Functional connectome of arousal and motor brainstem nuclei in living humans by 7 Tesla resting-state fMRI.

Brainstem nuclei play a pivotal role in many functions, such as arousal and motor control. Nevertheless, the connectivity of arousal and motor brainstem nuclei is understudied in living humans due to the limited sensitivity and spatial resolution of conventional imaging, and to the lack of atlases of these deep tiny regions of the brain. For a holistic comprehension of sleep, arousal and associated motor processes, we investigated in 20 healthy subjects the resting-state functional connectivity of 18 arousal and motor brainstem nuclei in living humans. To do so, we used high spatial-resolution 7 Tesla resting-state fMRI, as well as a recently developed in-vivo probabilistic atlas of these nuclei in stereotactic space. Further, we verified the translatability of our brainstem connectome approach to conventional (e.g. 3 Tesla) fMRI. Arousal brainstem nuclei displayed high interconnectivity, as well as connectivity to the thalamus, hypothalamus, basal forebrain and frontal cortex, in line with animal studies and as expected for arousal regions. Motor brainstem nuclei showed expected connectivity to the cerebellum, basal ganglia and motor cortex, as well as high interconnectivity. Comparison of 3 Tesla to 7 Tesla connectivity results indicated good translatability of our brainstem connectome approach to conventional fMRI, especially for cortical and subcortical (non-brainstem) targets and to a lesser extent for brainstem targets. The functional connectome of 18 arousal and motor brainstem nuclei with the rest of the brain might provide a better understanding of arousal, sleep and accompanying motor functions in living humans in health and disease.

Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI.

Despite remarkable advances in mapping the functional connectivity of the cortex, the functional connectivity of subcortical regions is understudied in living humans. This is the case for brainstem nuclei that control vital processes, such as autonomic, limbic, nociceptive and sensory functions. This is because of the lack of precise brainstem nuclei localization, of adequate sensitivity and resolution in the deepest brain regions, as well as of optimized processing for the brainstem. To close the gap between the cortex and the brainstem, on 20 healthy subjects, we computed a correlation-based functional connectome of 15 brainstem nuclei involved in autonomic, limbic, nociceptive, and sensory function (superior and inferior colliculi, ventral tegmental area-parabrachial pigmented nucleus complex, microcellular tegmental nucleus-prabigeminal nucleus complex, lateral and medial parabrachial nuclei, vestibular and superior olivary complex, superior and inferior medullary reticular formation, viscerosensory motor nucleus, raphe magnus, pallidus, and obscurus, and parvicellular reticular nucleus - alpha part) with the rest of the brain. Specifically, we exploited 1.1mm isotropic resolution 7 Tesla resting-state fMRI, ad-hoc coregistration and physiological noise correction strategies, and a recently developed probabilistic template of brainstem nuclei. Further, we used 2.5mm isotropic resolution resting-state fMRI data acquired on a 3 Tesla scanner to assess the translatability of our results to conventional datasets. We report highly consistent correlation coefficients across subjects, confirming available literature on autonomic, limbic, nociceptive and sensory pathways, as well as high interconnectivity within the central autonomic network and the vestibular network. Interestingly, our results showed evidence of vestibulo-autonomic interactions in line with previous work. Comparison of 7 Tesla and 3 Tesla findings showed high translatability of results to conventional settings for brainstem-cortical connectivity and good yet weaker translatability for brainstem-brainstem connectivity. The brainstem functional connectome might bring new insight in the understanding of autonomic, limbic, nociceptive and sensory function in health and disease.

Disruption of Brainstem Structural Connectivity in REM Sleep Behavior Disorder Using 7 Tesla Magnetic Resonance Imaging.

BACKGROUND: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the earliest manifestations of α synucleinopathies. Brainstem pathophysiology underlying REM sleep behavior disorder has been described in animal models, yet it is understudied in living humans because of the lack of an in vivo brainstem nuclei atlas and to the limited magnetic resonance imaging (MRI) sensitivity. OBJECTIVE: To investigate brainstem structural connectivity changes in iRBD patients by using an in vivo probabilistic brainstem nuclei atlas and 7 Tesla MRI. METHODS: Structural connectivity of 12 iRBD patients and 12 controls was evaluated by probabilistic tractography. Two-sided Wilcoxon rank-sum test was used to compare the structural connectivity indices across groups. RESULTS: In iRBD, we found impaired (Z = 2.6, P < 0.01) structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on (eg, subcoeruleus [SubC]) and REM sleep muscle atonia (eg, medullary reticular formation) areas. CONCLUSIONS: The brainstem nuclei diagram of impaired connectivity in human iRBD expands animal models and is a promising tool to study and possibly assess prodromal synucleinopathy stages. © 2021 International Parkinson and Movement Disorder Society.

My Healthy Brain: a multimodal lifestyle program to promote brain health.

BACKGROUND: Promoting brain health depends on sustaining healthy behaviors across the lifespan. Yet, public adoption of lifestyle behaviors and knowledge of cognitive decline (CD) prevention remains poor. Our multidisciplinary team developed My Healthy Brain (MHB) to promote a healthy lifestyle (e.g. diet, exercise, alcohol, sleep) and build cognitive reserve (e.g. memory compensatory strategies). Our objective was to demonstrate early proof-of-concept for MHB by exploring the feasibility, acceptability, and improvement in primary lifestyle outcomes as well as secondary outcomes of self-determination and subjective wellbeing. MATERIALS AND METHODS: Older adults with subjective (self-report only) or objective (confirmed by cognitive testing) CD, referred by neurologists to modify lifestyle risk factors (e.g. sedentary), participated in a non-randomized open pilot of MHB (N = 24). Participants completed the 8-week MHB group (90 min each) and pre-post outcome measures. RESULTS: MHB met all a-priori set benchmarks, including good feasibility of recruitment (71% of patients screened) and enrollment (75% completed baseline), and good acceptability of treatment (75% completed 6 of 8 sessions and post-testing). Program satisfaction was excellent (100% of participants) and no adverse events were reported. We also observed improvements in primary lifestyle outcomes as well as secondary outcomes of self-determination and subjective well-being. DISCUSSION: While MHB demonstrated preliminary feasibility and the potential to modify lifestyle risk factors for CD, the program can be improved. Future work will explore the integration of mindfulness skills with behavioral principles to bolster multidomain lifestyle change, and the live video delivery format to bypass barriers to participation.

Depression, sleep quality, and social isolation among people with epilepsy in Bhutan: A cross-sectional study.

PURPOSE: The aim of this study was to analyze the possible contributions of seizure burden, sleep quality, and social integration to depression among people with epilepsy (PWE) in Bhutan. METHODS: Bhutan is a lower-middle-income country in Southeast Asia with a public healthcare system without neurologists. People with epilepsy were prospectively recruited from psychiatrist-run epilepsy clinics at the National Referral Hospital in the capital city of Thimphu. Adult participants with epilepsy were interviewed for clinical history, sleep quality using the Pittsburgh Sleep Quality Index, social networks using the Berkman-Syme Social Network Index, and depressive symptoms using the Patient Health Questionnaire - 9 (PHQ-9). A multivariable regression model was built to assess the relationship between depression as an outcome and the possible contributors of sleep quality, sex, and seizure in the prior month. RESULTS: Out of 80 participants (39 women, mean age: 29.4 years old, range: 18-56 years, 58 [73%] with a seizure in the previous month), 33% had poor sleep quality, 68% were socially isolated, 30% had a mild depressive symptom burden or more, and 18% reported suicidal ideation at the time of their interview. Women had a higher average PHQ-9 score versus men, which showed a trend towards statistical significance (5.6 versus 3.3 PHQ-9 points, p = 0.07), and on average met criteria for mild depression. Social integration was not significantly associated with sleep quality and had no relationship with depressive burden. There was a small positive correlation between poorer sleep quality and depressive symptoms which showed a trend towards statistical significance (r = 0.21, p = 0.06). In a multivariable regression, poor sleep quality was associated with higher depressive symptom burden, adjusting for participant sex and having a seizure in the previous month (p = 0.01). CONCLUSIONS: Our exploratory study disentangles the multilayered psychosocial burden of disease experienced by PWE in Bhutan, a lower-middle-income country with access to antiseizure medications and psychiatrists but not expert epilepsy services or human resources. Further investigation into the interrelationships among social isolation, poor sleep quality, depression, and seizure burden could identify preventable and remediable constituents of this burden.

Examining cross-sectional and longitudinal relationships between multidomain physical fitness metrics, education, and cognition in Black older adults.

A limited number of studies examine cognitive aging in Black or African American older adults. The purpose of this study was to explore the relationship between health-related fitness metrics, education, and cognition at baseline and over a 4-year follow-up in a sample of 321 Black or African American older adults in the Health and Retirement Study (HRS). Physical fitness was assessed with measures of gait speed, peak expiratory flow, grip strength, and body mass index. Global cognition was assessed with an adapted version of the Telephone Interview for Cognitive Status (TICS). Analyses of relative importance and hierarchical multiple regression were used to examine baseline cross-sectional relationships. Multiple logistic regression was used to examine prospective relationships with longitudinal cognitive status. Education was the strongest predictor of global cognition at baseline and follow-up. More years of education significantly increased the odds of maintaining cognitive status at 4-year follow-up. After accounting for education, gait speed was independently associated with baseline cognitive performance and accounted for additional variance. Grip strength, peak expiratory flow, and body mass index were not significantly associated with cognition. The results indicated that modifiable variables, including years of educational attainment and gait speed, were more strongly associated with global cognition than other modifiable variables including body mass index, grip strength, and peak expiratory flow. The lack of observed associations between other fitness variables and cognition may be attributable to the brief assessment methods implemented, which was necessitated by the large-scale, epidemiological approach of the HRS.

Relationships of self-reported and objective measures of sleep, sleepiness, and sleep quality in Parkinson's disease.

INTRODUCTION: Disrupted sleep and excessive daytime sleepiness (EDS) are common and disabling symptoms of Parkinson's disease (PD). The relationships between subjective and objective assessments of sleep and sleepiness in PD are not well established. We aimed to examine the relationships between self-reported (subjective) and objective assessments of sleep and sleepiness in PD. METHODS: Epworth Sleepiness Scale (ESS), Pittsburg Sleep Quality Index (PSQI), Parkinson's Disease Sleep Scale (PDSS), sleep diaries, and overnight polysomnography (PSG) with next-morning multiple sleep latency testing (MSLT) were collected from 27 individuals with PD and EDS who participated in a clinical trial of light therapy for EDS in PD. RESULTS: No significant correlations were found between measures of EDS and night-time sleep quality and quantity. PDSS was correlated with PSQI. PDSS and PSQI had significant relationships with multiple metrics derived from sleep diaries, including sleep latency, quality, and ease of falling asleep. Several PSG-derived sleep metrics correlated well with sleep diary metrics. CONCLUSIONS: There is a poor correlation between metrics used to assess sleep and sleepiness in PD. A sleep diary may be a valuable tool for this purpose. Accurate clinical and research assessment and monitoring require refinement of existing and development of novel methods for measuring sleep and sleepiness in PD.

The role of mindfulness and relaxation in improved sleep quality following a mind-body and activity program for chronic pain.

OBJECTIVES: Poor sleep quality is prevalent among individuals with chronic pain and contributes to increased physical and emotional dysfunction. However, treatments that improve sleep quality among individuals with chronic pain are scant. A previously developed mind-body activity program for chronic pain has been shown to be feasible and associated with improvements in pain and physical and emotional function. Using secondary data-analysis, the purpose of this study was to understand whether participants also experienced significant and sustained improvements in sleep quality over time and whether these improvements were explained by change in two core treatment targets, relaxation and mindfulness. METHODS: Participants with heterogenous chronic pain (N = 82) were randomized to a mind-body activity intervention with (GetActive-Fitbit; n=41) or without (GetActive; n=41) a Fitbit device. Sleep quality was measured with the PSQI, mindfulness with the CAMS-R, and relaxation with the relaxation subscale of the MOCS-A. Mediation was tested via mixed-models analysis. RESULTS: Both intervention groups experienced significant and comparable improvements in sleep quality from baseline to post-treatment, which were sustained through a 3-month follow-up. Mindfulness and relaxation also improved significantly over time and these improvements were associated with improved sleep quality. Mindfulness and relaxation fully mediated improvement in sleep quality (medium to large effect sizes). CONCLUSIONS: Results suggest that, despite not targeting sleep explicitly, the two mind-body activity programs hold promise for sustainably improving sleep quality among patients with chronic pain. Targeting mindfulness and relaxation may facilitate these improvements.

Light therapy for multiple sclerosis-associated fatigue: a randomized, controlled phase II trial.

BACKGROUND: Bright white light therapy (LT) can improve fatigue in several disease states but has not been studied in multiple sclerosis (MS). OBJECTIVE: To determine whether controlled home-based LT is feasible, tolerable, and well-adhered to in MS-associated fatigue. METHODS: A randomized, controlled trial of twice-daily 1-h bright white LT (BWLT) (10,000 lx, active arm) versus dim red LT (DRLT) (< 300 lx, control arm) was performed. Adults with MS-associated fatigue were enrolled for 10 weeks: 2-week baseline, 4-week intervention, 4-week washout. RESULTS: 41 participants were enrolled; 35 were randomized (average age 42 years, 80% female; BWLT n = 20; DRLT n = 15). 31 were in the intention to treat analysis. The average duration of LT sessions was similar between groups (BWLT 60.9 min, DRLT 61.5 min, p = 0.70). The most commonly reported adverse event was headache. There were no events that led to discontinuation. Baseline fatigue was severe in both arms (each 53/63 points on the Fatigue Severity Scale (FSS), p = 0.92). FSS was lower following BWLT (FSS 45.8 post-LT, p = 0.04; 44.9 post-washout, p = 0.02 intra-group compared to baseline FSS) and DRLT (FSS 46.7 post-LT, p = 0.03; 43.9 post-washout, p = 0.002 intragroup compared to baseline FSS). There was no difference between BWLT and DRLT groups in the magnitude of reduction of FSS scores (p = 0.81 after LT; p = 0.77 after washout for between group comparisons). Similarly, MS quality of life metrics improved in both arms but were not significantly different between groups after LT (p = 0.22) or washout. CONCLUSIONS: LT is safe, feasible, and well-tolerated in people with MS-associated fatigue. Improvement in both light spectra likely indicates a strong placebo effect for the DRLT group.