M. Cluitmans, D. H. Brooks, R. MacLeod, O. Dössel, M. S. Guillem, P. M. van Dam, J. Svehlikova, B. He, J. Sapp, L. Wang, L. Bear.
Validation and Opportunities of Electrocardiographic Imaging: From Technical Achievements to Clinical Applications, In Frontiers in Physiology, Vol. 9, Frontiers Media SA, pp. 1305. 2018.
Electrocardiographic imaging (ECGI) reconstructs the electrical activity of the heart from a dense array of body-surface electrocardiograms and a patient-specific heart-torso geometry. Depending on how it is formulated, ECGI allows the reconstruction of the activation and recovery sequence of the heart, the origin of premature beats or tachycardia, the anchors/hotspots of re-entrant arrhythmias and other electrophysiological quantities of interest. Importantly, these quantities are directly and noninvasively reconstructed in a digitized model of the patient’s three-dimensional heart, which has led to clinical interest in ECGI’s ability to personalize diagnosis and guide therapy.
Despite considerable development over the last decades, validation of ECGI is challenging. Firstly, results depend considerably on implementation choices, which are necessary to deal with ECGI’s ill-posed character. Secondly, it is challenging to obtain (invasive) ground truth data of high quality. In this review, we discuss the current status of ECGI validation as well as the major challenges remaining for complete adoption of ECGI in clinical practice.
Specifically, showing clinical benefit is essential for the adoption of ECGI. Such benefit may lie in patient outcome improvement, workflow improvement, or cost reduction. Future studies should focus on these aspects to achieve broad adoption of ECGI, but only after the technical challenges have been solved for that specific application/pathology. We propose ‘best’ practices for technical validation and highlight collaborative efforts recently organized in this field. Continued interaction between engineers, basic scientists and physicians remains essential to find a hybrid between technical achievements, pathological mechanisms insights, and clinical benefit, to evolve this powerful technique towards a useful role in clinical practice.
Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models, In Journal of Visualized Experiments, No. 138, MyJove Corporation, Aug, 2018.
Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for movement disorders and is being applied to a growing number of disorders. Computational modeling has been successfully used to predict the clinical effects of DBS; however, there is a need for novel modeling techniques to keep pace with the growing complexity of DBS devices. These models also need to generate predictions quickly and accurately. The goal of this project is to develop an image processing pipeline to incorporate structural magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) into an interactive, patient specific model to simulate the effects of DBS. A virtual DBS lead can be placed inside of the patient model, along with active contacts and stimulation settings, where changes in lead position or orientation generate a new finite element mesh and solution of the bioelectric field problem in near real-time, a timespan of approximately 10 seconds. This system also enables the simulation of multiple leads in close proximity to allow for current steering by varying anodes and cathodes on different leads. The techniques presented in this paper reduce the burden of generating and using computational models while providing meaningful feedback about the effects of electrode position, electrode design, and stimulation configurations to researchers or clinicians who may not be modeling experts.
Traumatic brain injury (TBI) is a looming epidemic, growing most rapidly in the elderly population. Some of the most devastating sequelae of TBI are related to depressed levels of consciousness (e.g., coma, minimally conscious state) or deficits in executive function. To date, pharmacological and rehabilitative therapies to treat these sequelae are limited. Deep brain stimulation (DBS) has been used to treat a number of pathologies, including Parkinson disease, essential tremor, and epilepsy. Animal and clinical research shows that targets addressing depressed levels of consciousness include components of the ascending reticular activating system and areas of the thalamus. Targets for improving executive function are more varied and include areas that modulate attention and memory, such as the frontal and prefrontal cortex, fornix, nucleus accumbens, internal capsule, thalamus, and some brainstem nuclei. The authors review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients, while also offering suggestions on directions for future research.
Personalized virtual-heart technology for guiding the ablation of infarct-related ventricular tachycardia, In Nature Biomedical Engineering, Springer Nature America, Inc, September, 2018.
Ventricular tachycardia (VT), which can lead to sudden cardiac death, occurs frequently in patients with myocardial infarction. Catheter-based radio-frequency ablation of cardiac tissue has achieved only modest efficacy, owing to the inaccurate identification of ablation targets by current electrical mapping techniques, which can lead to extensive lesions and to a prolonged, poorly tolerated procedure. Here, we show that personalized virtual-heart technology based on cardiac imaging and computational modelling can identify optimal infarct-related VT ablation targets in retrospective animal (five swine) and human studies (21 patients), as well as in a prospective feasibility study (five patients). We first assessed, using retrospective studies (one of which included a proportion of clinical images with artefacts), the capability of the technology to determine the minimum-size ablation targets for eradicating all VTs. In the prospective study, VT sites predicted by the technology were targeted directly, without relying on prior electrical mapping. The approach could improve infarct-related VT ablation guidance, where accurate identification of patient-specific optimal targets could be achieved on a personalized virtual heart before the clinical procedure.
A. Rodenhauser, W.W. Good, B. Zenger, J. Tate, K. Aras, B. Burton, R.S. Macleod.
PFEIFER: Preprocessing Framework for Electrograms Intermittently Fiducialized from Experimental Recordings, In The Journal of Open Source Software, Vol. 3, No. 21, The Open Journal, pp. 472. Jan, 2018.
Preprocessing Framework for Electrograms Intermittently Fiducialized from Experimental Recordings (PFEIFER) is a MATLAB Graphical User Interface designed to process bioelectric signals acquired from experiments.
PFEIFER was specifically designed to process electrocardiographic recordings from electrodes placed on or around the heart or on the body surface. Specific steps included in PFEIFER allow the user to remove some forms of noise, correct for signal drift, and mark specific instants or intervals in time (fiducialize) within all of the time sampled channels. PFEIFER includes many unique features that allow the user to process electrical signals in a consistent and time efficient manner, with additional options for advanced user configurations and input. PFEIFER is structured as a consolidated framework that provides many standard processing pipelines but also has flexibility to allow the user to customize many of the steps. PFEIFER allows the user to import time aligned cardiac electrical signals, semi-automatically determine fiducial markings from those signals, and perform computational tasks that prepare the signals for subsequent display and analysis.
S. Thomas, J. Silvernagel, N. Angel, E. Kholmovski, E. Ghafoori, N. Hu, J. Ashton, D.J. Dosdall, R.S. MacLeod, R. Ranjan.
Higher contact force during radiofrequency ablation leads to a much larger increase in edema as compared to chronic lesion size, In Journal of Cardiovascular Electrophysiology, Wiley, June, 2018.
Reversible edema is a part of any radiofrequency ablation but its relationship with contact force is unknown. The goal of this study was to characterize through histology and MRI, acute and chronic ablation lesions and reversible edema with contact force.
2 Methods and results
In a canine model (n = 14), chronic ventricular lesions were created with a 3.5‐mm tip ThermoCool SmartTouch (Biosense Webster) catheter at 25 W or 40 W for 30 seconds. Repeat ablation was performed after 3 months to create a second set of lesions (acute). Each ablation procedure was followed by in vivo T2‐weighted MRI for edema and late‐gadolinium enhancement (LGE) MRI for lesion characterization. For chronic lesions, the mean scar volumes at 25 W and 40 W were 77.8 ± 34.5 mm3 (n = 24) and 139.1 ± 69.7 mm3 (n = 12), respectively. The volume of chronic lesions increased (25 W: P < 0.001, 40 W: P < 0.001) with greater contact force. For acute lesions, the mean volumes of the lesion were 286.0 ± 129.8 mm3 (n = 19) and 422.1 ± 113.1 mm3 (n = 16) for 25 W and 40 W, respectively (P < 0.001 compared to chronic scar). On T2‐weighted MRI, the acute edema volume was on average 5.6–8.7 times higher than the acute lesion volume and increased with contact force (25 W: P = 0.001, 40 W: P = 0.011).
With increasing contact force, there is a marginal increase in lesion size but accompanied with a significantly larger edema. The reversible edema that is much larger than the chronic lesion volume may explain some of the chronic procedure failures.
Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia. Current treatments for AF remain suboptimal due to a lack of understanding of the underlying atrial structures that directly sustain AF. Existing approaches for analyzing atrial structures in 3D, especially from late gadolinium-enhanced (LGE)-MRIs, rely heavily on manual segmentation methods which are extremely labor-intensive and prone to errors. As a result, a robust and automated method for analyzing atrial structures in 3D is of high interest. We have therefore developed AtriaNet, a 16-layer convolutional neural network (CNN), on 154 3D LGE-MRIs with a spatial resolution of 0.625 mm × 0.625 mm × 1.25 mm from patients with AF, to automatically segment the left atrial (LA) epicardium and endocardium. AtriaNet consists of a multi-scaled, dual pathway architecture that captures both the local atrial tissue geometry, and the global positional information of LA using 13 successive convolutions, and 3 further convolutions for merging. By utilizing computationally efficient batch prediction, AtriaNet was able to successfully process each 3D LGE-MRI within one minute. Furthermore, benchmarking experiments showed that AtriaNet outperformed state-of-the-art CNNs, with a DICE score of 0.940 and 0.942 for the LA epicardium and endocardium respectively, and an inter-patient variance of <0.001. The estimated LA diameter and volume computed from the automatic segmentations were accurate to within 1.59 mm and 4.01 cm³ of the ground truths. Our proposed CNN was tested on the largest known dataset for LA segmentation, and to the best of our knowledge, it is the most robust approach that has ever been developed for segmenting LGE-MRIs. The increased accuracy of atrial reconstruction and analysis could potentially improve the understanding and treatment of AF.
We compared the cranial base of newborn Pax7-deficient and wildtype mice using a computational shape modeling technology called particle-based modeling (PBM). We found systematic differences in the morphology of the basiooccipital bone, including a broadening of the basioccipital bone and an antero-inferior inflection of its posterior edge in the Pax7-deficient mice. We show that the Pax7 cell lineage contributes to the basioccipital bone and that the location of the Pax7 lineage correlates with the morphology most effected by Pax7 deficiency. Our results suggest that the Pax7-deficient mouse may be a suitable model for investigating the genetic control of the location and orientation of the foramen magnum, and changes in the breadth of the basioccipital.
J. Coll-Font, S. Ariafar, D. H Brooks. ECG-Based Reconstruction of Heart Position and Orientation with Bayesian Optimization, In Computing in Cardiology, Vol. 44, 2017.
Respiratory motion is known to cause beat-to-beat variation of the ECG. This observation suggests that it may be possible to use this variation to track position and orientation of the heart. Electrocardiographic Imaging (ECGI) would benefit from such a reconstruction since one contribution to errors in its solutions is respiratory motion of the heart. ECGI solutions generally rely on prior computation of a "forward" model that relates cardiac electrical activity to ECGs. However, the ill-posed nature of the inverse solution leads to large errors in ECGI even for small amounts of error in the forward model. The current work is a first step towards reducing those errors using a nominal forward model and the ECG itself. We describe a method that can reconstruct cardiac position / orientation using known potentials on both the heart and torso. Our current implementation is based on Bayesian Optimization and efficiently optimizes for the position / orientation of the heart to minimize error between measured and forward-computed torso potentials. We evaluated our approach with synthesized torso potentials under a model of respiratory motion and also using potentials recorded in a tank experiment on a canine epicardium and the tank surfaces. Our results show that our method performs accurately in synthetic experiments and can account for part of the error between forward-computed and measured ECGs in the tank experiments.
Background Magnetic resonance imaging (MRI) has been used to acutely visualize radiofrequency ablation lesions, but its accuracy in predicting chronic lesion size is unknown. The main goal of this study was to characterize different areas of enhancement in late gadolinium enhancement MRI done immediately after ablation to predict acute edema and chronic lesion size.
Methods and Results In a canine model (n=10), ventricular radiofrequency lesions were created using ThermoCool SmartTouch (Biosense Webster) catheter. All animals underwent MRI (late gadolinium enhancement and T2-weighted edema imaging) immediately after ablation and after 1, 2, 4, and 8 weeks. Edema, microvascular obstruction, and enhanced volumes were identified in MRI and normalized to chronic histological volume. Immediately after contrast administration, the microvascular obstruction region was 3.2±1.1 times larger than the chronic lesion volume in acute MRI. Even 60 minutes after contrast administration, edema was 8.7±3.31 times and the enhanced area 6.14±2.74 times the chronic lesion volume. Exponential fit to the microvascular obstruction volume was found to be the best predictor of chronic lesion volume at 26.14 minutes (95% prediction interval, 24.35–28.11 minutes) after contrast injection. The edema volume in late gadolinium enhancement correlated well with edema volume in T2-weighted MRI with an R2 of 0.99.
Conclusion Microvascular obstruction region on acute late gadolinium enhancement images acquired 26.1 minutes after contrast administration can accurately predict the chronic lesion volume. We also show that T1-weighted MRI images acquired immediately after contrast injection accurately shows edema resulting from radiofrequency ablation.
S. Ghimire, J. Dhamala, J. Coll-Font, J. D. Tate, M. S. Guillem, D. H. Brooks, R. S. MacLeod, L. Wang. Overcoming Barriers to Quantification and Comparison of Electrocardiographic Imaging Methods: A Community-Based Approach, In Computing in Cardiology, Vol. 44, 2017.
There has been a recent upsurge in the development of electrocardiographic imaging (ECGI) methods, along with a significant increase in clinical application. To better assess the state-of-the-art, enable reliable progress, and facilitate clinical adoption, it is important to be able to compare results in a comprehensive manner, scientifically and clinically. However, studies vary in modeling choices, computational methods, validation mechanisms and metrics, and clinical applications, making unified evaluation and comparison of ECGI a critical challenge.
This paper describes initial results of a project to address this challenge via a community-based approach organized by the Consortium for Electrocardiographic Imaging (CEI). We detail different aspects of this collective effort including a data sharing repository, a platform for comparison of different algorithms and modeling approaches on the same datasets, several active workgroups and progress made along these directions. We also summarize the results from groups participating in this collaboration and contributing solutions by applying their methods to the same dataset for comparison.
W. W. Good, B. Erem, J. Coll-Font, D. H. Brooks, R. S. MacLeod. Detecting Ischemic Stress to the Myocardium Using Laplacian Eigenmaps and Changes to Conduction Velocity, In Computing in Cardiology, Vol. 44, IEEE, 2017.
The underlying pathophysiology of ischemia and its electrocardiographic consequences are poorly understood, resulting in unreliable diagnosis of this disease. This limited knowledge of underlying mechanisms suggests a data driven approach, which seeks to identify patterns in the ECG that can be linked statistically to underlying behavior and conditions of ischemic stress. The gold standard ECG metrics for evaluating ischemia monitor vertical deflections within the ST segment. However, ischemia influences all portions of the electrogram. Another metric that targets the QRS complex during ischemia is Conduction Velocity (CV). An even more inclusive, data driven approach is known as "Laplacian Eigenmaps" (LE), which can identify trajectories, or "manifolds", that respond to different spatiotemporal consequences of ischemic stress, and these changes to the trajectories on the manifold may serve as a clinically relevant biomarker. On this study, we compared the LE- and CV-based markers against two gold standards for detecting ischemic stress, both derived from the ST segment. We evaluated the response time and fidelity of each biomarker using a Time to Threshold (TTT) and Contrast Ratio (CR) measure, over 51 episodes recorded as cardiac electrograms from a canine model of controlled ischemia. The results show that metrics designed to monitor regions beyond the ST segment can perform at least as well, if not better, than traditional ST segment based metrics.
M. Kern, A. Lex, N. Gehlenborg, C. R. Johnson.
Interactive Visual Exploration And Refinement Of Cluster Assignments, In BMC Bioinformatics, Cold Spring Harbor Laboratory, April, 2017.
With ever-increasing amounts of data produced in biology research, scientists are in need of efficient data analysis methods. Cluster analysis, combined with visualization of the results, is one such method that can be used to make sense of large data volumes. At the same time, cluster analysis is known to be imperfect and depends on the choice of algorithms, parameters, and distance measures. Most clustering algorithms don't properly account for ambiguity in the source data, as records are often assigned to discrete clusters, even if an assignment is unclear. While there are metrics and visualization techniques that allow analysts to compare clusterings or to judge cluster quality, there is no comprehensive method that allows analysts to evaluate, compare, and refine cluster assignments based on the source data, derived scores, and contextual data.
In this paper, we introduce a method that explicitly visualizes the quality of cluster assignments, allows comparisons of clustering results and enables analysts to manually curate and refine cluster assignments. Our methods are applicable to matrix data clustered with partitional, hierarchical, and fuzzy clustering algorithms. Furthermore, we enable analysts to explore clustering results in context of other data, for example, to observe whether a clustering of genomic data results in a meaningful differentiation in phenotypes.
Our methods are integrated into Caleydo StratomeX, a popular, web-based, disease subtype analysis tool. We show in a usage scenario that our approach can reveal ambiguities in cluster assignments and produce improved clusterings that better differentiate genotypes and phenotypes.
J. Tate, K. Gillette, B. Burton, W. Good, J. Coll-Font, D. Brooks, R. MacLeod. Analyzing Source Sampling to Reduce Error in ECG Forward Simulations, In Computing in Cardiology, Vol. 44, 2017.
A continuing challenge in validating ECG Imaging is the persistent error in the associated forward problem observed in experimental studies. One possible cause of error is insufficient representation of the cardiac sources, which is often measured from only the ventricular epicardium, ignoring the endocardium and the atria. We hypothesize that measurements that completely cover the heart are required for accurate forward solutions. In this study, we used simulated and measured cardiac potentials to test the effect of different levels of sampling on the forward simulation. We found that omitting source samples on the atria increases the peak RMS error by a mean of 464 μV when compared the the fully sampled cardiac surface. Increasing the sampling on the atria in stages reduced the average error of the forward simulation proportionally to the number of additional samples and revealed some strategies may reduce error with fewer samples, such as adding samples to the AV plane and the atrial roof. Based on these results, we can design a sampling strategy to use in future validation studies.
Y. Wan, C. Hansen. Uncertainty Footprint: Visualization of Nonuniform Behavior of Iterative Algorithms Applied to 4D Cell Tracking, In Computer Graphics Forum, Wiley, 2017.
Research on microscopy data from developing biological samples usually requires tracking individual cells over time. When cells are three-dimensionally and densely packed in a time-dependent scan of volumes, tracking results can become unreliable and uncertain. Not only are cell segmentation results often inaccurate to start with, but it also lacks a simple method to evaluate the tracking outcome. Previous cell tracking methods have been validated against benchmark data from real scans or artificial data, whose ground truth results are established by manual work or simulation. However, the wide variety of real-world data makes an exhaustive validation impossible. Established cell tracking tools often fail on new data, whose issues are also difficult to diagnose with only manual examinations. Therefore, data-independent tracking evaluation methods are desired for an explosion of microscopy data with increasing scale and resolution. In this paper, we propose the uncertainty footprint, an uncertainty quantification and visualization technique that examines nonuniformity at local convergence for an iterative evaluation process on a spatial domain supported by partially overlapping bases. We demonstrate that the patterns revealed by the uncertainty footprint indicate data processing quality in two algorithms from a typical cell tracking workflow – cell identification and association. A detailed analysis of the patterns further allows us to diagnose issues and design methods for improvements. A 4D cell tracking workflow equipped with the uncertainty footprint is capable of self diagnosis and correction for a higher accuracy than previous methods whose evaluation is limited by manual examinations.
Image segmentation and registration techniques have enabled biologists to place large amounts of volume data from fluorescence microscopy, morphed three-dimensionally, onto a common spatial frame. Existing tools built on volume visualization pipelines for single channel or red-green-blue (RGB) channels have become inadequate for the new challenges of fluorescence microscopy. For a three-dimensional atlas of the insect nervous system, hundreds of volume channels are rendered simultaneously, whereas fluorescence intensity values from each channel need to be preserved for versatile adjustment and analysis. Although several existing tools have incorporated support of multichannel data using various strategies, the lack of a flexible design has made true many-channel visualization and analysis unavailable. The most common practice for many-channel volume data presentation is still converting and rendering pseudosurfaces, which are inaccurate for both qualitative and quantitative evaluations.
Here, we present an alternative design strategy that accommodates the visualization and analysis of about 100 volume channels, each of which can be interactively adjusted, selected, and segmented using freehand tools. Our multichannel visualization includes a multilevel streaming pipeline plus a triple-buffer compositing technique. Our method also preserves original fluorescence intensity values on graphics hardware, a crucial feature that allows graphics-processing-unit (GPU)-based processing for interactive data analysis, such as freehand segmentation. We have implemented the design strategies as a thorough restructuring of our original tool, FluoRender.
The redesign of FluoRender not only maintains the existing multichannel capabilities for a greatly extended number of volume channels, but also enables new analysis functions for many-channel data from emerging biomedical-imaging techniques.
K. Aras B. Burton, D. Swenson, R.S. MacLeod. Spatial organization of acute myocardial ischemia, In Journal of Electrocardiology, Vol. 49, No. 3, Elsevier, pp. 323–336. May, 2016.
Myocardial ischemia is a pathological condition initiated by supply and demand imbalance of the blood to the heart. Previous studies suggest that ischemia originates in the subendocardium, i.e., that nontransmural ischemia is limited to the subendocardium. By contrast, we hypothesized that acute myocardial ischemia is not limited to the subendocardium and sought to document its spatial distribution in an animal preparation. The goal of these experiments was to investigate the spatial organization of ischemia and its relationship to the resulting shifts in ST segment potentials during short episodes of acute ischemia.
We conducted acute ischemia studies in open-chest canines (N = 19) and swines (N = 10), which entailed creating carefully controlled ischemia using demand, supply or complete occlusion ischemia protocols and recording intramyocardial and epicardial potentials. Elevation of the potentials at 40% of the ST segment between the J-point and the peak of the T-wave (ST40%) provided the metric for local ischemia. The threshold for ischemic ST segment elevations was defined as two standard deviations away from the baseline values.
The relative frequency of occurrence of acute ischemia was higher in the subendocardium (78% for canines and 94% for swines) and the mid-wall (87% for canines and 97% for swines) in comparison with the subepicardium (30% for canines and 22% for swines). In addition, acute ischemia was seen arising throughout the myocardium (distributed pattern) in 87% of the canine and 94% of the swine episodes. Alternately, acute ischemia was seen originating only in the subendocardium (subendocardial pattern) in 13% of the canine episodes and 6% of the swine episodes (p < 0.05).
Our findings suggest that the spatial distribution of acute ischemia is a complex phenomenon arising throughout the myocardial wall and is not limited to the subendocardium.
P.R. Atkins, S.Y. Elhabian, P. Agrawal, M.D. Harris, R.T. Whitaker, J.A. Weiss, C.L. Peters, A.E. Anderson.
Quantitative comparison of cortical bone thickness using correspondence-based shape modeling in patients with cam femoroacetabular impingement, In Journal of Orthopaedic Research, Wiley-Blackwell, Nov, 2016.
The proximal femur is abnormally shaped in patients with cam-type femoroacetabular impingement (FAI). Impingement
may elicit bone remodeling at the proximal femur, causing increases in cortical bone thickness. We used correspondence-based shape modeling to quantify and compare cortical thickness between cam patients and controls for the location of the cam lesion and the proximal femur. Computed tomography images were segmented for 45 controls and 28 cam-type FAI patients. The segmentations were input to a correspondence-based shape model to identify the region of the cam lesion. Median cortical thickness data over the region of the cam lesion and the proximal femur were compared between mixed-gender and gender-speciﬁc groups. Median [interquartile range] thickness was signiﬁcantly greater in FAI patients than controls in the cam lesion (1.47 [0.64] vs. 1.13 [0.22] mm, respectively; p < 0.001) and proximal femur (1.28 [0.30] vs. 0.97 [0.22] mm, respectively; p < 0.001). Maximum thickness in the region of the cam lesion was more anterior and less lateral (p < 0.001) in FAI patients. Male FAI patients had increased thickness compared to male controls in the cam lesion (1.47 [0.72] vs. 1.10 [0.19] mm, respectively; p < 0.001) and proximal femur (1.25 [0.29] vs. 0.94 [0.17] mm, respectively; p < 0.001). Thickness was not signiﬁcantly different between male and female controls. Clinical signiﬁcance: Studies of non-pathologic cadavers have provided guidelines regarding safe surgical resection depth for FAI patients. However, our results suggest impingement induces cortical thickening in cam patients, which may strengthen the proximal femur. Thus, these previously established guidelines may be too conservative.
The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.
Probabilistic label maps are a useful tool for important medical image analysis tasks such as segmentation, shape analysis, and atlas building. Existing methods typically rely on blurred signed distance maps or smoothed label maps to model uncertainties and shape variabilities, which do not conform to any generative model or estimation process, and are therefore suboptimal. In this paper, we propose to learn probabilistic label maps using a generative model on given set of binary label maps. The proposed approach generalizes well on unseen data while simultaneously capturing the variability in the training samples. Efficiency of the proposed approach is demonstrated for consensus generation and shape-based clustering using synthetic datasets as well as left atrial segmentations from late-gadolinium enhancement MRI.