Artificial Intelligence (AI) has apparently become one of the most important techniques discovered by humans in history while the human brain is widely recognized as one of the most complex systems in the universe. One fundamental critical question which would affect human sustainability remains open: Will artificial intelligence (AI) evolve to surpass human intelligence in the future? This paper shows that in theory new AI twins with fresh cellular level of AI techniques for neuroscience could approximate the brain and its functioning systems (e.g. perception and cognition functions) with any expected small error and AI without restrictions could surpass human intelligence with probability one in the end. This paper indirectly proves the validity of the conjecture made by Frank Rosenblatt 70 years ago about the potential capabilities of AI, especially in the realm of artificial neural networks. Intelligence is just one of fortuitous but sophisticated creations of the nature which has not been fully discovered. Like mathematics and physics, with no restrictions artificial intelligence would lead to a new subject with its self-contained systems and principles. We anticipate that this paper opens new doors for 1) AI twins and other AI techniques to be used in cellular level of efficient neuroscience dynamic analysis, functioning analysis of the brain and brain illness solutions; 2) new worldwide collaborative scheme for interdisciplinary teams concurrently working on and modelling different types of neurons and synapses and different level of functioning subsystems of the brain with AI techniques; 3) development of low energy of AI techniques with the aid of fundamental neuroscience properties; and 4) new controllable, explainable and safe AI techniques with reasoning capabilities of discovering principles in nature.

Traditional sleep staging categorizes sleep and wakefulness into five coarse-grained classes, overlooking subtle variations within each stage. It provides limited information about the probability of arousal and may hinder the diagnosis of sleep disorders, such as insomnia. To address this issue, we propose a deep-learning method for automatic and scalable annotation of sleep depth index using existing sleep staging labels. Our approach is validated using polysomnography from over ten thousand recordings across four large-scale cohorts. The results show a strong correlation between the decrease in sleep depth index and the increase in arousal likelihood. Several case studies indicate that the sleep depth index captures more nuanced sleep structures than conventional sleep staging. Sleep biomarkers extracted from the whole-night sleep depth index exhibit statistically significant differences with medium-to-large effect sizes across groups of varied subjective sleep quality and insomnia symptoms. These sleep biomarkers also promise utility in predicting the severity of obstructive sleep apnea, particularly in severe cases. Our study underscores the utility of the proposed method for continuous sleep depth annotation, which could reveal more detailed structures and dynamics within whole-night sleep and yield novel digital biomarkers beneficial for sleep health.

Recent statistical and reinforcement learning methods have significantly advanced patient care strategies. However, these approaches face substantial challenges in high-stakes contexts, including missing data, inherent stochasticity, and the critical requirements for interpretability and patient safety. Our work operationalizes a safe and interpretable framework to identify optimal treatment regimes. This approach involves matching patients with similar medical and pharmacological characteristics, allowing us to construct an optimal policy via interpolation. We perform a comprehensive simulation study to demonstrate the framework's ability to identify optimal policies even in complex settings. Ultimately, we operationalize our approach to study regimes for treating seizures in critically ill patients. Our findings strongly support personalized treatment strategies based on a patient's medical history and pharmacological features. Notably, we identify that reducing medication doses for patients with mild and brief seizure episodes while adopting aggressive treatment for patients in intensive care unit experiencing intense seizures leads to more favorable outcomes.

Biological signals, such as electroencephalograms (EEG), play a crucial role in numerous clinical applications, exhibiting diverse data formats and quality profiles. Current deep learning models for biosignals are typically specialized for specific datasets and clinical settings, limiting their broader applicability. Motivated by the success of large language models in text processing, we explore the development of foundational models that are trained from multiple data sources and can be fine-tuned on different downstream biosignal tasks. To overcome the unique challenges associated with biosignals of various formats, such as mismatched channels, variable sample lengths, and prevalent missing values, we propose a Biosignal Transformer (\method). The proposed \method model can enable cross-data learning with mismatched channels, variable lengths, and missing values by tokenizing diverse biosignals into unified "biosignal sentences". Specifically, we tokenize each channel into fixed-length segments containing local signal features, flattening them to form consistent "sentences". Channel embeddings and {\em relative} position embeddings are added to preserve spatio-temporal features. The \method model is versatile and applicable to various biosignal learning settings across different datasets, including joint pre-training for larger models. Comprehensive evaluations on EEG, electrocardiogram (ECG), and human activity sensory signals demonstrate that \method outperforms robust baselines in common settings and facilitates learning across multiple datasets with different formats. Use CHB-MIT seizure detection task as an example, our vanilla \method model shows 3\% improvement over baselines in balanced accuracy, and the pre-trained \method models (optimized from other data sources) can further bring up to 4\% improvements.

In intensive care units (ICUs), critically ill patients are monitored with electroencephalograms (EEGs) to prevent serious brain injury. The number of patients who can be monitored is constrained by the availability of trained physicians to read EEGs, and EEG interpretation can be subjective and prone to inter-observer variability. Automated deep learning systems for EEG could reduce human bias and accelerate the diagnostic process. However, black box deep learning models are untrustworthy, difficult to troubleshoot, and lack accountability in real-world applications, leading to a lack of trust and adoption by clinicians. To address these challenges, we propose a novel interpretable deep learning model that not only predicts the presence of harmful brainwave patterns but also provides high-quality case-based explanations of its decisions. Our model performs better than the corresponding black box model, despite being constrained to be interpretable. The learned 2D embedded space provides the first global overview of the structure of ictal-interictal-injury continuum brainwave patterns. The ability to understand how our model arrived at its decisions will not only help clinicians to diagnose and treat harmful brain activities more accurately but also increase their trust and adoption of machine learning models in clinical practice; this could be an integral component of the ICU neurologists' standard workflow.

Epileptiform activity (EA) is associated with worse outcomes including increased risk of disability and death. However, the effect of EA on the neurologic outcome is confounded by the feedback between treatment with anti-seizure medications (ASM) and EA burden. A randomized clinical trial is challenging due to the sequential nature of EA-ASM feedback, as well as ethical reasons. However, some mechanistic knowledge is available, e.g., how drugs are absorbed. This knowledge together with observational data could provide a more accurate effect estimate using causal inference. We performed a retrospective cross-sectional study with 995 patients with the modified Rankin Scale (mRS) at discharge as the outcome and the EA burden defined as the mean or maximum proportion of time spent with EA in six-hour windows in the first 24 hours of electroencephalography as the exposure. We estimated the change in discharge mRS if everyone in the dataset had experienced a certain EA burden and were untreated. We combined pharmacological modeling with an interpretable matching method to account for confounding and EA-ASM feedback. Our matched groups' quality was validated by the neurologists. Having a maximum EA burden greater than 75% when untreated had a 22% increased chance of a poor outcome (severe disability or death), and mild but long-lasting EA increased the risk of a poor outcome by 14%. The effect sizes were heterogeneous depending on pre-admission profile, e.g., patients with hypoxic-ischemic encephalopathy (HIE) or acquired brain injury (ABI) were more affected. Interventions should put a higher priority on patients with an average EA burden higher than 10%, while treatment should be more conservative when the maximum EA burden is low.

The vast amount of health data has been continuously collected for each patient, providing opportunities to support diverse healthcare predictive tasks such as seizure detection and hospitalization prediction. Existing models are mostly trained on other patients data and evaluated on new patients. Many of them might suffer from poor generalizability. One key reason can be overfitting due to the unique information related to patient identities and their data collection environments, referred to as patient covariates in the paper. These patient covariates usually do not contribute to predicting the targets but are often difficult to remove. As a result, they can bias the model training process and impede generalization. In healthcare applications, most existing domain generalization methods assume a small number of domains. In this paper, considering the diversity of patient covariates, we propose a new setting by treating each patient as a separate domain (leading to many domains). We develop a new domain generalization method ManyDG, that can scale to such many-domain problems. Our method identifies the patient domain covariates by mutual reconstruction and removes them via an orthogonal projection step. Extensive experiments show that ManyDG can boost the generalization performance on multiple real-world healthcare tasks (e.g., 3.7% Jaccard improvements on MIMIC drug recommendation) and support realistic but challenging settings such as insufficient data and continuous learning.

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Despite deep learning (DL) success in classification problems, DL classifiers do not provide a sound mechanism to decide when to refrain from predicting. Recent works tried to control the overall prediction risk with classification with rejection options. However, existing works overlook the different significance of different classes. We introduce Set-classifier with Class-specific RIsk Bounds (SCRIB) to tackle this problem, assigning multiple labels to each example. Given the output of a black-box model on the validation set, SCRIB constructs a set-classifier that controls the class-specific prediction risks with a theoretical guarantee. The key idea is to reject when the set classifier returns more than one label. We validated SCRIB on several medical applications, including sleep staging on electroencephalogram (EEG) data, X-ray COVID image classification, and atrial fibrillation detection based on electrocardiogram (ECG) data. SCRIB obtained desirable class-specific risks, which are 35\%-88\% closer to the target risks than baseline methods.

Sleep staging is a crucial task for diagnosing sleep disorders. It is tedious and complex as it can take a trained expert several hours to annotate just one patient's polysomnogram (PSG) from a single night. Although deep learning models have demonstrated state-of-the-art performance in automating sleep staging, interpretability which defines other desiderata, has largely remained unexplored. In this study, we propose Sleep staging via Prototypes from Expert Rules (SLEEPER), which combines deep learning models with expert defined rules using a prototype learning framework to generate simple interpretable models. In particular, SLEEPER utilizes sleep scoring rules and expert defined features to derive prototypes which are embeddings of PSG data fragments via convolutional neural networks. The final models are simple interpretable models like a shallow decision tree defined over those phenotypes. We evaluated SLEEPER using two PSG datasets collected from sleep studies and demonstrated that SLEEPER could provide accurate sleep stage classification comparable to human experts and deep neural networks with about 85% ROC-AUC and .7 kappa.