Multimodal Characterization of the Semantic N400 Response within a Rapid Evaluation Brain Vital Sign Framework

Background: For nearly four decades, the N400 has been an important brainwave marker of semantic processing. It can be recorded non-invasively from the scalp using electrical and/or magnetic sensors, but largely within the restricted domain of research laboratories specialized to run specifc N400 experiments. However, there is increasing evidence of signifcant clinical utility for the N400 in neurological evaluation, particularly at the individual level. To enable clinical applications, we recently reported a rapid evaluation framework known as “brain vital signs” that successfully incorporated the N400 response as one of the core components for cognitive function evaluation. The current study characterized the rapidly evoked N400 response to demonstrate that it shares consistent features with traditional N400 responses acquired in research laboratory settings—thereby enabling its translation into brain vital signs applications. Methods: Data were collected from 17 healthy individuals using magnetoencephalography (MEG) and electroencephalography (EEG), with analysis of sensor-level efects as well as evaluation of brain sources. Individual-level N400 responses were classifed using machine learning to determine the percentage of participants in whom the response was successfully detected. Results: The N400 response was observed in both M/EEG modalities showing signifcant diferences to incongruent versus congruent condition in the expected time range (p<0.05). Also as expected, N400-related brain activity was observed in the temporal and inferior frontal cortical regions, with typical left-hemispheric asymmetry. Classifcation robustly confrmed the N400 efect at the individual level with high accuracy (89%), sensitivity (0.88) and specifcity (0.90). Conclusion: The brain vital sign N400 characteristics were highly consistent with features of the previously reported N400 responses acquired using traditional laboratory-based experiments. These results provide important evidence supporting clinical translation of the rapidly acquired N400 response as a potential tool for assessments of higher cognitive functions

Brain Vital Signs: Expanding From the Auditory to Visual Modality

The critical need for rapid objective, physiological evaluation of brain function at point-of-care has led to the emergence of brain vital signs—a framework encompassing a portable electroencephalography (EEG) and an automated, quick test protocol. This framework enables access to well-established event-related potential (ERP) markers, which are specific to sensory, attention, and cognitive functions in both healthy and patient populations. However, all our applications to-date have used auditory stimulation, which have highlighted application challenges in persons with hearing impairments (e.g., aging, seniors, dementia). Consequently, it has become important to translate brain vital signs into a visual sensory modality. Therefore, the objectives of this study were to: 1) demonstrate the feasibility of visual brain vital signs; and 2) compare and normalize results from visual and auditory brain vital signs. Data were collected from 34 healthy adults (33 ± 13 years) using a 64-channel EEG system. Visual and auditory sequences were kept as comparable as possible to elicit the N100, P300, and N400 responses. Visual brain vital signs were elicited successfully for all three responses across the group (N100: F = 29.8380, p < 0.001; P300: F = 138.8442, p < 0.0001; N400: F = 6.8476, p = 0.01). Initial auditory-visual comparisons across the three components showed attention processing (P300) was found to be the most transferrable across modalities, with no group-level differences and correlated peak amplitudes (rho = 0.7, p = 0.0001) across individuals. Auditory P300 latencies were shorter than visual (p < 0.0001) but normalization and correlation (r = 0.5, p = 0.0033) implied a potential systematic difference across modalities. Reduced auditory N400 amplitudes compared to visual (p = 0.0061) paired with normalization and correlation across individuals (r = 0.6, p = 0.0012), also revealed potential systematic modality differences between reading and listening language comprehension. This study provides an initial understanding of the relationship between the visual and auditory sequences, while importantly establishing a visual sequence within the brain vital signs framework. With both auditory and visual stimulation capabilities available, it is possible to broaden applications across the lifespan. The critical need for rapid objective, physiological evaluation of brain function at point-of-care has led to the emergence of brain vital signs—a framework encompassing a portable electroencephalography (EEG) and an automated, quick test protocol. This framework enables access to well-established event-related potential (ERP) markers, which are specific to sensory, attention, and cognitive functions in both healthy and patient populations. However, all our applications to-date have used auditory stimulation, which have highlighted application challenges in persons with hearing impairments (e.g., aging, seniors, dementia). Consequently, it has become important to translate brain vital signs into a visual sensory modality. Therefore, the objectives of this study were to: 1) demonstrate the feasibility of visual brain vital signs; and 2) compare and normalize results from visual and auditory brain vital signs. Data were collected from 34 healthy adults (33 ± 13 years) using a 64-channel EEG system. Visual and auditory sequences were kept as comparable as possible to elicit the N100, P300, and N400 responses. Visual brain vital signs were elicited successfully for all three responses across the group (N100: F = 29.8380, p < 0.001; P300: F = 138.8442, p < 0.0001; N400: F = 6.8476, p = 0.01). Initial auditory-visual comparisons across the three components showed attention processing (P300) was found to be the most transferrable across modalities, with no group-level differences and correlated peak amplitudes (rho = 0.7, p = 0.0001) across individuals. Auditory P300 latencies were shorter than visual (p < 0.0001) but normalization and correlation (r = 0.5, p = 0.0033) implied a potential systematic difference across modalities. Reduced auditory N400 amplitudes compared to visual (p = 0.0061) paired with normalization and correlation across individuals (r = 0.6, p = 0.0012), also revealed potential systematic modality differences between reading and listening language comprehension. This study provides an initial understanding of the relationship between the visual and auditory sequences, while importantly establishing a visual sequence within the brain vital signs framework. With both auditory and visual stimulation capabilities available, it is possible to broaden applications across the lifespan

Brain Vital Signs in Elite Ice Hockey: Towards Characterizing Objective and Specific Neurophysiological Reference Values for Concussion Management.

Background: Prior concussion studies have shown that objective neurophysiological measures are sensitive to detecting concussive and subconcussive impairments in youth ice-hockey. These studies monitored brain vital signs at rink-side using a within-subjects design to demonstrate significant changes from pre-season baseline scans. However, practical clinical implementation must overcome inherent challenges related to any dependence on a baseline. This requires establishing the start of normative reference data sets. Methods: The current study collected specific reference data for N = 58 elite, youth, male ice-hockey players and compared these with a general reference dataset from N = 135 of males and females across the lifespan. The elite hockey players were recruited to a select training camp through CAA Hockey, a management agency for players drafted to leagues such as the National Hockey League (NHL). The statistical analysis included a test-retest comparison to establish reliability, and a multivariate analysis of covariance to evaluate differences in brain vital signs between groups with age as a covariate. Findings: Test-retest assessments for brain vital signs evoked potentials showed moderate-to-good reliability (Cronbach's Alpha > 0.7, Intraclass correlation coefficient > 0.5) in five out of six measures. The multivariate analysis of covariance showed no overall effect for group (p = 0.105), and a significant effect of age as a covariate was observed (p < 0.001). Adjusting for the effect of age, a significant difference was observed in the measure of N100 latency (p = 0.022) between elite hockey players and the heterogeneous control group. Interpretation: The findings support the concept that normative physiological data can be used in brain vital signs evaluation in athletes, and should additionally be stratified for age, skill level, and experience. These can be combined with general norms and/or individual baseline assessments where appropriate and/or possible. The current results allow for brain vital sign evaluation independent of baseline assessment, therefore enabling objective neurophysiological evaluation of concussion management and cognitive performance optimization in ice-hockey

Brain Vital Signs: Expanding From the Auditory to Visual Modality

The critical need for rapid objective, physiological evaluation of brain function at point-of-care has led to the emergence of brain vital signs—a framework encompassing a portable electroencephalography (EEG) and an automated, quick test protocol. This framework enables access to well-established event-related potential (ERP) markers, which are specific to sensory, attention, and cognitive functions in both healthy and patient populations. However, all our applications to-date have used auditory stimulation, which have highlighted application challenges in persons with hearing impairments (e.g., aging, seniors, dementia). Consequently, it has become important to translate brain vital signs into a visual sensory modality. Therefore, the objectives of this study were to: 1) demonstrate the feasibility of visual brain vital signs; and 2) compare and normalize results from visual and auditory brain vital signs. Data were collected from 34 healthy adults (33 ± 13 years) using a 64-channel EEG system. Visual and auditory sequences were kept as comparable as possible to elicit the N100, P300, and N400 responses. Visual brain vital signs were elicited successfully for all three responses across the group (N100: F = 29.8380, p &lt; 0.001; P300: F = 138.8442, p &lt; 0.0001; N400: F = 6.8476, p = 0.01). Initial auditory-visual comparisons across the three components showed attention processing (P300) was found to be the most transferrable across modalities, with no group-level differences and correlated peak amplitudes (rho = 0.7, p = 0.0001) across individuals. Auditory P300 latencies were shorter than visual (p &lt; 0.0001) but normalization and correlation (r = 0.5, p = 0.0033) implied a potential systematic difference across modalities. Reduced auditory N400 amplitudes compared to visual (p = 0.0061) paired with normalization and correlation across individuals (r = 0.6, p = 0.0012), also revealed potential systematic modality differences between reading and listening language comprehension. This study provides an initial understanding of the relationship between the visual and auditory sequences, while importantly establishing a visual sequence within the brain vital signs framework. With both auditory and visual stimulation capabilities available, it is possible to broaden applications across the lifespan

Developing Brain Vital Signs: Initial Framework for Monitoring Brain Function Changes over Time

Clinical assessment of brain function relies heavily on indirect behavior-based tests. Unfortunately, behavior-based assessments are subjective and therefore susceptible to several confounding factors. Event-related brain potentials (ERPs), derived from electroencephalography (EEG), are often used to provide objective, physiological measures of brain function. Historically, ERPs have been characterized extensively within research settings, with limited but growing clinical applications. Over the past 20 years, we have developed clinical ERP applications for the evaluation of functional status following serious injury and/or disease. This work has identified an important gap: the need for a clinically accessible framework to evaluate ERP measures. Crucially, this enables baseline measures before brain dysfunction occurs, and might enable the routine collection of brain function metrics in the future much like blood pressure measures today. Here, we propose such a framework for extracting specific ERPs as potential “brain vital signs.” This framework enabled the translation/transformation of complex ERP data into accessible metrics of brain function for wider clinical utilization. To formalize the framework, three essential ERPs were selected as initial indicators: (1) the auditory N100 (Auditory sensation); (2) the auditory oddball P300 (Basic attention); and (3) the auditory speech processing N400 (Cognitive processing). First step validation was conducted on healthy younger and older adults (age range: 22–82 years). Results confirmed specific ERPs at the individual level (86.81–98.96%), verified predictable age-related differences (P300 latency delays in older adults, p &lt; 0.05), and demonstrated successful linear transformation into the proposed brain vital sign (BVS) framework (basic attention latency sub-component of BVS framework reflects delays in older adults, p &lt; 0.05). The findings represent an initial critical step in developing, extracting, and characterizing ERPs as vital signs, critical for subsequent evaluation of dysfunction in conditions like concussion and/or dementia

Electrophysiology of Inhibitory Control in the Context of Emotion Processing in Children With Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is an increasingly common developmental disorder that affects 1 in 59 children. Despite this high prevalence of ASD, knowledge regarding the biological basis of its associated cognitive difficulties remains scant. In this study, we aimed to identify altered neurophysiological responses underlying inhibitory control and emotion processing difficulties in ASD, together with their associations with age and various domains of cognitive and social function. This was accomplished by assessing electroencephalographic recordings during an emotional go/nogo task alongside parent rating scales of behavior. Event related potential (ERP) N200 component amplitudes were reduced in children with ASD compared to typically developing (TD) children. No group differences were found, however, for task performance, P300 amplitude or latency, or N170 amplitude or latency, suggesting that individuals with ASD may only present conflict monitoring abnormalities, as reflected by the reduced N200 component, compared to TD individuals. Consistent with previous findings, increased age correlated with improved task performance scores and reduced N200 amplitude in the TD group, indicating that as these children develop, their neural systems become more efficient. These associations were not identified in the ASD group. Results also showed significant associations between increased N200 amplitudes and improved executive control abilities and decreased autism traits in TD children only. The newly discovered findings of decreased brain activation in children with ASD, alongside differences in correlations with age compared to TD children, provide a potential neurophysiological indicator of atypical development of inhibitory control mechanisms in these individuals

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy