Targeting AAV vectors to the central nervous system by engineering capsid-receptor interactions that enable crossing of the blood-brain barrier.

Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood-brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections. The reproducible and quantitative data derived via this method enabled both saturation mutagenesis and machine learning (ML)-guided exploration of the capsid sequence space. Notably, during our validation process, we determined that nearly all published AAV capsids that were selected for their ability to cross the BBB in mice leverage either the LY6A or LY6C1 protein, which are not present in primates. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms.

Comparing supervised and unsupervised approaches to emotion categorization in the human brain, body, and subjective experience.

Machine learning methods provide powerful tools to map physical measurements to scientific categories. But are such methods suitable for discovering the ground truth about psychological categories? We use the science of emotion as a test case to explore this question. In studies of emotion, researchers use supervised classifiers, guided by emotion labels, to attempt to discover biomarkers in the brain or body for the corresponding emotion categories. This practice relies on the assumption that the labels refer to objective categories that can be discovered. Here, we critically examine this approach across three distinct datasets collected during emotional episodes-measuring the human brain, body, and subjective experience-and compare supervised classification solutions with those from unsupervised clustering in which no labels are assigned to the data. We conclude with a set of recommendations to guide researchers towards meaningful, data-driven discoveries in the science of emotion and beyond.

An Event-Driven AR-Process Model for EEG-Based BCIs With Rapid Trial Sequences.

Electroencephalography (EEG) is an effective non-invasive measurement method to infer user intent in brain-computer interface (BCI) systems for control and communication, however, these systems often lack sufficient accuracy and speed due to low separability of class-conditional EEG feature distributions. Many factors impact system performance, including inadequate training datasets and models' ignorance of the temporal dependency of brain responses to serial stimuli. Here, we propose a signal model for event-related responses in the EEG evoked with a rapid sequence of stimuli in BCI applications. The model describes the EEG as a superposition of impulse responses time-locked to stimuli corrupted with an autoregressive noise process. The performance of the signal model is assessed in the context of RSVP keyboard, a language-model-assisted EEG-based BCI for typing. EEG data obtained for model calibration from 10 healthy participants are used to fit and compare two models: the proposed sequence-based EEG model and the trial-based feature-class-conditional distribution model that ignores temporal dependencies, which has been used in the previous work. The simulation studies indicate that the earlier model that ignores temporal dependencies may be causing drastic reductions in achievable information transfer rate (ITR). Furthermore, the proposed model, with better regularization, may achieve improved accuracy with fewer calibration data samples, potentially helping to reduce calibration time. Specifically, results show an average 8.6% increase in (cross-validated) calibration AUC for a single channel of EEG, and 54% increase in the ITR in a typing task.

A Parametric EEG Signal Model for BCIs with Rapid-Trial Sequences.

Electroencephalogram (EEG) signals have been shown very effective for inferring user intents in brain-computer interface (BCI) applications. However, existing EEG-based BCIs, in many cases, lack sufficient performance due to utilizing classifiers that operate on EEG signals induced by individual trials. While many factors influence the classification performance, an important aspect that is often ignored is the temporal dependency of these trial-EEG signals, in some cases impacted by interference of brain responses to consecutive target and non-target trials. In this study, the EEG signals are analyzed in a parametric sequence-based fashion, which considers all trials that induce brain responses in a rapid-sequence fashion, including a mixture of consecutive target and non-target trials. EEG signals are described as a linear combination of time-shifted cortical source activities plus measurement noise. Using a superposition of time invariant with an auto-regressive (AR) process, EEG signals are treated as a linear combination of a stationary Gaussian process and time-locked impulse responses to the stimulus (input events) onsets. The model performance is assessed in the framework of a rapid serial visualization presentation (RSVP) based typing task for three healthy subjects across two sessions. Signal modeling in this fashion yields promising performance outcomes considering a single EEG channel to estimate the user intent.