M2M-InvNet: Human Motor Cortex Mapping From Multi-Muscle Response Using TMS and Generative 3D Convolutional Network.

Transcranial magnetic stimulation (TMS) is often applied to the motor cortex to stimulate a collection of motor evoked potentials (MEPs) in groups of peripheral muscles. The causal interface between TMS and MEP is the selective activation of neurons in the motor cortex; moving around the TMS 'spot' over the motor cortex causes different MEP responses. A question of interest is whether a collection of MEP responses can be used to identify the stimulated locations on the cortex, which could potentially be used to then place the TMS coil to produce chosen sets of MEPs. In this work we leverage our previous report on a 3D convolutional neural network (CNN) architecture that predicted MEPs from the induced electric field, to tackle an inverse imaging task in which we start with the MEPs and estimate the stimulated regions on the motor cortex. We present and evaluate five different inverse imaging CNN architectures, both conventional and generative, in terms of several measures of reconstruction accuracy. We found that one architecture, which we propose as M2M-InvNet, consistently achieved the best performance.

Uncertainty quantification of the effect of cardiac position variability in the inverse problem of electrocardiographic imaging.

Objective.Electrocardiographic imaging (ECGI) is a functional imaging modality that consists of two related problems, the forward problem of reconstructing body surface electrical signals given cardiac bioelectric activity, and the inverse problem of reconstructing cardiac bioelectric activity given measured body surface signals. ECGI relies on a model for how the heart generates bioelectric signals which is subject to variability in inputs. The study of how uncertainty in model inputs affects the model output is known as uncertainty quantification (UQ). This study establishes develops, and characterizes the application of UQ to ECGI.Approach.We establish two formulations for applying UQ to ECGI: a polynomial chaos expansion (PCE) based parametric UQ formulation (PCE-UQ formulation), and a novel UQ-aware inverse formulation which leverages our previously established 'joint-inverse' formulation (UQ joint-inverse formulation). We apply these to evaluate the effect of uncertainty in the heart position on the ECGI solutions across a range of ECGI datasets.Main results.We demonstrated the ability of our UQ-ECGI formulations to characterize the effect of parameter uncertainty on the ECGI inverse problem. We found that while the PCE-UQ inverse solution provided more complex outputs such as sensitivities and standard deviation, the UQ joint-inverse solution provided a more interpretable output in the form of a single ECGI solution. We find that between these two methods we are able to assess a wide range of effects that heart position variability has on the ECGI solution.Significance.This study, for the first time, characterizes in detail the application of UQ to the ECGI inverse problem. We demonstrated how UQ can provide insight into the behavior of ECGI using variability in cardiac position as a test case. This study lays the groundwork for future development of UQ-ECGI studies, as well as future development of ECGI formulations which are robust to input parameter variability.

Neuromodulatory effects and reproducibility of the most widely used repetitive transcranial magnetic stimulation protocols.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is widely used in both research and clinical settings to modulate human brain function and behavior through the engagement of the mechanisms of plasticity. Based upon experiments using single-pulse TMS as a probe, the physiologic mechanism of these effects is often assumed to be via changes in cortical excitability, with 10 Hz rTMS increasing and 1 Hz rTMS decreasing the excitability of the stimulated region. However, the reliability and reproducibility of these rTMS protocols on cortical excitability across and within individual subjects, particularly in comparison to robust sham stimulation, have not been systematically examined. OBJECTIVES: In a cohort of 28 subjects (39 ± 16 years), we report the first comprehensive study to (1) assess the neuromodulatory effects of traditional 1 Hz and 10 Hz rTMS on corticospinal excitability against both a robust sham control, and two other widely used patterned rTMS protocols (intermittent theta burst stimulation, iTBS; and continuous theta burst stimulation, cTBS), and (2) determine the reproducibility of all rTMS protocols across identical repeat sessions. RESULTS: At the group level, neither 1 Hz nor 10 Hz rTMS significantly modulated corticospinal excitability. 1 Hz and 10 Hz rTMS were also not significantly different from sham and both TBS protocols. Reproducibility was poor for all rTMS protocols except for sham. Importantly, none of the real rTMS and TBS protocols demonstrated greater neuromodulatory effects or reproducibility after controlling for potential experimental factors including baseline corticospinal excitability, TMS coil deviation and the number of individual MEP trials. CONCLUSIONS: These results call into question the effectiveness and reproducibility of widely used rTMS techniques for modulating corticospinal excitability, and suggest the need for a fundamental rethinking regarding the potential mechanisms by which rTMS affects brain function and behavior in humans.

Improving the study of brain-behavior relationships by revisiting basic assumptions.

Neuroimaging research has been at the forefront of concerns regarding the failure of experimental findings to replicate. In the study of brain-behavior relationships, past failures to find replicable and robust effects have been attributed to methodological shortcomings. Methodological rigor is important, but there are other overlooked possibilities: most published studies share three foundational assumptions, often implicitly, that may be faulty. In this paper, we consider the empirical evidence from human brain imaging and the study of non-human animals that calls each foundational assumption into question. We then consider the opportunities for a robust science of brain-behavior relationships that await if scientists ground their research efforts in revised assumptions supported by current empirical evidence.

UncertainSCI: Uncertainty quantification for computational models in biomedicine and bioengineering.

BACKGROUND: Computational biomedical simulations frequently contain parameters that model physical features, material coefficients, and physiological effects, whose values are typically assumed known a priori. Understanding the effect of variability in those assumed values is currently a topic of great interest. A general-purpose software tool that quantifies how variation in these parameters affects model outputs is not broadly available in biomedicine. For this reason, we developed the 'UncertainSCI' uncertainty quantification software suite to facilitate analysis of uncertainty due to parametric variability. METHODS: We developed and distributed a new open-source Python-based software tool, UncertainSCI, which employs advanced parameter sampling techniques to build polynomial chaos (PC) emulators that can be used to predict model outputs for general parameter values. Uncertainty of model outputs is studied by modeling parameters as random variables, and model output statistics and sensitivities are then easily computed from the emulator. Our approaches utilize modern, near-optimal techniques for sampling and PC construction based on weighted Fekete points constructed by subsampling from a suitably randomized candidate set. RESULTS: Concentrating on two test cases-modeling bioelectric potentials in the heart and electric stimulation in the brain-we illustrate the use of UncertainSCI to estimate variability, statistics, and sensitivities associated with multiple parameters in these models. CONCLUSION: UncertainSCI is a powerful yet lightweight tool enabling sophisticated probing of parametric variability and uncertainty in biomedical simulations. Its non-intrusive pipeline allows users to leverage existing software libraries and suites to accurately ascertain parametric uncertainty in a variety of applications.

Similarity of hand muscle synergies elicited by transcranial magnetic stimulation and those found during voluntary movement.

Converging evidence in human and animal models suggests that exogenous stimulation of the motor cortex (M1) elicits responses in the hand with similar modular structure to that found during voluntary grasping movements. The aim of this study was to establish the extent to which modularity in muscle responses to transcranial magnetic stimulation (TMS) to M1 resembles modularity in muscle activation during voluntary hand movements involving finger fractionation. Electromyography (EMG) was recorded from eight hand-forearm muscles in eight healthy individuals. Modularity was defined using non-negative matrix factorization to identify low-rank approximations (spatial muscle synergies) of the complex activation patterns of EMG data recorded during high-density TMS mapping of M1 and voluntary formation of gestures in the American Sign Language alphabet. Analysis of synergies revealed greater than chance similarity between those derived from TMS and those derived from voluntary movement. Both data sets included synergies dominated by single intrinsic hand muscles presumably to meet the demand for highly fractionated finger movement. These results suggest that corticospinal connectivity to individual intrinsic hand muscles may be combined with modular multimuscle activation via synergies in the formation of hand postures.NEW & NOTEWORTHY This is the first work to examine the similarity of modularity in hand muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex and that derived from voluntary hand movement. We show that TMS-elicited muscle synergies of the hand, measured at rest, reflect those found in voluntary behavior involving finger fractionation. This work provides a basis for future work using TMS to investigate muscle activation modularity in the human motor system.

Spatiotemporal approximation of cardiac activation and recovery isochrones.

BACKGROUND: The sequence of myocardial activation and recovery can be studied in detail by invasive catheter recordings of cardiac electrograms (EGMs), or noninvasive inverse reconstructions thereof with electrocardiographic imaging (ECGI). Local activation and recovery times are obtained from a unipolar EGM by the moment of maximum downslope of the QRS complex or maximum upslope of the T wave, respectively. However, both invasive and noninvasive recordings of intracardiac EGMs may suffer from noise and fractionation, making reliable detection of these deflections nontrivial. METHODS: Here, we introduce a novel method that benefits from the spatial coupling of these processes, and incorporate not only the temporal EGM deflection, but also the spatial gradients. We validated this approach in computer simulations, in animal data with ECGI and invasive electrode recordings, and illustrated its use in a clinical case. RESULTS: In the simulated data, the spatiotemporal approach was able to incorporate spatial information to better select the correct deflection in artificially fractionated EGMs and outperformed the traditional temporal-only method. In experimental data, the accuracy of time estimation from ECGI compared to invasive recordings significantly increased from R = 0.73 (activation) and R = 0.58 (recovery) with the temporal-only method to R = 0.79 (activation) and R = 0.72 (recovery) with the novel approach. Localization of the pacing origin of paced beats improved significantly from 36 mm mean error with the temporal-only approach to 23 mm with the spatiotemporal approach. CONCLUSION: The spatiotemporal method to compute activation and recovery times from EGMs outperformed the traditional temporal-only approach in which spatial information was not taken into account.

Reconstruction of cardiac position using body surface potentials.

Electrocardiographic imaging (ECGI) is a noninvasive technique to assess the bioelectric activity of the heart which has been applied to aid in clinical diagnosis and management of cardiac dysfunction. ECGI is built on mathematical models that take into account several patient specific factors including the position of the heart within the torso. Errors in the localization of the heart within the torso, as might arise due to natural changes in heart position from respiration or changes in body position, contribute to errors in ECGI reconstructions of the cardiac activity, thereby reducing the clinical utility of ECGI. In this study we present a novel method for the reconstruction of cardiac geometry utilizing noninvasively acquired body surface potential measurements. Our geometric correction method simultaneously estimates the cardiac position over a series of heartbeats by leveraging an iterative approach which alternates between estimating the cardiac bioelectric source across all heartbeats and then estimating cardiac positions for each heartbeat. We demonstrate that our geometric correction method is able to reduce geometric error and improve ECGI accuracy in a wide range of testing scenarios. We examine the performance of our geometric correction method using different activation sequences, ranges of cardiac motion, and body surface electrode configurations. We find that after geometric correction resulting ECGI solution accuracy is improved and variability of the ECGI solutions between heartbeats is substantially reduced.

CineECG: A novel method to image the average activation sequence in the heart from the 12-lead ECG.

The standard 12-lead electrocardiogram (ECG) is a diagnostic tool to asses cardiac electrical activity. The vectorcardiogram is a related tool that represents that activity as the direction of a vector. In this work we investigate CineECG, a new 12-lead ECG based analysis method designed to directly estimate the average cardiac anatomical location of activation over time. We describe CineECG calculation and a novel comparison parameter, the average isochrone position (AIP). In a model study, fourteen different activation sequences were simulated and corresponding 12-lead ECGs were computed. The CineECG was compared to AIP in terms of location and direction. In addition, 67-lead body surface potential maps from ten patients were used to study the sensitivity of CineECG to electrode mispositioning and anatomical model selection. Epicardial activation maps from four patients were used for further evaluation. The average distance between CineECG and AIP across the fourteen sequences was 23.7 ± 2.4 mm, with significantly better agreement in the terminal (27.3 ± 5.7 mm) versus the initial QRS segment (34.2 ± 6.1 mm). Up to four cm variation in electrode positioning produced an average distance of 6.5 ± 4.5 mm between CineECG trajectories, while substituting a generic heart/torso model for a patient-specific one produced an average difference of 6.1 ± 4.8 mm. Dominant epicardial activation map features were recovered. Qualitatively, CineECG captured significant features of activation sequences and was robust to electrode misplacement. CineECG provides a realistic representation of the average cardiac activation in normal and diseased hearts. In particular, the terminal segment of the CineECG might be useful to detect pathology.

Effect of Segmentation Uncertainty on the ECGI Inverse Problem Solution and Source Localization.

Electrocardiographic Imaging (ECGI) is a promising tool to non-invasively map the electrical activity of the heart using body surface potentials (BSPs) and the patient specific anatomical data. One of the first steps of ECGI is the segmentation of the heart and torso geometries. In the clinical practice, the segmentation procedure is not fully-automated yet and is in consequence operator-dependent. We expect that the inter-operator variation in cardiac segmentation would influence the ECGI solution. This effect remains however non quantified. In the present work, we study the effect of segmentation variability on the ECGI estimation of the cardiac activity with 262 shape models generated from fifteen different segmentations. Therefore, we designed two test cases: with and without shape model uncertainty. Moreover, we used four cases for ectopic ventricular excitation and compared the ECGI results in terms of reconstructed activation times and excitation origins. The preliminary results indicate that a small variation of the activation maps can be observed with a model uncertainty but no significant effect on the source localization is observed.

The Effect of Segmentation Variability in Forward ECG Simulation.

Segmentation of patient-specific anatomical models is one of the first steps in Electrocardiographic imaging (ECGI). However, the effect of segmentation variability on ECGI remains unexplored. In this study, we assess the effect of heart segmentation variability on ECG simulation. We generated a statistical shape model from segmentations of the same patient and generated 262 cardiac geometries to run in an ECG forward computation of body surface potentials (BSPs) using an equivalent dipole layer cardiac source model and 5 ventricular stimulation protocols. Variability between simulated BSPs for all models and protocols was assessed using Pearson's correlation coefficient (CC). Compared to the BSPs of the mean cardiac shape model, the lowest variability (average CC = 0.98 ± 0.03) was found for apical pacing whereas the highest variability (average CC = 0.90 ± 0.23) was found for right ventricular free wall pacing. Furthermore, low amplitude BSPs show a larger variation in QRS morphology compared to high amplitude signals. The results indicate that the uncertainty in cardiac shape has a significant impact on ECGI.

Reducing Line-of-Block Artifacts in Cardiac Activation Maps Estimated Using ECG Imaging: A Comparison of Source Models and Estimation Methods.

OBJECTIVE: To investigatecardiac activation maps estimated using electrocardiographic imaging and to find methods reducing line-of-block (LoB) artifacts, while preserving real LoBs. METHODS: Body surface potentials were computed for 137 simulated ventricular excitations. Subsequently, the inverse problem was solved to obtain extracellular potentials (EP) and transmembrane voltages (TMV). From these, activation times (AT) were estimated using four methods and compared to the ground truth. This process was evaluated with two cardiac mesh resolutions. Factors contributing to LoB artifacts were identified by analyzing the impact of spatial and temporal smoothing on the morphology of source signals. RESULTS: AT estimation using a spatiotemporal derivative performed better than using a temporal derivative. Compared to deflection-based AT estimation, correlation-based methods were less prone to LoB artifacts but performed worse in identifying real LoBs. Temporal smoothing could eliminate artifacts for TMVs but not for EPs, which could be linked to their temporal morphology. TMVs led to more accurate ATs on the septum than EPs. Mesh resolution had anegligible effect on inverse reconstructions, but small distances were important for cross-correlation-based estimation of AT delays. CONCLUSION: LoB artifacts are mainly caused by the inherent spatial smoothing effect of the inverse reconstruction. Among the configurations evaluated, only deflection-based AT estimation in combination with TMVs and strong temporal smoothing can prevent LoB artifacts, while preserving real LoBs. SIGNIFICANCE: Regions of slow conduction are of considerable clinical interest and LoB artifacts observed in non-invasive ATs can lead to misinterpretations. We addressed this problem by identifying factors causing such artifacts.

Interoception as modeling, allostasis as control.

The brain regulates the body by anticipating its needs and attempting to meet them before they arise - a process called allostasis. Allostasis requires a model of the changing sensory conditions within the body, a process called interoception. In this paper, we examine how interoception may provide performance feedback for allostasis. We suggest studying allostasis in terms of control theory, reviewing control theory's applications to related issues in physiology, motor control, and decision making. We synthesize these by relating them to the important properties of allostatic regulation as a control problem. We then sketch a novel formalism for how the brain might perform allostatic control of the viscera by analogy to skeletomotor control, including a mathematical view on how interoception acts as performance feedback for allostasis. Finally, we suggest ways to test implications of our hypotheses.

Variation is the Norm: Brain State Dynamics Evoked By Emotional Video Clips.

For the last several decades, emotion research has attempted to identify a "biomarker" or consistent pattern of brain activity to characterize a single category of emotion (e.g., fear) that will remain consistent across all instances of that category, regardless of individual and context. In this study, we investigated variation rather than consistency during emotional experiences while people watched video clips chosen to evoke instances of specific emotion categories. Specifically, we developed a sequential probabilistic approach to model the temporal dynamics in a participant's brain activity during video viewing. We characterized brain states during these clips as distinct state occupancy periods between state transitions in blood oxygen level dependent (BOLD) signal patterns. We found substantial variation in the state occupancy probability distributions across individuals watching the same video, supporting the hypothesis that when it comes to the brain correlates of emotional experience, variation may indeed be the norm.

Validating Patient-Specific Finite Element Models of Direct Electrocortical Stimulation.

Direct electrocortical stimulation (DECS) with electrocorticography electrodes is an established therapy for epilepsy and an emerging application for stroke rehabilitation and brain-computer interfaces. However, the electrophysiological mechanisms that result in a therapeutic effect remain unclear. Patient-specific computational models are promising tools to predict the voltages in the brain and better understand the neural and clinical response to DECS, but the accuracy of such models has not been directly validated in humans. A key hurdle to modeling DECS is accurately locating the electrodes on the cortical surface due to brain shift after electrode implantation. Despite the inherent uncertainty introduced by brain shift, the effects of electrode localization parameters have not been investigated. The goal of this study was to validate patient-specific computational models of DECS against in vivo voltage recordings obtained during DECS and quantify the effects of electrode localization parameters on simulated voltages on the cortical surface. We measured intracranial voltages in six epilepsy patients during DECS and investigated the following electrode localization parameters: principal axis, Hermes, and Dykstra electrode projection methods combined with 0, 1, and 2 mm of cerebral spinal fluid (CSF) below the electrodes. Greater CSF depth between the electrode and cortical surface increased model errors and decreased predicted voltage accuracy. The electrode localization parameters that best estimated the recorded voltages across six patients with varying amounts of brain shift were the Hermes projection method and a CSF depth of 0 mm (r = 0.92 and linear regression slope = 1.21). These results are the first to quantify the effects of electrode localization parameters with in vivo intracranial recordings and may serve as the basis for future studies investigating the neuronal and clinical effects of DECS for epilepsy, stroke, and other emerging closed-loop applications.

Simultaneous Multi-Heartbeat ECGI Solution with a Time-Varying Forward Model: a Joint Inverse Formulation.

Electrocardiographic imaging (ECGI) is an effective tool for noninvasive diagnosis of a range of cardiac dysfunctions. ECGI leverages a model of how cardiac bioelectric sources appear on the torso surface (the forward problem) and uses recorded body surface potential signals to reconstruct the bioelectric source (the inverse problem). Solutions to the inverse problem are sensitive to noise and variations in the body surface potential (BSP) recordings such as those caused by changes or errors in cardiac position. Techniques such as signal averaging seek to improve ECGI solutions by incorporating BSP signals from multiple heartbeats into an averaged BSP with a higher SNR to use when estimating the cardiac bioelectric source. However, signal averaging is limited when it comes to addressing sources of BSP variability such as beat to beat differences in the forward solution. We present a novel joint inverse formulation to solve for the cardiac source given multiple BSP recordings and known changes in the forward solution, here changes in the heart position. We report improved ECGI accuracy over signal averaging and averaged individual inverse solutions using this joint inverse formulation across multiple activation sequence types and regularization techniques with measured canine data and simulated heart motion. Our joint inverse formulation builds upon established techniques and consequently can easily be applied with many existing regularization techniques, source models, and forward problem formulations.

Efficient TMS-Based Motor Cortex Mapping Using Gaussian Process Active Learning.

Transcranial Magnetic Stimulation (TMS) can be used to map cortical motor topography by spatially sampling the sensorimotor cortex while recording Motor Evoked Potentials (MEP) with surface electromyography (EMG). Traditional sampling strategies are time-consuming and inefficient, as they ignore the fact that responsive sites are typically sparse and highly spatially correlated. An alternative approach, commonly employed when TMS mapping is used for presurgical planning, is to leverage the expertise of the coil operator to use MEPs elicited by previous stimuli as feedback to decide which loci to stimulate next. In this paper, we propose to automatically infer optimal future stimulus loci using active learning Gaussian Process-based sampling in place of user expertise. We first compare the user-guided (USRG) method to the traditional grid selection method and randomized sampling to verify that the USRG approach has superior performance. We then compare several novel active Gaussian Process (GP) strategies with the USRG approach. Experimental results using real data show that, as expected, the USRG method is superior to the grid and random approach in both time efficiency and MEP map accuracy. We also found that an active warped GP entropy and a GP random-based strategy performed equally as well as, or even better than, the USRG method. These methods were completely automatic, and succeeded in efficiently sampling the regions in which the MEP response variations are largely confined. This work provides the foundation for highly efficient, fully automatized TMS mapping, especially when considered in the context of advances in robotic coil operation.

Skin strata delineation in reflectance confocal microscopy images using recurrent convolutional networks with attention.

Reflectance confocal microscopy (RCM) is an effective non-invasive tool for cancer diagnosis. However, acquiring and reading RCM images requires extensive training and experience, and novice clinicians exhibit high discordance in diagnostic accuracy. Quantitative tools to standardize image acquisition could reduce both required training and diagnostic variability. To perform diagnostic analysis, clinicians collect a set of RCM mosaics (RCM images concatenated in a raster fashion to extend the field view) at 4-5 specific layers in skin, all localized in the junction between the epidermal and dermal layers (dermal-epidermal junction, DEJ), necessitating locating that junction before mosaic acquisition. In this study, we automate DEJ localization using deep recurrent convolutional neural networks to delineate skin strata in stacks of RCM images collected at consecutive depths. Success will guide to automated and quantitative mosaic acquisition thus reducing inter operator variability and bring standardization in imaging. Testing our model against an expert labeled dataset of 504 RCM stacks, we achieved [Formula: see text] classification accuracy and nine-fold reduction in the number of anatomically impossible errors compared to the previous state-of-the-art.

Semantic segmentation of reflectance confocal microscopy mosaics of pigmented lesions using weak labels.

Reflectance confocal microscopy (RCM) is a non-invasive imaging tool that reduces the need for invasive histopathology for skin cancer diagnoses by providing high-resolution mosaics showing the architectural patterns of skin, which are used to identify malignancies in-vivo. RCM mosaics are similar to dermatopathology sections, both requiring extensive training to interpret. However, these modalities differ in orientation, as RCM mosaics are horizontal (parallel to the skin surface) while histopathology sections are vertical, and contrast mechanism, RCM with a single (reflectance) mechanism resulting in grayscale images and histopathology with multi-factor color-stained contrast. Image analysis and machine learning methods can potentially provide a diagnostic aid to clinicians to interpret RCM mosaics, eventually helping to ease the adoption and more efficiently utilizing RCM in routine clinical practice. However standard supervised machine learning may require a prohibitive volume of hand-labeled training data. In this paper, we present a weakly supervised machine learning model to perform semantic segmentation of architectural patterns encountered in RCM mosaics. Unlike more widely used fully supervised segmentation models that require pixel-level annotations, which are very labor-demanding and error-prone to obtain, here we focus on training models using only patch-level labels (e.g. a single field of view within an entire mosaic). We segment RCM mosaics into "benign" and "aspecific (nonspecific)" regions, where aspecific regions represent the loss of regular architecture due to injury and/or inflammation, pre-malignancy, or malignancy. We adopt Efficientnet, a deep neural network (DNN) proven to accurately accomplish classification tasks, to generate class activation maps, and use a Gaussian weighting kernel to stitch smaller images back into larger fields of view. The trained DNN achieved an average area under the curve of 0.969, and Dice coefficient of 0.778 showing the feasibility of spatial localization of aspecific regions in RCM images, and making the diagnostics decision model more interpretable to the clinicians.