verbal memory (p = 0.012) and executive function (p = 0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p = 0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p < 0.05), and larger right sided and contralesional hippocampal volumes, at both time-points (p < 0.05). CONCLUSION: APOE ɛ4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke.