More than words: Neurophysiological correlates of semantic dissimilarity depend on comprehension of the speech narrative.

Speech comprehension relies on the ability to understand words within a coherent context. Recent studies have attempted to obtain electrophysiological indices of this process by modelling how brain activity is affected by a word's semantic dissimilarity to preceding words. Although the resulting indices appear robust and are strongly modulated by attention, it remains possible that, rather than capturing the contextual understanding of words, they may actually reflect word-to-word changes in semantic content without the need for a narrative-level understanding on the part of the listener. To test this, we recorded electroencephalography from subjects who listened to speech presented in either its original, narrative form, or after scrambling the word order by varying amounts. This manipulation affected the ability of subjects to comprehend the speech narrative but not the ability to recognise individual words. Neural indices of semantic understanding and low-level acoustic processing were derived for each scrambling condition using the temporal response function. Signatures of semantic processing were observed when speech was unscrambled or minimally scrambled and subjects understood the speech. The same markers were absent for higher scrambling levels as speech comprehension dropped. In contrast, word recognition remained high and neural measures related to envelope tracking did not vary significantly across scrambling conditions. This supports the previous claim that electrophysiological indices based on the semantic dissimilarity of words to their context reflect a listener's understanding of those words relative to that context. It also highlights the relative insensitivity of neural measures of low-level speech processing to speech comprehension.

Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (ß-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.

Utility of a Telephone Triage Hotline in Response to the COVID-19 Pandemic: Longitudinal Observational Study.

BACKGROUND: During the initial months of the COVID-19 pandemic, rapidly rising disease prevalence in the United States created a demand for patient-facing information exchanges that addressed questions and concerns about the disease. One approach to managing increased patient volumes during a pandemic involves the implementation of telephone-based triage systems. During a pandemic, telephone triage hotlines can be employed in innovative ways to conserve medical resources and offer useful population-level data about disease symptomatology and risk factor profiles. OBJECTIVE: The aim of this study is to describe and evaluate the COVID-19 telephone triage hotline used by a large academic medical center in the midwestern United States. METHODS: Michigan Medicine established a telephone hotline to triage inbound patient calls related to COVID-19. For calls received between March 24, 2020, and May 5, 2020, we described total call volume, data reported by callers including COVID-19 risk factors and symptomatology, and distribution of callers to triage algorithm endpoints. We also described symptomatology reported by callers who were directed to the institutional patient portal (online medical visit questionnaire). RESULTS: A total of 3929 calls (average 91 calls per day) were received by the call center during the study period. The maximum total number of daily calls peaked at 211 on March 24, 2020. Call volumes were the highest from 6 AM to 11 AM and during evening hours. Callers were most often directed to the online patient portal (1654/3929, 42%), nursing hotlines (1338/3929, 34%), or employee health services (709/3929, 18%). Cough (126/370 of callers, 34%), shortness of breath (101/370, 27%), upper respiratory infection (28/111, 25%), and fever (89/370, 24%) were the most commonly reported symptoms. Immunocompromised state (23/370, 6%) and age >65 years (18/370, 5%) were the most commonly reported risk factors. CONCLUSIONS: The triage algorithm successfully diverted low-risk patients to suitable algorithm endpoints, while directing high-risk patients onward for immediate assessment. Data collected from hotline calls also enhanced knowledge of symptoms and risk factors that typified community members, demonstrating that pandemic hotlines can aid in the clinical characterization of novel diseases.

The Reporting of Race and Ethnicity in Surgery Literature.

Importance: The reporting of race provides transparency to the representativeness of data and helps inform health care disparities. The International Committee of Medical Journal Editors (ICMJE) developed recommendations to promote quality reporting of race; however, the frequency of reporting continues to be low among most medical journals. Objective: To assess the frequency as well as quality of race reporting among publications from high-ranking broad-focused surgical research journals. Design, Setting, and Participants: A literature review and bibliometric analysis was performed examining all human-based primary research articles published in 2019 from 7 surgical journals: JAMA Surgery, Journal of the American College of Surgeons, Annals of Surgery, Surgery, American Journal of Surgery, Journal of Surgical Research, and Journal of Surgical Education. The 5 journals that stated they follow the ICMJE recommendations were analyzed against the 2 journals that did not explicitly claim adherence. Main Outcomes and Measures: Measured study outcomes included race reporting frequency and use of the ICMJE recommendations for quality reporting of race. Results: A total of 2485 publications were included in the study. The mean (SD) frequency of reporting of race and ethnicity in publications of ICMJE vs non-ICMJE journals was 32.8% (8.4) and 32.0% (20.9), respectively (P = .72). Adherence to ICMJE recommendations for reporting race was more frequent in ICMJE journals than non-ICMJE journals (mean [SD] of 73.1% [17.8] vs 37.0% [10.2]; P < .001). Conclusions and Relevance: The frequency of race and ethnicity reporting among surgical journals is low. A journal's statement of adherence to ICMJE recommendations did not affect the frequency of race and ethnicity reporting; however, there was an increase in the use of ICMJE quality metrics. These findings suggest the need for increased and more standardized reporting of racial and ethnic demographic data among surgical journals.

Applying to be Doctors of Tomorrow: A Qualitative Study Exploring Motivations Towards Applying to a Medical Pipeline Program.

PURPOSE: To identify the motivations of adolescent students applying into medical pipeline programs that are focused on populations underrepresented in medicine. METHODS: The Doctors of Tomorrow (DoT) program is a medical pipeline program between the University of Michigan Medical School and Cass Technical High School in Detroit, Michigan, USA. As a component of the application process, ninth-grade students complete multiple free response essays that allow students to articulate their reasons for applying and their goals for participation in the program. Between 2013 and 2019, 323 ninth-grade students applied to DoT and 216 were accepted. The authors qualitatively analyzed all applications using theoretical coding methods to identify common themes discussed by students regarding their motivations for applying. The authors used Dedoose 8.3.17 (Los Angeles, CA) for qualitative analysis. RESULTS: Four main themes emerged after coding and thematic analysis: (1) Career Aspiration, (2) Exposure to the Medical Field, (3) Breadth of Mentorship, and (4) Longitudinal Professional Development. 'Health Disparities in Minority Communities,' a code used when students commented on issues of race, social determinants of health, and health disparities as motivators, was not identified as frequently as the other codes, despite it being a main topic within the pipeline program. CONCLUSIONS: Applicants to medical school pipeline programs articulate similar intrinsic motivations that can be used to inform what drives students to apply. Pipeline programs should consider these intrinsic motivations, while also creating structured activities from which students can learn and gain tangible benefits when designing curricula. While ninth-grade students acknowledge health disparities in minority communities, their current level of personal experience may not lead them to identify these disparities as significant motivators, and pipeline leaders should be aware of this when designing lesson plans concerning these topics.

Cognitive network hyperactivation and motor cortex decline correlate with ALS prognosis.

We aimed to quantitatively characterize progressive brain network disruption in Amyotrophic Lateral Sclerosis (ALS) during cognition using the mismatch negativity (MMN), an electrophysiological index of attention switching. We measured the MMN using 128-channel EEG longitudinally (2-5 timepoints) in 60 ALS patients and cross-sectionally in 62 healthy controls. Using dipole fitting and linearly constrained minimum variance beamforming we investigated cortical source activity changes over time. In ALS, the inferior frontal gyri (IFG) show significantly lower baseline activity compared to controls. The right IFG and both superior temporal gyri (STG) become progressively hyperactive longitudinally. By contrast, the left motor and dorsolateral prefrontal cortices are initially hyperactive, declining progressively. Baseline motor hyperactivity correlates with cognitive disinhibition, and lower baseline IFG activities correlate with motor decline rate, while left dorsolateral prefrontal activity predicted cognitive and behavioural impairment. Shorter survival correlates with reduced baseline IFG and STG activity and later STG hyperactivation. Source-resolved EEG facilitates quantitative characterization of symptom-associated and symptom-preceding motor and cognitive-behavioral cortical network decline in ALS.

Effects of Moringa Extract on Aminoglycoside-Induced Hair Cell Death and Organ of Corti Damage.

HYPOTHESIS: Moringa extract, a naturally occurring anti-oxidant, protects against aminoglycoside-induced hair cell death and hearing loss within the organ of Corti. BACKGROUND: Reactive oxygen species (ROS) arise primarily in the mitochondria and have been implicated in aminoglycoside-induced ototoxicity. Mitochondrial dysfunction results in loss of membrane potential, release of caspases, and cell apoptosis. Moringa extract has not previously been examined as a protective agent for aminoglycoside-induced ototoxicity. METHODS: Putative otoprotective effects of moringa extract were investigated in an organotypic model using murine organ of Corti explants subjected to gentamicin-induced ototoxicity. Assays evaluated hair cell loss, cytochrome oxidase expression, mitochondrial membrane potential integrity, and caspase activity. RESULTS: In vitro application of moringa conferred significant protection from gentamicin-induced hair cell loss at dosages from 25 to 300 µg/mL, with dosages above 100 µg/mL conferring near complete protection. Assays demonstrated moringa extract suppression of ROS, preservation of cytochrome oxidase activity, and reduction in caspase production. CONCLUSION: Moringa extract demonstrated potent antioxidant properties with significant protection against gentamicin ototoxicity in cochlear explants.

Dissociable electrophysiological measures of natural language processing reveal differences in speech comprehension strategy in healthy ageing.

Healthy ageing leads to changes in the brain that impact upon sensory and cognitive processing. It is not fully clear how these changes affect the processing of everyday spoken language. Prediction is thought to play an important role in language comprehension, where information about upcoming words is pre-activated across multiple representational levels. However, evidence from electrophysiology suggests differences in how older and younger adults use context-based predictions, particularly at the level of semantic representation. We investigate these differences during natural speech comprehension by presenting older and younger subjects with continuous, narrative speech while recording their electroencephalogram. We use time-lagged linear regression to test how distinct computational measures of (1) semantic dissimilarity and (2) lexical surprisal are processed in the brains of both groups. Our results reveal dissociable neural correlates of these two measures that suggest differences in how younger and older adults successfully comprehend speech. Specifically, our results suggest that, while younger and older subjects both employ context-based lexical predictions, older subjects are significantly less likely to pre-activate the semantic features relating to upcoming words. Furthermore, across our group of older adults, we show that the weaker the neural signature of this semantic pre-activation mechanism, the lower a subject's semantic verbal fluency score. We interpret these findings as prediction playing a generally reduced role at a semantic level in the brains of older listeners during speech comprehension and that these changes may be part of an overall strategy to successfully comprehend speech with reduced cognitive resources.

Head and Neck Reconstruction in the Vessel Depleted Neck.

Microvascular free tissue transfer has revolutionized reconstruction and subsequently functional outcomes in the head and neck, but requires suitable recipient vessels for successful results. Recipient vessels can be significantly compromised by prior surgery, radiation therapy, or existing and/or underlying vascular disease in the neck. When further microvascular reconstruction is required in the vessel-depleted neck, identification of appropriate vessels for anastomosis can be difficult and can present complex decisions for the surgeon as well as the patient. In this article, we review the available literature on the vessel depleted neck and the possible vessel options. We present critical strategies for preoperative treatment planning and vessel selection in these patients. We also discuss the benefits and limitations of arterial and venous options while commenting on our unique institution's experiences. The external carotid branches as well as the available subclavian artery branches are presented in detail. The venous anatomy is also described, with particular focus on the accompanying veins and cephalic vein. We provide guidance on the selection and modification of free flaps to achieve the greatest function and cosmetic outcomes in the vessel depleted neck. Our collection of advanced management techniques will provide surgeons with more options to manage the complexity of the vessel depleted neck, and to further help patients understand the risk and benefits of these selections.

Experiential-Learning Opportunities Enhance Engagement in Pipeline Program: A Qualitative Study of the Doctors of Tomorrow Summer Internship Program.

PURPOSE: Doctors of Tomorrow (DoT) is a pipeline program between the University of Michigan Medical School and Cass Technical High School in Detroit where the overall mission is to encourage youth from communities that are underrepresented in medicine to pursue their interests in healthcare careers. Students have the opportunity to apply for a summer internship between 9th grade and 10th grade. There is limited literature on the effectiveness of experiential-learning opportunities in pipeline programs to support development of personal and professional skills. The purpose of this study was to examine the experiences of students participating in the DoT summer internship program in order to better understand how their engagement influenced personal and professional development. METHOD: An exploratory qualitative study was conducted using responses from 27 students who participated in the DoT summer internship program between 2014 and 2018. Students engaged in self-reflective practices prompted by weekly surveys. Data were analyzed through an inductive process by coding and thematic analysis. RESULTS: Four overarching themes were identified: (1) engagement in authentic experiential-learning opportunities; (2) development of professional skills; (3) self-reflection and actualization; and (4) real world barriers in experiential-learning. CONCLUSIONS: High school students engaged in a variety of different community internships and shared insights that illustrated depth and diversity of understanding health in their community. Their reflections illustrate the added value of experiential-education in pipeline programs.

Local Control and Toxicity of Multilevel Spine Stereotactic Body Radiotherapy.

BACKGROUND: Spine stereotactic body radiotherapy (sSBRT) is commonly limited to 1 or 2 vertebral levels given a paucity of efficacy and toxicity data when more than 2 levels are treated. OBJECTIVE: To prove our hypothesis that multilevel sSBRT could provide similar rates of local control (LC) (primary endpoint) and toxicity as single-level treatment using the same clinical target, planning target, and planning organ-at-risk volumes. METHODS: We analyzed consecutive cases of sSBRT treated from 2013 to 2017. Time-to-event outcomes for single-level and multilevel cases were compared using mixed effect Cox models and differences in toxicity rates were evaluated using linear mixed effect models. All models incorporate a patient-level random intercept to account for any within-patient correlation across cases. RESULTS: There were 101 single-level and 84 multilevel sSBRT cases (2-7 continuous vertebral levels). One-year LC was 95% vs 85%, respectively. After adjusting for baseline covariates, dose delivered, and accounting for within-patient correlation, there was no significant difference in time to local failure (hazard ratio, HR 1.79 [0.59-5.4]; P = .30). Pain improved in 83.5% of the 139 initially symptomatic tumors. There were no significant differences in grade 2+ acute or late toxicities between single-level and multilevel sSBRT. CONCLUSION: With rigorous patient immobilization, quality assurance, and image guidance, multilevel sSBRT provides high rates of LC, similar to single-level treatment, without need for larger planning volume margins. Efforts to improve prognostication and case selection for multilevel sSBRT are warranted to ensure that the benefits of improved LC over palliative radiation are justified.

Semantic Context Enhances the Early Auditory Encoding of Natural Speech.

Speech perception involves the integration of sensory input with expectations based on the context of that speech. Much debate surrounds the issue of whether or not prior knowledge feeds back to affect early auditory encoding in the lower levels of the speech processing hierarchy, or whether perception can be best explained as a purely feedforward process. Although there has been compelling evidence on both sides of this debate, experiments involving naturalistic speech stimuli to address these questions have been lacking. Here, we use a recently introduced method for quantifying the semantic context of speech and relate it to a commonly used method for indexing low-level auditory encoding of speech. The relationship between these measures is taken to be an indication of how semantic context leading up to a word influences how its low-level acoustic and phonetic features are processed. We record EEG from human participants (both male and female) listening to continuous natural speech and find that the early cortical tracking of a word's speech envelope is enhanced by its semantic similarity to its sentential context. Using a forward modeling approach, we find that prediction accuracy of the EEG signal also shows the same effect. Furthermore, this effect shows distinct temporal patterns of correlation depending on the type of speech input representation (acoustic or phonological) used for the model, implicating a top-down propagation of information through the processing hierarchy. These results suggest a mechanism that links top-down prior information with the early cortical entrainment of words in natural, continuous speech.SIGNIFICANCE STATEMENT During natural speech comprehension, we use semantic context when processing information about new incoming words. However, precisely how the neural processing of bottom-up sensory information is affected by top-down context-based predictions remains controversial. We address this discussion using a novel approach that indexes a word's similarity to context and how well a word's acoustic and phonetic features are processed by the brain at the time of its utterance. We relate these two measures and show that lower-level auditory tracking of speech improves for words that are more related to their preceding context. These results suggest a mechanism that links top-down prior information with bottom-up sensory processing in the context of natural, narrative speech listening.

Patterned functional network disruption in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor function, with additional evidence of extensive nonmotor involvement. Despite increasing recognition of the disease as a multisystem network disorder characterised by impaired connectivity, the precise neuroelectric characteristics of impaired cortical communication remain to be fully elucidated. Here, we characterise changes in functional connectivity using beamformer source analysis on resting-state electroencephalography recordings from 74 ALS patients and 47 age-matched healthy controls. Spatiospectral characteristics of network changes in the ALS patient group were quantified by spectral power, amplitude envelope correlation (co-modulation) and imaginary coherence (synchrony). We show patterns of decreased spectral power in the occipital and temporal (δ- to ß-band), lateral/orbitofrontal (δ- to θ-band) and sensorimotor (ß-band) regions of the brain in patients with ALS. Furthermore, we show increased co-modulation of neural oscillations in the central and posterior (δ-, θ- and γl -band) and frontal (δ- and γl -band) regions, as well as decreased synchrony in the temporal and frontal (δ- to ß-band) and sensorimotor (ß-band) regions. Factorisation of these complex connectivity patterns reveals a distinct disruption of both motor and nonmotor networks. The observed changes in connectivity correlated with structural MRI changes, functional motor scores and cognitive scores. Characteristic patterned changes of cortical function in ALS signify widespread disease-associated network disruption, pointing to extensive dysfunction of both motor and cognitive networks. These statistically robust findings, that correlate with clinical scores, provide a strong rationale for further development as biomarkers of network disruption for future clinical trials.

Naval Health Research Center Surveillance for Meningococcal Disease.

Historically, meningococcal disease has had a devastating impact on U.S. military personnel, but since the introduction of a vaccine in the 1970s, rates have dropped over 90%.1 Department of Defense instructions mandate a meningococcal vaccine for all service personnel. In the last 5 years, rates of meningococcal disease in the military are similar to the U.S. general population. The active duty incidence was 0.21 cases per 100,000 person-years from 2013-2017. Six cases occurred in the 6 months between September 2016 and February 2017; of these, only one was determined to be a vaccine-covered strain. Ongoing surveillance shows vaccination has resulted in a dramatic reduction in meningococcal cases in the military; however, it also demonstrates cases continue to occur sporadically. The recent emergence of new cases reminds us that surveillance and accompanying research are important for evaluating changes in the disease and informing new vaccine development and policy.

Dysfunction of attention switching networks in amyotrophic lateral sclerosis.

OBJECTIVE: To localise and characterise changes in cognitive networks in Amyotrophic Lateral Sclerosis (ALS) using source analysis of mismatch negativity (MMN) waveforms. RATIONALE: The MMN waveform has an increased average delay in ALS. MMN has been attributed to change detection and involuntary attention switching. This therefore indicates pathological impairment of the neural network components which generate these functions. Source localisation can mitigate the poor spatial resolution of sensor-level EEG analysis by associating the sensor-level signals to the contributing brain sources. The functional activity in each generating source can therefore be individually measured and investigated as a quantitative biomarker of impairment in ALS or its sub-phenotypes. METHODS: MMN responses from 128-channel electroencephalography (EEG) recordings in 58 ALS patients and 39 healthy controls were localised to source by three separate localisation methods, including beamforming, dipole fitting and exact low resolution brain electromagnetic tomography. RESULTS: Compared with controls, ALS patients showed significant increase in power of the left posterior parietal, central and dorsolateral prefrontal cortices (false discovery rate = 0.1). This change correlated with impaired cognitive flexibility (rho = 0.45, 0.45, 0.47, p = .042, .055, .031 respectively). ALS patients also exhibited a decrease in the power of dipoles representing activity in the inferior frontal (left: p = 5.16 × 10-6, right: p = 1.07 × 10-5) and left superior temporal gyri (p = 9.30 × 10-6). These patterns were detected across three source localisation methods. Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95). INTERPRETATION: Source localization of evoked potentials can reliably discriminate patterns of functional network impairment in ALS and ALS subgroups during involuntary attention switching. The discriminative ability of the detected cognitive changes in specific brain regions are comparable to those of functional magnetic resonance imaging (fMRI). Source analysis of high-density EEG patterns has excellent potential to provide non-invasive, data-driven quantitative biomarkers of network disruption that could be harnessed as novel neurophysiology-based outcome measures in clinical trials.

Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a terminal progressive adult-onset neurodegeneration of the motor system. Although originally considered a pure motor degeneration, there is increasing evidence of disease heterogeneity with varying degrees of extra-motor involvement. How the combined motor and nonmotor degeneration occurs in the context of broader disruption in neural communication across brain networks has not been well characterized. Here, we have performed high-density crossectional and longitudinal resting-state electroencephalography (EEG) recordings on 100 ALS patients and 34 matched controls, and have identified characteristic patterns of altered EEG connectivity that have persisted in longitudinal analyses. These include strongly increased EEG coherence between parietal-frontal scalp regions (in γ-band) and between bilateral regions over motor areas (in θ-band). Correlation with structural MRI from the same patients shows that disease-specific structural degeneration in motor areas and corticospinal tracts parallels a decrease in neural activity over scalp motor areas, while the EEG over the scalp regions associated with less extensively involved extra-motor regions on MRI exhibit significantly increased neural communication. Our findings demonstrate that EEG-based connectivity mapping can provide novel insights into progressive network decline in ALS. These data pave the way for development of validated cost-effective spectral EEG-based biomarkers that parallel changes in structural imaging.

Neuroscience: Great Expectations at the Speech-Language Interface.

How heard speech is transformed into words in the brain remains poorly understood. New research reveals signals in auditory cortex that reflect predictions the brain makes in transforming phonetic information into words.

Electrophysiological Correlates of Semantic Dissimilarity Reflect the Comprehension of Natural, Narrative Speech.

People routinely hear and understand speech at rates of 120-200 words per minute [1, 2]. Thus, speech comprehension must involve rapid, online neural mechanisms that process words' meanings in an approximately time-locked fashion. However, electrophysiological evidence for such time-locked processing has been lacking for continuous speech. Although valuable insights into semantic processing have been provided by the "N400 component" of the event-related potential [3-6], this literature has been dominated by paradigms using incongruous words within specially constructed sentences, with less emphasis on natural, narrative speech comprehension. Building on the discovery that cortical activity "tracks" the dynamics of running speech [7-9] and psycholinguistic work demonstrating [10-12] and modeling [13-15] how context impacts on word processing, we describe a new approach for deriving an electrophysiological correlate of natural speech comprehension. We used a computational model [16] to quantify the meaning carried by words based on how semantically dissimilar they were to their preceding context and then regressed this measure against electroencephalographic (EEG) data recorded from subjects as they listened to narrative speech. This produced a prominent negativity at a time lag of 200-600 ms on centro-parietal EEG channels, characteristics common to the N400. Applying this approach to EEG datasets involving time-reversed speech, cocktail party attention, and audiovisual speech-in-noise demonstrated that this response was very sensitive to whether or not subjects understood the speech they heard. These findings demonstrate that, when successfully comprehending natural speech, the human brain responds to the contextual semantic content of each word in a relatively time-locked fashion.