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Title: Computing Functional Brain Connectivity in Neurological Disorders: Efficient Processing and Retrieval of Electrophysiological Signal Data
Brain functional network connectivity is an important measure for characterizing changes in a variety of neurological disorders, for example Alzheimer’s Disease, Parkinson Disease, and Epilepsy. Epilepsy is a serious neurological disorder affecting more than 50 million persons worldwide with severe impact on the quality of life of patients and their family members due to recurrent seizures. More than 30% of epilepsy patients are refractive to pharmacotherapy and are considered for resection to disrupt epilepsy seizure networks. However, 20-50% of these patients continue to have seizures after surgery. Therefore, there is a critical need to gain new insights into the characteristics of epilepsy seizure networks involving one of more brain regions and accurately delineate epileptogenic zone as a target for surgery. Although there is growing availability of large volume of high resolution stereotactic electroencephalogram (SEEG) data recorded from intracranial electrodes during presurgical evaluation of patients, there are significant informatics challenges associated with processing and analyzing this large signal dataset for characterizing epilepsy seizure networks. In this paper, we describe the development and application of a high-performance indexing structure for efficient retrieval of large-scale SEEG signal data to compute seizure network patterns corresponding to brain functional connectivity networks. This novel Neuro-Integrative Connectivity (NIC) search and retrieval method has been developed by extending the red-black tree index model together with an efficient lookup algorithm. We systematically perform a comparative evaluation of the proposed NIC index using de-identified SEEG data from a patient with temporal lobe epilepsy to retrieve segments of signal data corresponding to multiple seizure events and demonstrate the significant advantages of the NIC index as compared to existing methods. This new NIC Index enables faster computation of brain functional connectivity measures in epilepsy patients for large-scale network analysis and potentially provide new insights into the organization as well as evolution of seizure networks in epilepsy patients.  more » « less
Award ID(s):
1636850
NSF-PAR ID:
10110488
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
AMIA Jt Summits Transl Sci Proc.
Page Range / eLocation ID:
107–116
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Obeid, Iyad Selesnick (Ed.)
    Electroencephalography (EEG) is a popular clinical monitoring tool used for diagnosing brain-related disorders such as epilepsy [1]. As monitoring EEGs in a critical-care setting is an expensive and tedious task, there is a great interest in developing real-time EEG monitoring tools to improve patient care quality and efficiency [2]. However, clinicians require automatic seizure detection tools that provide decisions with at least 75% sensitivity and less than 1 false alarm (FA) per 24 hours [3]. Some commercial tools recently claim to reach such performance levels, including the Olympic Brainz Monitor [4] and Persyst 14 [5]. In this abstract, we describe our efforts to transform a high-performance offline seizure detection system [3] into a low latency real-time or online seizure detection system. An overview of the system is shown in Figure 1. The main difference between an online versus offline system is that an online system should always be causal and has minimum latency which is often defined by domain experts. The offline system, shown in Figure 2, uses two phases of deep learning models with postprocessing [3]. The channel-based long short term memory (LSTM) model (Phase 1 or P1) processes linear frequency cepstral coefficients (LFCC) [6] features from each EEG channel separately. We use the hypotheses generated by the P1 model and create additional features that carry information about the detected events and their confidence. The P2 model uses these additional features and the LFCC features to learn the temporal and spatial aspects of the EEG signals using a hybrid convolutional neural network (CNN) and LSTM model. Finally, Phase 3 aggregates the results from both P1 and P2 before applying a final postprocessing step. 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The difference between the maximum and minimum temporal energy terms is calculated in this range. Then, the first derivative or the delta features are calculated using another 0.9-second window. Finally, the second derivative or delta-delta features are calculated using a 0.3-second window [6]. The differential energy for the delta-delta features is not included. In total, we extract 26 features from the raw sample windows which add 1.1 seconds of delay to the system. We used the Temple University Hospital Seizure Database (TUSZ) v1.2.1 for developing the online system [10]. The statistics for this dataset are shown in Table 1. A channel-based LSTM model was trained using the features derived from the train set using the online feature extractor module. A window-based normalization technique was applied to those features. In the offline model, we scale features by normalizing using the maximum absolute value of a channel [11] before applying a sliding window approach. 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These filters evaluate the average confidence, the duration of a seizure, and the channels where the seizures were observed. The postprocessor delivers the label and confidence to the visualizer. The visualizer starts to display the signal as soon as it gets access to the signal file, as shown in Figure 1 using the “Signal File” and “Visualizer” blocks. Once the visualizer receives the label and confidence for the latest epoch from the postprocessor, it overlays the decision and color codes that epoch. The visualizer uses red for seizure with the label SEIZ and green for the background class with the label BCKG. Once the streaming finishes, the system saves three files: a signal file in which the sample frames are saved in the order they were streamed, a time segmented event (TSE) file with the overall decisions and confidences, and a hypotheses (HYP) file that saves the label and confidence for each epoch. 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Using the offline decoder and postprocessor, the model performed at 36.23% sensitivity with 9.52 FAs per 24 hours. The trained model was then evaluated with the online modules. The current performance of the overall online system is 45.80% sensitivity with 28.14 FAs per 24 hours. Table 2 summarizes the performances of these systems. The performance of the online system deviates from the offline P1 model because the online postprocessor fails to combine the events as the seizure probability fluctuates during an event. The modules in the online system add a total of 11.1 seconds of delay for processing each second of the data, as shown in Figure 3. In practice, we also count the time for loading the model and starting the visualizer block. When we consider these facts, the system consumes 15 seconds to display the first hypothesis. The system detects seizure onsets with an average latency of 15 seconds. Implementing an automatic seizure detection model in real time is not trivial. We used a variety of techniques such as the file locking mechanism, multithreading, circular buffers, real-time event decoding, and signal-decision plotting to realize the system. A video demonstrating the system is available at: https://www.isip.piconepress.com/projects/nsf_pfi_tt/resources/videos/realtime_eeg_analysis/v2.5.1/video_2.5.1.mp4. The final conference submission will include a more detailed analysis of the online performance of each module. ACKNOWLEDGMENTS Research reported in this publication was most recently supported by the National Science Foundation Partnership for Innovation award number IIP-1827565 and the Pennsylvania Commonwealth Universal Research Enhancement Program (PA CURE). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the official views of any of these organizations. REFERENCES [1] A. Craik, Y. He, and J. L. Contreras-Vidal, “Deep learning for electroencephalogram (EEG) classification tasks: a review,” J. Neural Eng., vol. 16, no. 3, p. 031001, 2019. https://doi.org/10.1088/1741-2552/ab0ab5. [2] A. C. Bridi, T. Q. Louro, and R. C. L. Da Silva, “Clinical Alarms in intensive care: implications of alarm fatigue for the safety of patients,” Rev. Lat. Am. Enfermagem, vol. 22, no. 6, p. 1034, 2014. https://doi.org/10.1590/0104-1169.3488.2513. [3] M. Golmohammadi, V. Shah, I. Obeid, and J. Picone, “Deep Learning Approaches for Automatic Seizure Detection from Scalp Electroencephalograms,” in Signal Processing in Medicine and Biology: Emerging Trends in Research and Applications, 1st ed., I. Obeid, I. Selesnick, and J. Picone, Eds. New York, New York, USA: Springer, 2020, pp. 233–274. https://doi.org/10.1007/978-3-030-36844-9_8. [4] “CFM Olympic Brainz Monitor.” [Online]. Available: https://newborncare.natus.com/products-services/newborn-care-products/newborn-brain-injury/cfm-olympic-brainz-monitor. [Accessed: 17-Jul-2020]. [5] M. L. Scheuer, S. B. Wilson, A. Antony, G. Ghearing, A. Urban, and A. I. Bagic, “Seizure Detection: Interreader Agreement and Detection Algorithm Assessments Using a Large Dataset,” J. Clin. Neurophysiol., 2020. https://doi.org/10.1097/WNP.0000000000000709. [6] A. Harati, M. Golmohammadi, S. Lopez, I. Obeid, and J. Picone, “Improved EEG Event Classification Using Differential Energy,” in Proceedings of the IEEE Signal Processing in Medicine and Biology Symposium, 2015, pp. 1–4. https://doi.org/10.1109/SPMB.2015.7405421. [7] V. Shah, C. Campbell, I. Obeid, and J. Picone, “Improved Spatio-Temporal Modeling in Automated Seizure Detection using Channel-Dependent Posteriors,” Neurocomputing, 2021. [8] W. Tatum, A. Husain, S. Benbadis, and P. Kaplan, Handbook of EEG Interpretation. New York City, New York, USA: Demos Medical Publishing, 2007. [9] D. P. Bovet and C. Marco, Understanding the Linux Kernel, 3rd ed. O’Reilly Media, Inc., 2005. https://www.oreilly.com/library/view/understanding-the-linux/0596005652/. [10] V. Shah et al., “The Temple University Hospital Seizure Detection Corpus,” Front. Neuroinform., vol. 12, pp. 1–6, 2018. https://doi.org/10.3389/fninf.2018.00083. [11] F. Pedregosa et al., “Scikit-learn: Machine Learning in Python,” J. Mach. Learn. Res., vol. 12, pp. 2825–2830, 2011. https://dl.acm.org/doi/10.5555/1953048.2078195. [12] J. Gotman, D. Flanagan, J. Zhang, and B. Rosenblatt, “Automatic seizure detection in the newborn: Methods and initial evaluation,” Electroencephalogr. Clin. Neurophysiol., vol. 103, no. 3, pp. 356–362, 1997. https://doi.org/10.1016/S0013-4694(97)00003-9. 
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  3. Obeid, Iyad ; Selesnick, Ivan ; Picone, Joseph (Ed.)
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A summary of the labels being used to annotate the data is shown in Table 2. Certain standards are put into place to optimize the annotation process while not sacrificing consistency. Due to the nature of EEG recordings, some records start off with a segment of calibration. This portion of the EEG is instantly recognizable and transitions from what resembles lead artifact to a flat line on all the channels. For the sake of seizure annotation, the calibration is ignored, and no time is wasted on it. During the identification of seizure events, a hard “3 second rule” is used to determine whether two events should be combined into a single larger event. This greatly reduces the time that it takes to annotate a file with multiple events occurring in succession. In addition to the required minimum 3 second gap between seizures, part of our standard dictates that no seizure less than 3 seconds be annotated. Although there is no universally accepted definition for how long a seizure must be, we find that it is difficult to discern with confidence between burst suppression or other morphologically similar impressions when the event is only a couple seconds long. This is due to several reasons, the most notable being the lack of evolution which is oftentimes crucial for the determination of a seizure. After the EEG files have been triaged, a team of annotators at NEDC is provided with the files to begin data annotation. An example of an annotation is shown in Figure 1. A summary of the workflow for our annotation process is shown in Figure 2. Several passes are performed over the data to ensure the annotations are accurate. Each file undergoes three passes to ensure that no seizures were missed or misidentified. The first pass of TUSZ involves identifying which files contain seizures and annotating them using our annotation tool. The time it takes to fully annotate a file can vary drastically depending on the specific characteristics of each file; however, on average a file containing multiple seizures takes 7 minutes to fully annotate. This includes the time that it takes to read the patient report as well as traverse through the entire file. Once an event has been identified, the start and stop time for the seizure is stored in our annotation tool. This is done on a channel by channel basis resulting in an accurate representation of the seizure spreading across different parts of the brain. Files that do not contain any seizures take approximately 3 minutes to complete. Even though there is no annotation being made, the file is still carefully examined to make sure that nothing was overlooked. In addition to solely scrolling through a file from start to finish, a file is often examined through different lenses. Depending on the situation, low pass filters are used, as well as increasing the amplitude of certain channels. These techniques are never used in isolation and are meant to further increase our confidence that nothing was missed. Once each file in a given set has been looked at once, the annotators start the review process. The reviewer checks a file and comments any changes that they recommend. This takes about 3 minutes per seizure containing file, which is significantly less time than the first pass. After each file has been commented on, the third pass commences. This step takes about 5 minutes per seizure file and requires the reviewer to accept or reject the changes that the second reviewer suggested. Since tangible changes are made to the annotation using the annotation tool, this step takes a bit longer than the previous one. Assuming 18% of the files contain seizures, a set of 1,000 files takes roughly 127 work hours to annotate. Before an annotator contributes to the data interpretation pipeline, they are trained for several weeks on previous datasets. A new annotator is able to be trained using data that resembles what they would see under normal circumstances. An additional benefit of using released data to train is that it serves as a means of constantly checking our work. If a trainee stumbles across an event that was not previously annotated, it is promptly added, and the data release is updated. It takes about three months to train an annotator to a point where their annotations can be trusted. Even though we carefully screen potential annotators during the hiring process, only about 25% of the annotators we hire survive more than one year doing this work. To ensure that the annotators are consistent in their annotations, the team conducts an interrater agreement evaluation periodically to ensure that there is a consensus within the team. The annotation standards are discussed in Ochal et al. [4]. An extended discussion of interrater agreement can be found in Shah et al. [5]. The most recent release of TUSZ, v1.5.2, represents our efforts to review the quality of the annotations for two upcoming challenges we hosted: an internal deep learning challenge at IBM [6] and the Neureka 2020 Epilepsy Challenge [3]. One of the biggest changes that was made to the annotations was the imposition of a stricter standard for determining the start and stop time of a seizure. Although evolution is still included in the annotations, the start times were altered to start when the spike-wave pattern becomes distinct as opposed to merely when the signal starts to shift from background. This cuts down on background that was mislabeled as a seizure. For seizure end times, all post ictal slowing that was included was removed. The recent release of v1.5.2 did not include any additional data files. Two EEG files had been added because, originally, they were corrupted in v1.5.1 but were able to be retrieved and added for the latest release. The progression from v1.5.0 to v1.5.1 and later to v1.5.2, included the re-annotation of all of the EEG files in order to develop a confident dataset regarding seizure identification. Starting with v1.4.0, we have also developed a blind evaluation set that is withheld for use in competitions. The annotation team is currently working on the next release for TUSZ, v1.6.0, which is expected to occur in August 2020. It will include new data from 2016 to mid-2019. This release will contain 2,296 files from 2016 as well as several thousand files representing the remaining data through mid-2019. In addition to files that were obtained with our standard triaging process, a part of this release consists of EEG files that do not have associated patient reports. Since actual seizure events are in short supply, we are mining a large chunk of data for which we have EEG recordings but no reports. Some of this data contains interesting seizure events collected during long-term EEG sessions or data collected from patients with a history of frequent seizures. It is being mined to increase the number of files in the corpus that have at least one seizure event. We expect v1.6.0 to be released before IEEE SPMB 2020. The TUAR Corpus is an open-source database that is currently available for use by any registered member of our consortium. To register and receive access, please follow the instructions provided at this web page: https://www.isip.piconepress.com/projects/tuh_eeg/html/downloads.shtml. The data is located here: https://www.isip.piconepress.com/projects/tuh_eeg/downloads/tuh_eeg_artifact/v2.0.0/. 
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  5. Summary

    The human brain is a directional network system, in which brain regions are network nodes and the influence exerted by one region on another is a network edge. We refer to this directional information flow from one region to another as directional connectivity. Seizures arise from an epileptic directional network; abnormal neuronal activities start from a seizure onset zone and propagate via a network to otherwise healthy brain regions. As such, effective epilepsy diagnosis and treatment require accurate identification of directional connections among regions, i.e., mapping of epileptic patients’ brain networks. This article aims to understand the epileptic brain network using intracranial electroencephalographic data—recordings of epileptic patients’ brain activities in many regions. The most popular models for directional connectivity use ordinary differential equations (ODE). However, ODE models are sensitive to data noise and computationally costly. To address these issues, we propose a high-dimensional state-space multivariate autoregression (SSMAR) model for the brain’s directional connectivity. Different from standard multivariate autoregression and SSMAR models, the proposed SSMAR features a cluster structure, where the brain network consists of several clusters of densely connected brain regions. We develop an expectation–maximization algorithm to estimate the proposed model and use it to map the interregional networks of epileptic patients in different seizure stages. Our method reveals the evolution of brain networks during seizure development.

     
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