A pulmonary rehabilitation program is an effective strategy to improve forced vital capacity, muscle strength, and functional exercise capacity similarly in adults and older people with post-severe COVID-19 who required mechanical ventilation.

BACKGROUND: It is internationally known that our population is aging. At the same time, some patients with COVID-19, due to their symptoms, required mechanical ventilation (MV) and subsequent pulmonary rehabilitation (PR). This study aimed to compare the effects of a multimodal PR program "ADULT" versus "OLDER" people with COVID-19 who were on MV. METHODS: The intervention consisted of an 8-week hybrid PR program (2x week). Forced vital capacity (FVC) was measured at the beginning and end of PR, upper and lower limb strength was obtained through hand grip strength (HGS) and the sit-to-stand test (STST), respectively, and functional exercise capacity was measured with the 6-minute walking test (6MWT). RESULTS: The main results were an increase in the FVC in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.27), an increase in HGS in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.52), in the same way, the number of repetitions on the STST increased in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.55). Finally, the distance covered on the 6MWT increased in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.65). CONCLUSIONS: The PR program is an effective strategy to improve FVC, muscle strength, and functional exercise capacity similarly in adults and older people with post severe COVID-19 who required MV.

Whole-brain modeling explains the context-dependent effects of cholinergic neuromodulation.

Integration and segregation are two fundamental principles of brain organization. The brain manages the transitions and balance between different functional segregated or integrated states through neuromodulatory systems. Recently, computational and experimental studies suggest a pro-segregation effect of cholinergic neuromodulation. Here, we studied the effects of the cholinergic system on brain functional connectivity using both empirical fMRI data and computational modeling. First, we analyzed the effects of nicotine on functional connectivity and network topology in healthy subjects during resting-state conditions and during an attentional task. Then, we employed a whole-brain neural mass model interconnected using a human connectome to simulate the effects of nicotine and investigate causal mechanisms for these changes. The drug effect was modeled decreasing both the global coupling and local feedback inhibition parameters, consistent with the known cellular effects of acetylcholine. We found that nicotine incremented functional segregation in both empirical and simulated data, and the effects are context-dependent: observed during the task, but not in the resting state. In-task performance correlates with functional segregation, establishing a link between functional network topology and behavior. Furthermore, we found in the empirical data that the regional density of the nicotinic acetylcholine α4ß2 correlates with the decrease in functional nodal strength by nicotine during the task. Our results confirm that cholinergic neuromodulation promotes functional segregation in a context-dependent fashion, and suggest that this segregation is suited for simple visual-attentional tasks.

Computational modelling in disorders of consciousness: Closing the gap towards personalised models for restoring consciousness.

Disorders of consciousness are complex conditions characterised by persistent loss of responsiveness due to brain injury. They present diagnostic challenges and limited options for treatment, and highlight the urgent need for a more thorough understanding of how human consciousness arises from coordinated neural activity. The increasing availability of multimodal neuroimaging data has given rise to a wide range of clinically- and scientifically-motivated modelling efforts, seeking to improve data-driven stratification of patients, to identify causal mechanisms for patient pathophysiology and loss of consciousness more broadly, and to develop simulations as a means of testing in silico potential treatment avenues to restore consciousness. As a dedicated Working Group of clinicians and neuroscientists of the international Curing Coma Campaign, here we provide our framework and vision to understand the diverse statistical and generative computational modelling approaches that are being employed in this fast-growing field. We identify the gaps that exist between the current state-of-the-art in statistical and biophysical computational modelling in human neuroscience, and the aspirational goal of a mature field of modelling disorders of consciousness; which might drive improved treatments and outcomes in the clinic. Finally, we make several recommendations for how the field as a whole can work together to address these challenges.

High-order functional redundancy in ageing explained via alterations in the connectome in a whole-brain model.

The human brain generates a rich repertoire of spatio-temporal activity patterns, which support a wide variety of motor and cognitive functions. These patterns of activity change with age in a multi-factorial manner. One of these factors is the variations in the brain's connectomics that occurs along the lifespan. However, the precise relationship between high-order functional interactions and connnectomics, as well as their variations with age are largely unknown, in part due to the absence of mechanistic models that can efficiently map brain connnectomics to functional connectivity in aging. To investigate this issue, we have built a neurobiologically-realistic whole-brain computational model using both anatomical and functional MRI data from 161 participants ranging from 10 to 80 years old. We show that the differences in high-order functional interactions between age groups can be largely explained by variations in the connectome. Based on this finding, we propose a simple neurodegeneration model that is representative of normal physiological aging. As such, when applied to connectomes of young participant it reproduces the age-variations that occur in the high-order structure of the functional data. Overall, these results begin to disentangle the mechanisms by which structural changes in the connectome lead to functional differences in the ageing brain. Our model can also serve as a starting point for modeling more complex forms of pathological ageing or cognitive deficits.

Submandibular Skinfold Thickness Cut-off Values in Relation to Body Mass Index and Percentage Body Fat Among Chilean Adolescents.

The present study evaluates submandibular skinfold (SMS) cutoff values to estimate excess weight for BMI and percentage body fat (%BF) among Chilean adolescents. The results show an optimal area under the cutoff curve value of 83% among girls and 91% in boys to estimate SMS concerning %BF and BMI. The SMS cutoff value estimating obesity by %BF was 10 mm among girls and 9 mm among boys, 10 mm among girls, and 7 mm among boys by BMI. Our results showed that SMS is significantly associated with anthropometric parameters for obesity.

Cholinergic neuromodulation of inhibitory interneurons facilitates functional integration in whole-brain models.

Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although whole-brain computational models have reproduced this neuromodulatory effect, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, we introduce a local inhibitory feedback as a plausible biophysical mechanism that enables the integration of whole-brain activity, and that interacts with the other neuromodulatory influences to facilitate the transition between different functional segregation/integration regimes in the brain.

Eight Weeks of Supervised Pulmonary Rehabilitation Are Effective in Improving Resting Heart Rate and Heart Rate Recovery in Severe COVID-19 Patient Survivors of Mechanical Ventilation.

Background and Objectives: Patients who survive severe COVID-19 require significant pulmonary rehabilitation. Heart rate (HR) has been used as a safety variable in the evaluation of the results of interventions in patients undergoing pulmonary rehabilitation. The aim of this research was to analyse HR during a pulmonary rehabilitation program in post-severe COVID-19 patients who survived mechanical ventilation (MV). The study includes the initial and final evaluations and aerobic training sessions. Materials and Methods: Twenty patients (58 ± 13 years, 11 men) were trained for 8 weeks. A 6-minute walk test (6 MWT) was performed and, subsequently, a supervised and individualised training plan was created. Resting heart rate (RHR), heart rate recovery (HRR), heart rate at minute 6 (HR6 min) and the product of HR6 min and systolic blood pressure (HR6 minxSBP) were measured at 6 MWT. In addition, HR was measured at each training session. Results: After 8 weeks of pulmonary rehabilitation, patients decreased their RHR from 81.95 ± 9.36 to 73.60 ± 9.82 beats/min (p < 0.001) and significantly increased their HRR from 12.45 ± 10.22 to 20.55 ± 7.33 beats/min (p = 0.005). HR6 min presented a significant relationship with walking speed and walked distance after the pulmonary rehabilitation period (r = 0.555, p = 0.011 and r = 0.613, p = 0.011, respectively). HR6 minxSBP presented a significant relationship with walking speed and walked distance after training (r = 0.538, p = 0.014 and r = 0.568, p = 0.008, respectively). In the pulmonary rehabilitation sessions, a significant decrease in HR was observed at minutes 1, 6 and 15 (p < 0.05) between sessions 1 and 6 and at minute 1 between sessions 1 and 12. Conclusions: Eight weeks of individualised and supervised pulmonary rehabilitation were effective in improving RHR and HRR in COVID-19 patients surviving MV. HR is an easily accessible indicator that could help to monitor the evaluation and development of a pulmonary rehabilitation program in COVID-19 patients who survived MV.

Linear Response of General Observables in Spiking Neuronal Network Models.

We establish a general linear response relation for spiking neuronal networks, based on chains with unbounded memory. This relation allow us to predict the influence of a weak amplitude time dependent external stimuli on spatio-temporal spike correlations, from the spontaneous statistics (without stimulus) in a general context where the memory in spike dynamics can extend arbitrarily far in the past. Using this approach, we show how the linear response is explicitly related to the collective effect of the stimuli, intrinsic neuronal dynamics, and network connectivity on spike train statistics. We illustrate our results with numerical simulations performed over a discrete time integrate and fire model.

Thermodynamic Formalism in Neuronal Dynamics and Spike Train Statistics.

The Thermodynamic Formalism provides a rigorous mathematical framework for studying quantitative and qualitative aspects of dynamical systems. At its core, there is a variational principle that corresponds, in its simplest form, to the Maximum Entropy principle. It is used as a statistical inference procedure to represent, by specific probability measures (Gibbs measures), the collective behaviour of complex systems. This framework has found applications in different domains of science. In particular, it has been fruitful and influential in neurosciences. In this article, we review how the Thermodynamic Formalism can be exploited in the field of theoretical neuroscience, as a conceptual and operational tool, in order to link the dynamics of interacting neurons and the statistics of action potentials from either experimental data or mathematical models. We comment on perspectives and open problems in theoretical neuroscience that could be addressed within this formalism.

Information Entropy Production of Maximum Entropy Markov Chains from Spike Trains.

The spiking activity of neuronal networks follows laws that are not time-reversal symmetric; the notion of pre-synaptic and post-synaptic neurons, stimulus correlations and noise correlations have a clear time order. Therefore, a biologically realistic statistical model for the spiking activity should be able to capture some degree of time irreversibility. We use the thermodynamic formalism to build a framework in the context maximum entropy models to quantify the degree of time irreversibility, providing an explicit formula for the information entropy production of the inferred maximum entropy Markov chain. We provide examples to illustrate our results and discuss the importance of time irreversibility for modeling the spike train statistics.

Large Deviations Properties of Maximum Entropy Markov Chains from Spike Trains.

We consider the maximum entropy Markov chain inference approach to characterize the collective statistics of neuronal spike trains, focusing on the statistical properties of the inferred model. To find the maximum entropy Markov chain, we use the thermodynamic formalism, which provides insightful connections with statistical physics and thermodynamics from which large deviations properties arise naturally. We provide an accessible introduction to the maximum entropy Markov chain inference problem and large deviations theory to the community of computational neuroscience, avoiding some technicalities while preserving the core ideas and intuitions. We review large deviations techniques useful in spike train statistics to describe properties of accuracy and convergence in terms of sampling size. We use these results to study the statistical fluctuation of correlations, distinguishability, and irreversibility of maximum entropy Markov chains. We illustrate these applications using simple examples where the large deviation rate function is explicitly obtained for maximum entropy models of relevance in this field.

Local orchestration of distributed functional patterns supporting loss and restoration of consciousness in the primate brain.

A central challenge of neuroscience is to elucidate how brain function supports consciousness. Here, we combine the specificity of focal deep brain stimulation with fMRI coverage of the entire cortex, in awake and anaesthetised non-human primates. During propofol, sevoflurane, or ketamine anaesthesia, and subsequent restoration of responsiveness by electrical stimulation of the central thalamus, we investigate how loss of consciousness impacts distributed patterns of structure-function organisation across scales. We report that distributed brain activity under anaesthesia is increasingly constrained by brain structure across scales, coinciding with anaesthetic-induced collapse of multiple dimensions of hierarchical cortical organisation. These distributed signatures are observed across different anaesthetics, and they are reversed by electrical stimulation of the central thalamus, coinciding with recovery of behavioural markers of arousal. No such effects were observed upon stimulating the ventral lateral thalamus, demonstrating specificity. Overall, we identify consistent distributed signatures of consciousness that are orchestrated by specific thalamic nuclei.

Predictive value of invasive mechanical ventilation parameters for mortality in COVID-19 related ARDS: a retrospective cohort study.

The 2019 coronavirus (COVID-19) can generate acute respiratory distress syndrome (ARDS), requiring advanced management within the Intensive Care Unit (ICU) using invasive mechanical ventilation (IMV However, managing this phenomenon has seen learning and improvements through direct experience. Therefore, this study aims were to describe the assessment of the different IMV variables in patients with post-COVID-19 hospitalized in the ICU and their relation with mortality. Observational and retrospective study. The sample was divided into two, the surviving group (SG) and the non-surviving group (NSG). Clinical data were extracted from the electronic clinical file and the respiratory therapist record sheet. The following information was obtained: Patient medical history: gender, age, co-morbidities, arterial gases, days on IMV, and IMV parameters. Out of a total of 101 patients, the total mortality was 32%. There was a significant decrease in respiratory rate (RR) (29.12 ± 4.24-26.78 ± 3.59, p = 0.006), Driving pressure (DP) (11.33 ± 2.39-9.67 ± 1.84, p = 0.002), Ventilatory rate (VR) (2.26 ± 0.66-1.89 ± 0.45, p = 0.001) and a significant rise in Static compliance (Cest) (35.49 ± 8.64-41.45 ± 9.62, p = 0.003) and relation between Arterial oxygen pressure/Inspirated oxygen fraction (PaO2/FiO2) (201.5 ± 53.98- 227.8 ± 52.11, p = 0.008) after 72 h of IMV, within the NSG compared to the SG. Apart from these points, multi-morbidity (HR = 3.208, p = 0.010) and DP (HR = 1.228, p = 0.030) and VR variables (HR = 2.267, p = 0.027) had more death probabilities. The results of this study indicate that there was a significant increase in RR, DP, VR, and CO2 and a significant drop in Cest and PaO2/FiO2 among the NSG compared with the SG. Apart from this, the DP and VR variables, multi-morbidity and being male. have more possibility of death.

Retrospective Analysis of the Ventilatory Workload Kinetic Index during Stability and Crisis in Patients with Asthma and COPD in a Monitored Program.

To assess ventilatory evolution through the Ventilatory Workload Kinetic Index (VWKI) in patients with asthma and chronic obstructive pulmonary disease (COPD) during stability and exacerbation. Retrospective analysis. Conducted at the Padre Alberto Hurtado Hospital, Santiago, Chile. Ten patients with asthma and fifty-five with COPD participated. Sixty-five clinical records were reviewed. The VWKI in stability and exacerbation of these patients was extracted. When analyzing the baseline with the peak in both asthma and COPD, there was a significant increase in the VWKI. Similarly, the loads, translations, and supports significantly increased from the baseline to the peak. However, in the loads, there were no changes in airway resistance for asthma or in cough for COPD. Likewise, the supports for asthma and COPD showed no changes in the O2. The VWKI determined ventilatory issues in outpatients and made locating the greatest compromise in loads, translations, or supports possible.

Comparison of distance covered, physiological cost, and perceived exertion in four six-minute walk test protocols.

Objective: There is evidence that indicates that the Walked Distance (WD) in the 6-Minute Walk Test (6MWT) would be sensitive to the type of track and encouragement. The aim of study was compared the impact of track type and verbal encouragement provided in the 6MWT on WD, physiological cost, perceived exertion, and gait efficiency in healthy young adults unfamiliar with the test. Method: WD, heart rate, subjective sensation of dyspnea (SSD), and fatigue (SSF) were measured in four 6MWT protocols: i) 30 m linear track and protocolized encouragement (LT + PE), ii) 30 m linear track and constant encouragement (LT + CE), iii) 81 m elliptical track and protocolized encouragement (ET + PE), and iv) 81 m elliptical track and constant encouragement (ET + CE). In addition, the Gait Efficiency Index (GIE) associated with physiological cost, dyspnea and fatigue was calculated and compared between the different protocols. Results: The WD was significantly higher in the ET + CE protocol. The percentage of the heart rate reserve used (%HRRu) at minute 6 was higher in the ET + CE protocol. The SSD and SSD had difference in startup time between the protocols. The GEI was higher in %HRRu, SSD, and SSF for the ET + CE protocol. Conclusion: The ET + CE protocol showed a significant increase in WD during the 6MWT in healthy young adults. Although it obtained the highest physiological cost, it did not present perceptual differences when entering cardiopulmonary assessment windows relevant to a more efficient test for the participant. It is advisable to discuss, based on the findings, the fundamental objective of the 6MWT and national and international recommendations to achieve a result as close as possible to the real maximal effort.

Effects of a pulmonary rehabilitation program on pulmonary function, exercise performance, and quality of life in patients with severe COVID-19.

BACKGROUND: Severe coronavirus 2019 disease (COVID-19) causes acute hypoxemic respiratory failure requiring invasive mechanical ventilation (IMV). Once these symptoms are resolved, patients can present systemic deterioration. OBJECTIVE: The two objectives of this study were as follows: to describe the results of a pulmonary rehabilitation program (PRP), which is divided into three groups with different numbers of sessions (12, 24, and 36), and to associate the variables of pulmonary function, exercise performance, and functionality with the number of sessions and functional improvement. DESIGN: Prospective, observational study. METHODS: PRP consisted of aerobic + strength + flexibility exercises under the supervision and individualized into 12, 24, or 36 sessions (12s, 24s, and 36s), depending on the evolution of each patient. At the beginning of the study and immediately after the intervention, forced vital capacity (FVC), maximal inspiratory pressure, 6-minute walk test (6MWT), sit-to-stand test (STS), maximal handgrip strength (HGS), Fatigue Assessment Scale, Post-COVID-19 Functional Status (PCFS), and health-related quality of life (HRQoL) were measured. RESULTS: The proposed PRP demonstrated a positive effect on pulmonary function, exercise performance, and HRQoL, regardless of the number of sessions. A higher score on the PCFS and more days on IMV were associated with the increased likelihood of needing more sessions, whereas more meters on the 6MWT in the initial evaluation was associated with a reduced likelihood of needing more sessions. Finally, more repetitions on the STS and less distance covered on the initial 6MWT were associated with a greater improvement in exercise performance evaluated with the 6MWT. CONCLUSION: Supervised and individualized PRP for patients with severe post-COVID-19 improves pulmonary function, exercise performance, functionality, and quality of life. Functionality, distance covered on the 6MWT, and the days on IMV are central to the scheduling of the number of sessions for these patients.

Entropy production of multivariate Ornstein-Uhlenbeck processes correlates with consciousness levels in the human brain.

Consciousness is supported by complex patterns of brain activity which are indicative of irreversible nonequilibrium dynamics. While the framework of stochastic thermodynamics has facilitated the understanding of physical systems of this kind, its application to infer the level of consciousness from empirical data remains elusive. We faced this challenge by calculating entropy production in a multivariate Ornstein-Uhlenbeck process fitted to Functional magnetic resonance imaging brain activity recordings. To test this approach, we focused on the transition from wakefulness to deep sleep, revealing a monotonous relationship between entropy production and the level of consciousness. Our results constitute robust signatures of consciousness while also advancing our understanding of the link between consciousness and complexity from the fundamental perspective of statistical physics.

A whole-brain model of the neural entropy increase elicited by psychedelic drugs.

Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in all regions, but the larger effect were localised in visuo-occipital regions. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain's anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.