Dynamic networks of cortico-muscular interactions in sleep and neurodegenerative disorders.

The brain plays central role in regulating physiological systems, including the skeleto-muscular and locomotor system. Studies of cortico-muscular coordination have primarily focused on associations between movement tasks and dynamics of specific brain waves. However, the brain-muscle functional networks of synchronous coordination among brain waves and muscle activity rhythms that underlie locomotor control remain unknown. Here we address the following fundamental questions: what are the structure and dynamics of cortico-muscular networks; whether specific brain waves are main network mediators in locomotor control; how the hierarchical network organization relates to distinct physiological states under autonomic regulation such as wake, sleep, sleep stages; and how network dynamics are altered with neurodegenerative disorders. We study the interactions between all physiologically relevant brain waves across cortical locations with distinct rhythms in leg and chin muscle activity in healthy and Parkinson's disease (PD) subjects. Utilizing Network Physiology framework and time delay stability approach, we find that 1) each physiological state is characterized by a unique network of cortico-muscular interactions with specific hierarchical organization and profile of links strength; 2) particular brain waves play role as main mediators in cortico-muscular interactions during each state; 3) PD leads to muscle-specific breakdown of cortico-muscular networks, altering the sleep-stage stratification pattern in network connectivity and links strength. In healthy subjects cortico-muscular networks exhibit a pronounced stratification with stronger links during wake and light sleep, and weaker links during REM and deep sleep. In contrast, network interactions reorganize in PD with decline in connectivity and links strength during wake and non-REM sleep, and increase during REM, leading to markedly different stratification with gradual decline in network links strength from wake to REM, light and deep sleep. Further, we find that wake and sleep stages are characterized by specific links strength profiles, which are altered with PD, indicating disruption in the synchronous activity and network communication among brain waves and muscle rhythms. Our findings demonstrate the presence of previously unrecognized functional networks and basic principles of brain control of locomotion, with potential clinical implications for novel network-based biomarkers for early detection of Parkinson's and neurodegenerative disorders, movement, and sleep disorders.

Longitudinal Study on Sustained Attention to Response Task (SART): Clustering Approach for Mobility and Cognitive Decline.

The Sustained Attention to Response Task (SART) is a computer-based go/no-go task to measure neurocognitive function in older adults. However, simplified average features of this complex dataset lead to loss of primary information and fail to express associations between test performance and clinically meaningful outcomes. Here, we combine a novel method to visualise individual trial (raw) information obtained from the SART test in a large population-based study of ageing in Ireland and an automatic clustering technique. We employed a thresholding method, based on the individual trial number of mistakes, to identify poorer SART performances and a fuzzy clusters algorithm to partition the dataset into 3 subgroups, based on the evolution of SART performance after 4 years. Raw SART data were available for 3468 participants aged 50 years and over at baseline. The previously reported SART visualisation-derived feature 'bad performance', indicating the number of SART trials with at least 4 mistakes, and its evolution over time, combined with the fuzzy c-mean (FCM) algorithm, individuated 3 clusters corresponding to 3 degrees of physiological dysregulation. The biggest cluster (94% of the cohort) was constituted by healthy participants, a smaller cluster (5% of the cohort) by participants who showed improvement in cognitive and psychological status, and the smallest cluster (1% of the cohort) by participants whose mobility and cognitive functions dramatically declined after 4 years. We were able to identify in a cohort of relatively high-functioning community-dwelling adults a very small group of participants who showed clinically significant decline. The selected smallest subset manifested not only mobility deterioration, but also cognitive decline, the latter being usually hard to detect in population-based studies. The employed techniques could identify at-risk participants with more specificity than current methods, and help clinicians better identify and manage the small proportion of community-dwelling older adults who are at significant risk of functional decline and loss of independence.

Dynamic networks of physiologic interactions of brain waves and rhythms in muscle activity.

The brain plays a central role in facilitating vital body functions and in regulating physiological and organ systems, including the skeleto-muscular and locomotor system. While neural control is essential to synchronize and coordinate activation of various muscle groups and muscle fibers within muscle groups in relation to body movements and distinct physiologic states, the dynamic networks of brain-muscle interactions have not been explored and the complex regulatory mechanism of brain-muscle control remains unknown. Here we present a first study of network interactions between brain waves at different cortical locations and peripheral muscle activity across key physiologic states - wake, sleep and distinct sleep stages. Utilizing a novel approach based on the Network Physiology framework and the concept of time delay stability, we find that for each physiologic state the network of cortico-muscular interactions is characterized by a specific hierarchical organization of network topology and network links strength, where particular brain waves are main mediators of interaction and control of muscular activity. Further, we uncover that with transition from one physiological state to another, the brain-muscle interaction network undergoes marked reorganization in the profile of network links strength, indicating a direct association between network structure and physiological state and function. The pronounced stratification in brain-muscle network characteristics across sleep stages is consistent for chin and leg muscle groups and persists across subjects, indicating a remarkable universality and a previously unrecognized basic physiologic mechanism that regulates muscle activity even during rest and in the absence targeted direct movement. Our findings demonstrate previously unrecognized coordination between brain waves and activation of different muscle fiber types within muscle groups, laws of brain-muscle cross-communication and principles of network integration and control. These investigations demonstrate the potential of network-based biomarkers for classification of distinct physiological states and conditions, for the diagnosis and prognosis of neurodegenerative, movement and sleep disorders, and for developing efficient treatment strategies.

SART and Individual Trial Mistake Thresholds: Predictive Model for Mobility Decline.

The Sustained Attention to Response Task (SART) has been used to measure neurocognitive functions in older adults. However, simplified average features of this complex dataset may result in loss of primary information and fail to express associations between test performance and clinically meaningful outcomes. Here, we describe a new method to visualise individual trial (raw) information obtained from the SART test, vis-à-vis age, and groups based on mobility status in a large population-based study of ageing in Ireland. A thresholding method, based on the individual trial number of mistakes, was employed to better visualise poorer SART performances, and was statistically validated with binary logistic regression models to predict mobility and cognitive decline after 4 years. Raw SART data were available for 4864 participants aged 50 years and over at baseline. The novel visualisation-derived feature bad performance, indicating the number of SART trials with at least 4 mistakes, was the most significant predictor of mobility decline expressed by the transition from Timed Up-and-Go (TUG) < 12 to TUG ≥ 12 s (OR = 1.29; 95% CI 1.14-1.46; p < 0.001), and the only significant predictor of new falls (OR = 1.11; 95% CI 1.03-1.21; p = 0.011), in models adjusted for multiple covariates. However, no SART-related variables resulted significant for the risk of cognitive decline, expressed by a decrease of ≥2 points in the Mini-Mental State Examination (MMSE) score. This novel multimodal visualisation could help clinicians easily develop clinical hypotheses. A threshold approach to the evaluation of SART performance in older adults may better identify subjects at higher risk of future mobility decline.

Transitions in frailty phenotype states and components over 8 years: Evidence from The Irish Longitudinal Study on Ageing.

AIM: Fried's frailty phenotype (FP) is defined by exhaustion (EX), unexplained weight loss (WL), weakness (WK), slowness (SL) and low physical activity (LA). Three or more components define the frail state, and one or two the prefrail. We described longitudinal transitions of FP states and components in The Irish Longitudinal Study on Ageing (TILDA). METHODS: We included participants aged ≥50 years with FP information at TILDA wave 1 (2010), who were followed-up over four longitudinal waves (2012, 2014, 2016, 2018). Next-wave transition probabilities were estimated with multi-state Markov models. RESULTS: 5683 wave 1 participants were included (2612 men and 3071 women; mean age 63.1 years). Probabilities from non-frail to prefrail, and non-frail to frail were 27% and 2%, respectively. Prefrail had a 32% probability of reversal to non-frail, and a 10% risk of progression to frail. Frail had an 18% probability of reversal to prefrail and 31% risk of death. Probabilities of transitioning from not having to having a component were: 17% for LA, 11% for SL, 9% for EX, 7% for WL and 6% for WK. Probabilities of having a FP component and dying were: 17% for WL, 15% for WK, 14% for SL, 13% for EX, and 10% for LA. Probabilities of having a component and recovering at the next wave were: 59% for WL, 58% for EX, 40% for WK, 35% for LA and 23% for SL. CONCLUSIONS: FP states and components are characterized by dynamic longitudinal transitions. Opportunities exist for reducing the probability of adverse transitions.

Brain-predicted age difference score is related to specific cognitive functions: a multi-site replication analysis.

Brain-predicted age difference scores are calculated by subtracting chronological age from 'brain' age, which is estimated using neuroimaging data. Positive scores reflect accelerated ageing and are associated with increased mortality risk and poorer physical function. To date, however, the relationship between brain-predicted age difference scores and specific cognitive functions has not been systematically examined using appropriate statistical methods. First, applying machine learning to 1359 T1-weighted MRI scans, we predicted the relationship between chronological age and voxel-wise grey matter data. This model was then applied to MRI data from three independent datasets, significantly predicting chronological age in each dataset: Dokuz Eylül University (n = 175), the Cognitive Reserve/Reference Ability Neural Network study (n = 380), and The Irish Longitudinal Study on Ageing (n = 487). Each independent dataset had rich neuropsychological data. Brain-predicted age difference scores were significantly negatively correlated with performance on measures of general cognitive status (two datasets); processing speed, visual attention, and cognitive flexibility (three datasets); visual attention and cognitive flexibility (two datasets); and semantic verbal fluency (two datasets). As such, there is firm evidence of correlations between increased brain-predicted age differences and reduced cognitive function in some domains that are implicated in cognitive ageing.

Comparison of Gait Speed Reserve, Usual Gait Speed, and Maximum Gait Speed of Adults Aged 50+ in Ireland Using Explainable Machine Learning.

Gait speed is a measure of general fitness. Changing from usual (UGS) to maximum (MGS) gait speed requires coordinated action of many body systems. Gait speed reserve (GSR) is defined as MGS-UGS. From a shortlist of 88 features across five categories including sociodemographic, cognitive, and physiological, we aimed to find and compare the sets of predictors that best describe UGS, MGS, and GSR. For this, we leveraged data from 3,925 adults aged 50+ from Wave 3 of The Irish Longitudinal Study on Ageing (TILDA). Features were selected by a histogram gradient boosting regression-based stepwise feature selection pipeline. Each model's feature importance and input-output relationships were explored using TreeExplainer from the Shapely Additive Explanations explainable machine learning package. The mean R a d j 2 (SD) from fivefold cross-validation on training data and the R a d j 2   score on test data were 0.38 (0.04) and 0.41 for UGS, 0.45 (0.04) and 0.46 for MGS, and 0.19 (0.02) and 0.21 for GSR. Each model selected features across all categories. Features common to all models were age, grip strength, chair stands time, mean motor reaction time, and height. Exclusive to UGS and MGS were educational attainment, fear of falling, Montreal cognitive assessment errors, and orthostatic intolerance. Exclusive to MGS and GSR were body mass index (BMI), and number of medications. No features were selected exclusively for UGS and GSR. Features unique to UGS were resting-state pulse interval, Center for Epidemiologic Studies Depression Scale (CESD) depression, sit-to-stand difference in diastolic blood pressure, and left visual acuity. Unique to MGS were standard deviation in sustained attention to response task times, resting-state heart rate, smoking status, total heartbeat power during paced breathing, and visual acuity. Unique to GSR were accuracy proportion in a sound-induced flash illusion test, Mini-mental State Examination errors, and number of cardiovascular conditions. No interactions were present in the GSR model. The four features that overall gave the most impactful interactions in the UGS and MGS models were age, chair stands time, grip strength, and BMI. These findings may help provide new insights into the multisystem predictors of gait speed and gait speed reserve in older adults and support a network physiology approach to their study.

Network Physiology of Cortico-Muscular Interactions.

Skeletal muscle activity is continuously modulated across physiologic states to provide coordination, flexibility and responsiveness to body tasks and external inputs. Despite the central role the muscular system plays in facilitating vital body functions, the network of brain-muscle interactions required to control hundreds of muscles and synchronize their activation in relation to distinct physiologic states has not been investigated. Recent approaches have focused on general associations between individual brain rhythms and muscle activation during movement tasks. However, the specific forms of coupling, the functional network of cortico-muscular coordination, and how network structure and dynamics are modulated by autonomic regulation across physiologic states remains unknown. To identify and quantify the cortico-muscular interaction network and uncover basic features of neuro-autonomic control of muscle function, we investigate the coupling between synchronous bursts in cortical rhythms and peripheral muscle activation during sleep and wake. Utilizing the concept of time delay stability and a novel network physiology approach, we find that the brain-muscle network exhibits complex dynamic patterns of communication involving multiple brain rhythms across cortical locations and different electromyographic frequency bands. Moreover, our results show that during each physiologic state the cortico-muscular network is characterized by a specific profile of network links strength, where particular brain rhythms play role of main mediators of interaction and control. Further, we discover a hierarchical reorganization in network structure across physiologic states, with high connectivity and network link strength during wake, intermediate during REM and light sleep, and low during deep sleep, a sleep-stage stratification that demonstrates a unique association between physiologic states and cortico-muscular network structure. The reported empirical observations are consistent across individual subjects, indicating universal behavior in network structure and dynamics, and high sensitivity of cortico-muscular control to changes in autonomic regulation, even at low levels of physical activity and muscle tone during sleep. Our findings demonstrate previously unrecognized basic principles of brain-muscle network communication and control, and provide new perspectives on the regulatory mechanisms of brain dynamics and locomotor activation, with potential clinical implications for neurodegenerative, movement and sleep disorders, and for developing efficient treatment strategies.

Universal spectral profile and dynamic evolution of muscle activation: a hallmark of muscle type and physiological state.

The skeletal muscle is an integrated multicomponent system with complex dynamics of continuous myoelectrical activation of various muscle types across time scales to facilitate muscle coordination among units and adaptation to physiological states. To understand the multiscale dynamics of neuromuscular activity, we investigated spectral characteristics of different muscle types across time scales and their evolution with physiological states. We hypothesized that each muscle type is characterized by a specific spectral profile, reflecting muscle composition and function, that remains invariant over time scales and is universal across subjects. Furthermore, we hypothesized that the myoelectrical activation and corresponding spectral profile during certain movements exhibit an evolution path in time that is unique for each muscle type and reflects responses in muscle dynamics to exercise, fatigue, and aging. To probe the multiscale mechanism of neuromuscular regulation, we developed a novel protocol of repeated squat exercise segments, each performed until exhaustion, and we analyzed differentiated spectral power responses over a range of frequency bands for leg and back muscle activation in young and old subjects. We found that leg and back muscle activation is characterized by muscle-specific spectral profiles, with differentiated frequency band contribution, and a muscle-specific evolution path in response to fatigue and aging that is universal across subjects in each age group. The uncovered universality among subjects in the spectral profile of each muscle at a given physiological state, as well as the robustness in the evolution of these profiles over a range of time scales and states, reveals a previously unrecognized multiscale mechanism underlying the differentiated response of distinct muscle types to exercise-induced fatigue and aging.NEW & NOTEWORTHY To understand coordinated function of distinct fibers in a muscle, we investigated spectral dynamics of muscle activation during maximal exercise across a range of frequency bands and time scales of observation. We discovered a spectral profile that is specific for each muscle type, robust at short, intermediate, and large time scales, universal across subjects, and characterized by a muscle-specific evolution path with accumulation of fatigue and aging, indicating a previously unrecognized multiscale mechanism of muscle tone regulation.

Mid-sagittal plane detection for advanced physiological measurements in brain scans.

OBJECTIVE: The process of diagnosing many neurodegenerative diseases, such as Parkinson's and progressive supranuclear palsy, involves the study of brain magnetic resonance imaging (MRI) scans in order to identify and locate morphological markers that can highlight the health status of the subject. A fundamental step in the pre-processing and analysis of MRI scans is the identification of the mid-sagittal plane, which corresponds to the mid-brain and allows a coordinate reference system for the whole MRI scan set. APPROACH: To improve the identification of the mid-sagittal plane we have developed an algorithm in Matlab® based on the k-means clustering function. The results have been compared with the evaluation of four experts who manually identified the mid-sagittal plane and whose performances have been combined with a cognitive decisional algorithm in order to define a gold standard. MAIN RESULTS: The comparison provided a mean percentage error of 1.84%. To further refine the automatic procedure we trained a machine learning system using the results from the proposed algorithm and the gold standard. We tested this machine learning system and obtained results comparable to medical raters with a mean absolute error of 1.86 slices. SIGNIFICANCE: The system is promising and could be directly incorporated into broader diagnostic support systems.