Exploring the aperiodic nature of parasympathetic activity during sleep in idiopathic gastroparesis.

The parasympathetic nervous system is necessary to regulate both sleep and digestion. Investigating abnormalities during the controlled setting of sleep can shed light on digestion, specifically for patients with idiopathic gastroparesis. In this study, we specifically investigate heartbeat-derived parasympathetic activity during sleep at very low frequencies, relevant to sleep cycle regulation. To do this, we adapt a method that extracts both periodic and aperiodic information from the power spectral density and recognize that the aperiodic activity may contain information relevant to very low frequencies. After testing on both synthetic noise data (pink and white) and overnight data from seven healthy controls and idiopathic gastroparetics, we find that the healthy controls' low-frequency aperiodic activity reflects pink noise structure, while the majority of the patients' aperiodic activity reflects white noise structure. At these low frequencies, these differences suggest differences in autonomic sleep cycle regulation.Clinical Relevance- This methodology can be optimized to track the health of the parasympathetic nervous system and suggest whether individual disease etiology is autonomic-related.

Exploring the Gut-Brain Connection in Gastroparesis With Autonomic and Gastric Myoelectric Monitoring.

OBJECTIVE: The goal of this study was to identify autonomic and gastric myoelectric biomarkers from throughout the day that differentiate patients with gastroparesis, diabetics without gastroparesis, and healthy controls, while providing insight into etiology. METHODS: We collected 19 24-hour recordings of electrocardiogram (ECG) and electrogastrogram (EGG) data from healthy controls and patients with diabetic or idiopathic gastroparesis. We used physiologically and statistically rigorous models to extract autonomic and gastric myoelectric information from the ECG and EGG data, respectively. From these, we constructed quantitative indices which differentiated the distinct groups and demonstrated their application in automatic classification paradigms and as quantitative summary scores. RESULTS: We identified several differentiators that separate healthy controls from gastroparetic patient groups, specifically around sleep and meals. We also demonstrated the downstream utility of these differentiators in automatic classification and quantitative scoring paradigms. Even with this small pilot dataset, automated classifiers achieved an accuracy of 79% separating autonomic phenotypes and 65% separating gastrointestinal phenotypes. We also achieved 89% accuracy separating controls from gastroparetic patients in general and 90% accuracy separating diabetics with and without gastroparesis. These differentiators also suggested varying etiologies for different phenotypes. CONCLUSION: The differentiators we identified were able to successfully distinguish between several autonomic and gastrointestinal (GI) phenotypes using data collected while at-home with non-invasive sensors. SIGNIFICANCE: Autonomic and gastric myoelectric differentiators, obtained using at-home recording of fully non-invasive signals, can be the first step towards dynamic quantitative markers to track severity, disease progression, and treatment response for combined autonomic and GI phenotypes.

An unsupervised automated paradigm for artifact removal from electrodermal activity in an uncontrolled clinical setting.

Objective. Electrodermal activity (EDA) reflects sympathetic nervous system activity through sweating-related changes in skin conductance and could be used in clinical settings in which patients cannot self-report pain, such as during surgery or when in a coma. To enable EDA data to be used robustly in clinical settings, we need to develop artifact detection and removal frameworks that can handle the types of interference experienced in clinical settings while salvaging as much useful information as possible.Approach. In this study, we collected EDA data from 70 subjects while they were undergoing surgery in the operating room. We then built a fully automated artifact removal framework to remove the heavy artifacts that resulted from the use of surgical electrocautery during the surgery and compared it to two existing state-of-the-art methods for artifact removal from EDA data. This automated framework consisted of first utilizing three unsupervised machine learning methods for anomaly detection, and then customizing the threshold to separate artifact for each data instance by taking advantage of the statistical properties of the artifact in that data instance. We also created simulated surgical data by introducing artifacts into cleaned surgical data and measured the performance of all three methods in removing it.Main results. Our method achieved the highest overall accuracy and precision and lowest overall error on simulated data. One of the other methods prioritized high sensitivity while sacrificing specificity and precision, while the other had low sensitivity, high error, and left behind several artifacts. These results were qualitatively similar between the simulated data instances and operating room data instances.Significance. Our framework allows for robust removal of heavy artifact from EDA data in clinical settings such as surgery, which is the first step to enable clinical integration of EDA as part of standard monitoring.

Automated classification of sleep and wake from single day triaxial accelerometer data.

Actigraphy allows for the remote monitoring of subjects' activity for clinical and research purposes. However, most standard methods are built for proprietary measures from specific devices that are not widely used. In this study, we develop an algorithm for classifying sleep and awake using a single day of triaxial accelerometer data, which can be acquired from all smart devices. This algorithm consists of two stages, clustering and hidden Markov modeling, and outperforms standard algorithms in sensitivity (94%), specificity (93 %), and overall accuracy (93%) across seven subjects. This method can help automate actigraphy analyses at scale using widely available technology using even a single day's worth of data. Clinical Relevance- Automated monitoring of patients' activity at home can help track recovery trajectories after surgery and injury, disease progression, treatment response.

Tonic Electrodermal Activity is a Robust Marker of Psychological and Physiological Changes during Induction of Anesthesia.

Electrodermal activity (EDA), which tracks sweat gland activity as a proxy for sympathetic activation, has the potential to be a biomarker of physiological and psychological changes in the clinic. To show this, in this study, we demonstrate that the tonic component of EDA responds consistently and robustly during induction of anesthesia in the operating room in 8 subjects during surgery. This response is seen bilaterally. The response shows a significant increase in EDA in anticipation of induction and then a gradual decrease in response to the administration of medication, which agrees with both the expected psychological effects of stress and anxiety and the physiological effects of anesthetic medication on sweat glands. The results also show a slightly faster response to drug in the arm directly receiving the medication intravenously compared to the opposite, though the magnitude of the effect evens out over time. Clinical Relevance- EDA can serve as a robust non-invasive biomarker in the clinic to track both psychologically and physiologically induced autonomic changes.

How Machine Learning is Powering Neuroimaging to Improve Brain Health.

This report presents an overview of how machine learning is rapidly advancing clinical translational imaging in ways that will aid in the early detection, prediction, and treatment of diseases that threaten brain health. Towards this goal, we aresharing the information presented at a symposium, "Neuroimaging Indicators of Brain Structure and Function - Closing the Gap Between Research and Clinical Application", co-hosted by the McCance Center for Brain Health at Mass General Hospital and the MIT HST Neuroimaging Training Program on February 12, 2021. The symposium focused on the potential for machine learning approaches, applied to increasingly large-scale neuroimaging datasets, to transform healthcare delivery and change the trajectory of brain health by addressing brain care earlier in the lifespan. While not exhaustive, this overview uniquely addresses many of the technical challenges from image formation, to analysis and visualization, to synthesis and incorporation into the clinical workflow. Some of the ethical challenges inherent to this work are also explored, as are some of the regulatory requirements for implementation. We seek to educate, motivate, and inspire graduate students, postdoctoral fellows, and early career investigators to contribute to a future where neuroimaging meaningfully contributes to the maintenance of brain health.

Unsupervised Machine Learning Methods for Artifact Removal in Electrodermal Activity.

Artifact detection and removal is a crucial step in all data preprocessing pipelines for physiological time series data, especially when collected outside of controlled experimental settings. The fact that such artifact is often readily identifiable by eye suggests that unsupervised machine learning algorithms may be a promising option that do not require manually labeled training datasets. Existing methods are often heuristic-based, not generalizable, or developed for controlled experimental settings with less artifact. In this study, we test the ability of three such unsupervised learning algorithms, isolation forests, 1-class support vector machine, and K-nearest neighbor distance, to remove heavy cautery-related artifact from electrodermal activity (EDA) data collected while six subjects underwent surgery. We first defined 12 features for each halfsecond window as inputs to the unsupervised learning methods. For each subject, we compared the best performing unsupervised learning method to four other existing methods for EDA artifact removal. For all six subjects, the unsupervised learning method was the only one successful at fully removing the artifact. This approach can easily be expanded to other modalities of physiological data in complex settings.Clinical Relevance- Robust artifact detection methods allow for the use of diverse physiological data even in complex clinical settings to inform diagnostic and therapeutic decisions.

Quantitative assessment of the relationship between behavioral and autonomic dynamics during propofol-induced unconsciousness.

During general anesthesia, both behavioral and autonomic changes are caused by the administration of anesthetics such as propofol. Propofol produces unconsciousness by creating highly structured oscillations in brain circuits. The anesthetic also has autonomic effects due to its actions as a vasodilator and myocardial depressant. Understanding how autonomic dynamics change in relation to propofol-induced unconsciousness is an important scientific and clinical question since anesthesiologists often infer changes in level of unconsciousness from changes in autonomic dynamics. Therefore, we present a framework combining physiology-based statistical models that have been developed specifically for heart rate variability and electrodermal activity with a robust statistical tool to compare behavioral and multimodal autonomic changes before, during, and after propofol-induced unconsciousness. We tested this framework on physiological data recorded from nine healthy volunteers during computer-controlled administration of propofol. We studied how autonomic dynamics related to behavioral markers of unconsciousness: 1) overall, 2) during the transitions of loss and recovery of consciousness, and 3) before and after anesthesia as a whole. Our results show a strong relationship between behavioral state of consciousness and autonomic dynamics. All of our prediction models showed areas under the curve greater than 0.75 despite the presence of non-monotonic relationships among the variables during the transition periods. Our analysis highlighted the specific roles played by fast versus slow changes, parasympathetic vs sympathetic activity, heart rate variability vs electrodermal activity, and even pulse rate vs pulse amplitude information within electrodermal activity. Further advancement upon this work can quantify the complex and subject-specific relationship between behavioral changes and autonomic dynamics before, during, and after anesthesia. However, this work demonstrates the potential of a multimodal, physiologically-informed, statistical approach to characterize autonomic dynamics.

Elementary integrate-and-fire process underlies pulse amplitudes in Electrodermal activity.

Electrodermal activity (EDA) is a direct read-out of sweat-induced changes in the skin's electrical conductance. Sympathetically-mediated pulsatile changes in skin sweat measured as EDA resemble an integrate-and-fire process, which yields an inverse Gaussian model as the inter-pulse interval distribution. We have previously showed that the inter-pulse intervals in EDA follow an inverse Gaussian distribution. However, the statistical structure of EDA pulse amplitudes has not yet been characterized based on the physiology. Expanding upon the integrate-and-fire nature of sweat glands, we hypothesized that the amplitude of an EDA pulse is proportional to the excess volume of sweat produced compared to what is required to just reach the surface of the skin. We modeled this as the difference of two inverse Gaussian models for each pulse, one which represents the time required to produce just enough sweat to rise to the surface of the skin and one which represents the time requires to produce the actual volume of sweat. We proposed and tested a series of four simplifications of our hypothesis, ranging from a single difference of inverse Gaussians to a single simple inverse Gaussian. We also tested four additional models for comparison, including the lognormal and gamma distributions. All models were tested on EDA data from two subject cohorts, 11 healthy volunteers during 1 hour of quiet wakefulness and a different set of 11 healthy volunteers during approximately 3 hours of controlled propofol sedation. All four models which represent simplifications of our hypothesis outperformed other models across all 22 subjects, as measured by Akaike's Information Criterion (AIC), as well as mean and maximum distance from the diagonal on a quantile-quantile plot. Our broader model set of four simplifications offered a useful framework to enhance further statistical descriptions of EDA pulse amplitudes. Some of the simplifications prioritize fit near the mode of the distribution, while others prioritize fit near the tail. With this new insight, we can summarize the physiologically-relevant amplitude information in EDA with at most four parameters. Our findings establish that physiologically based probability models provide parsimonious and accurate description of temporal and amplitude characteristics in EDA.

A Model-Based Framework for Assessing the Physiologic Structure of Electrodermal Activity.

OBJECTIVE: We present a statistical model for extracting physiologic characteristics from electrodermal activity (EDA) data in observational settings. METHODS: We based our model on the integrate-and-fire physiology of sweat gland bursts, which predicts inverse Gaussian (IG) inter-pulse interval structure. At the core of our model-based paradigm is a subject-specific amplitude threshold selection process for EDA pulses based on the statistical properties of four right-skewed models including the IG. By performing a sensitivity analysis across thresholds and fitting all four models, we selected for IG-like structure and verified the pulse selection with a goodness-of-fit analysis, maximizing capture of physiology at the time scale of EDA responses. RESULTS: We tested the model-based paradigm on simulated EDA time series and data from two different experimental cohorts recorded during different experimental conditions, using different equipment. In both the simulated and experimental data, our model-based method robustly recovered pulses that captured the IG-like structure predicted by physiology, despite large differences in noise level. In contrast, established EDA analysis tools, which attempted to estimate neural activity from slower EDA responses, did not provide physiological validation and were susceptible to noise. CONCLUSION: We present a computationally efficient, statistically rigorous, and physiology-informed paradigm for pulse selection from EDA data that is robust across individuals and experimental conditions, yet adaptable to varying noise level. SIGNIFICANCE: The robustness of the model-based paradigm and its physiological basis provide empirical support for the use of EDA as a clinical marker for sympathetic activity in conditions such as pain, anxiety, depression, and sleep states.

Point process temporal structure characterizes electrodermal activity.

Electrodermal activity (EDA) is a direct readout of the body's sympathetic nervous system measured as sweat-induced changes in the skin's electrical conductance. There is growing interest in using EDA to track physiological conditions such as stress levels, sleep quality, and emotional states. Standardized EDA data analysis methods are readily available. However, none considers an established physiological feature of EDA. The sympathetically mediated pulsatile changes in skin sweat measured as EDA resemble an integrate-and-fire process. An integrate-and-fire process modeled as a Gaussian random walk with drift diffusion yields an inverse Gaussian model as the interpulse interval distribution. Therefore, we chose an inverse Gaussian model as our principal probability model to characterize EDA interpulse interval distributions. To analyze deviations from the inverse Gaussian model, we considered a broader model set: the generalized inverse Gaussian distribution, which includes the inverse Gaussian and other diffusion and nondiffusion models; the lognormal distribution which has heavier tails (lower settling rates) than the inverse Gaussian; and the gamma and exponential probability distributions which have lighter tails (higher settling rates) than the inverse Gaussian. To assess the validity of these probability models we recorded and analyzed EDA measurements in 11 healthy volunteers during 1 h of quiet wakefulness. Each of the 11 time series was accurately described by an inverse Gaussian model measured by Kolmogorov-Smirnov measures. Our broader model set offered a useful framework to enhance further statistical descriptions of EDA. Our findings establish that a physiologically based inverse Gaussian probability model provides a parsimonious and accurate description of EDA.

Detecting Loss and Regain of Consciousness during Propofol Anesthesia using Multimodal Indices of Autonomic State.

We have traditionally defined `loss of consciousness' (LOC) and `regain of consciousness' (ROC) during general anesthesia in terms of behavioral correlates. We are starting to understand the dynamics in brain activity that may help define those events; however, we have not yet explored the possible autonomic correlates of LOC and ROC. In this study, we investigated the autonomic dynamics immediately surrounding loss and regain of consciousness in nine healthy volunteers under controlled propofol sedation. We used multimodal autonomic indices generated from physiologically accurate models and found that just before and after LOC and ROC could be differentiated with an AUC of 0.80. In addition, we saw that some of the autonomic changes accompanying LOC and ROC verify known information about the mechanism of action of propofol, while others indicate new avenues for exploration of propofol's effect on the autonomic nervous system. Overall, our work suggests that the autonomic dynamics surrounding the events of loss and regain of consciousness are worthy of further investigation.Clinical Relevance-This introduces the possibility of autonomic biomarkers for loss and regain of consciousness during general anesthesia that are more precise than behavioral tracking alone.

Risk-taking bias in human decision-making is encoded via a right-left brain push-pull system.

A person's decisions vary even when options stay the same, like when a gambler changes bets despite constant odds of winning. Internal bias (e.g., emotion) contributes to this variability and is shaped by past outcomes, yet its neurobiology during decision-making is not well understood. To map neural circuits encoding bias, we administered a gambling task to 10 participants implanted with intracerebral depth electrodes in cortical and subcortical structures. We predicted the variability in betting behavior within and across patients by individual bias, which is estimated through a dynamical model of choice. Our analysis further revealed that high-frequency activity increased in the right hemisphere when participants were biased toward risky bets, while it increased in the left hemisphere when participants were biased away from risky bets. Our findings provide electrophysiological evidence that risk-taking bias is a lateralized push-pull neural system governing counterintuitive and highly variable decision-making in humans.

Multitaper Infinite Hidden Markov Model for EEG.

Electroencephalographam (EEG) monitoring of neural activity is widely used for identifying underlying brain states. For inference of brain states, researchers have often used Hidden Markov Models (HMM) with a fixed number of hidden states and an observation model linking the temporal dynamics embedded in EEG to the hidden states. The use of fixed states may be limiting, in that 1) pre-defined states might not capture the heterogeneous neural dynamics across individuals and 2) the oscillatory dynamics of the neural activity are not directly modeled. To this end, we use a Hierarchical Dirichlet Process Hidden Markov Model (HDP-HMM), which discovers the set of hidden states that best describes the EEG data, without a-priori specification of state number. In addition, we introduce an observation model based on classical asymptotic results of frequency domain properties of stationary time series, along with the description of the conditional distributions for Gibbs sampler inference. We then combine this with multitaper spectral estimation to reduce the variance of the spectral estimates. By applying our method to simulated data inspired by sleep EEG, we arrive at two main results: 1) the algorithm faithfully recovers the spectral characteristics of the true states, as well as the right number of states and 2) the incorporation of the multitaper framework produces a more stable estimate than traditional periodogram spectral estimates.

A Systematic Method for Preprocessing and Analyzing Electrodermal Activity.

Electrodermal activity (EDA) is a measure of sympathetic tone using sweat gland activity that has applications in research and clinical medicine. We previously identified never-before-seen statistical structure in EDA. However, there is no systematic method to preprocess and analyze EDA data to capture such statistical structure. Therefore, in this study, we analyzed the data of two healthy volunteers while awake and at rest. We used a systematic process that takes advantage of the tail behavior of various statistical distributions to ensure capturing the point process structure in EDA. We verified the presence of this temporal structure in a new dataset of subjects. Our results demonstrate for the first time that point process structure of EDA pulses can be identified across multiple datasets using a systematic method that is still rooted in the underlying physiology.

A Point Process Characterization Of Electrodermal Activity.

Electrodermal activity (EDA) is a measure of sympathetic activity using skin conductance that has applications in research and in clinical medicine. However, current EDA analysis does not have physiologically-based statistical models that use stochastic structure to provide nuanced insight into autonomic dynamics. Therefore, in this study, we analyzed the data of two healthy volunteers under controlled propofol sedation. We identified a novel statistical model for EDA and used a point process framework to track instantaneous dynamics. Our results demonstrate for the first time that point process models rooted in physiology and built upon inherent statistical structure of EDA pulses have the potential to accurately track instantaneous dynamics in sympathetic tone.

Using network analysis to localize the epileptogenic zone from invasive EEG recordings in intractable focal epilepsy.

Treatment of medically intractable focal epilepsy (MIFE) by surgical resection of the epileptogenic zone (EZ) is often effective provided the EZ can be reliably identified. Even with the use of invasive recordings, the clinical differentiation between the EZ and normal brain areas can be quite challenging, mainly in patients without MRI detectable lesions. Consequently, despite relatively large brain regions being removed, surgical success rates barely reach 60-65%. Such variable and unfavorable outcomes associated with high morbidity rates are often caused by imprecise and/or inaccurate EZ localization. We developed a localization algorithm that uses network-based data analytics to process invasive EEG recordings. This network algorithm analyzes the centrality signatures of every contact electrode within the recording network and characterizes contacts into susceptible EZ based on the centrality trends over time. The algorithm was tested in a retrospective study that included 42 patients from four epilepsy centers. Our algorithm had higher agreement with EZ regions identified by clinicians for patients with successful surgical outcomes and less agreement for patients with failed outcomes. These findings suggest that network analytics and a network systems perspective of epilepsy may be useful in assisting clinicians in more accurately localizing the EZ.

Yeast heterochromatin regulators Sir2 and Sir3 act directly at euchromatic DNA replication origins.

Most active DNA replication origins are found within euchromatin, while origins within heterochromatin are often inactive or inhibited. In yeast, origin activity within heterochromatin is negatively controlled by the histone H4K16 deacetylase, Sir2, and at some heterochromatic loci also by the nucleosome binding protein, Sir3. The prevailing view has been that direct functions of Sir2 and Sir3 are confined to heterochromatin. However, growth defects in yeast mutants compromised for loading the MCM helicase, such as cdc6-4, are suppressed by deletion of either SIR2 or SIR3. While these and other observations indicate that SIR2,3 can have a negative impact on at least some euchromatic origins, the genomic scale of this effect was unknown. It was also unknown whether this suppression resulted from direct functions of Sir2,3 within euchromatin, or was an indirect effect of their previously established roles within heterochromatin. Using MCM ChIP-Seq, we show that a SIR2 deletion rescued MCM complex loading at ~80% of euchromatic origins in cdc6-4 cells. Therefore, Sir2 exhibited a pervasive effect at the majority of euchromatic origins. Using MNase-H4K16ac ChIP-Seq, we show that origin-adjacent nucleosomes were depleted for H4K16 acetylation in a SIR2-dependent manner in wild type (i.e. CDC6) cells. In addition, we present evidence that both Sir2 and Sir3 bound to nucleosomes adjacent to euchromatic origins. The relative levels of each of these molecular hallmarks of yeast heterochromatin-SIR2-dependent H4K16 hypoacetylation, Sir2, and Sir3 -correlated with how strongly a SIR2 deletion suppressed the MCM loading defect in cdc6-4 cells. Finally, a screen for histone H3 and H4 mutants that could suppress the cdc6-4 growth defect identified amino acids that map to a surface of the nucleosome important for Sir3 binding. We conclude that heterochromatin proteins directly modify the local chromatin environment of euchromatic DNA replication origins.

The influences and neural correlates of past and present during gambling in humans.

During financial decision-making tasks, humans often make "rational" decisions, where they maximize expected reward. However, this rationality may compete with a bias that reflects past outcomes. That is, if one just lost money or won money, this may impact future decisions. It is unclear how past outcomes influence future decisions in humans, and how neural circuits encode present and past information. In this study, six human subjects performed a financial decision-making task while we recorded local field potentials from multiple brain structures. We constructed a model for each subject characterizing bets on each trial as a function of present and past information. The models suggest that some patients are more influenced by previous trial outcomes (i.e., previous return and risk) than others who stick to more fixed decision strategies. In addition, past return and present risk modulated with the activity in the cuneus; while present return and past risk modulated with the activity in the superior temporal gyrus and the angular gyrus, respectively. Our findings suggest that these structures play a role in decision-making beyond their classical functions by incorporating predictions and risks in humans' decision strategy, and provide new insight into how humans link their internal biases to decisions.

Computing network-based features from intracranial EEG time series data: Application to seizure focus localization.

The surgical resection of the epileptogenic zone (EZ) is the only effective treatment for many drug-resistant epilepsy (DRE) patients, but the pre-surgical identification of the EZ is challenging. This study investigates whether the EZ exhibits a computationally identifiable signature during seizures. In particular, we compute statistics of the brain network from intracranial EEG (iEEG) recordings and track the evolution of network connectivity before, during, and after seizures. We define each node in the network as an electrode and weight each edge connecting a pair of nodes by the gamma band cross power of the corresponding iEEG signals. The eigenvector centrality (EVC) of each node is tracked over two seizures per patient and the electrodes are ranked according to the corresponding EVC value. We hypothesize that electrodes covering the EZ have a signature EVC rank evolution during seizure that differs from electrodes outside the EZ. We tested this hypothesis on multi-channel iEEG recordings from 2 DRE patients who had successful surgery (i.e., seizures were under control with or without medications) and 1 patient who had unsuccessful surgery. In the successful cases, we assumed that the resected region contained the EZ and found that the EVC rank evolution of the electrodes within the resected region had a distinct "arc" signature, i.e., the EZ ranks first rose together shortly after seizure onset and then fell later during seizure.