Testing the consequences of alcohol, cannabis, and nicotine use on hippocampal volume: a quasi-experimental cotwin control analysis of young adult twins.

BACKGROUND: Alcohol, cannabis, and nicotine use are highly comorbid and alarmingly prevalent in young adults. The hippocampus may be particularly sensitive to substance exposure. This remains largely untested in humans and familial risk may confound exposure effects. We extend prior work on alcohol and hippocampal volume in women by testing common and unique substance use effects and the potential moderating role of sex on hippocampal volume during emerging adulthood. A quasi-experimental cotwin control (CTC) design was used to separate familial risk from exposure consequences. METHODS: In a population-based sample of 435 24-year-old same-sex twins (58% women), dimensional measures (e.g. frequency, amount) of alcohol, cannabis, and nicotine use across emerging adulthood were assessed. Hippocampal volume was assessed using MRI. RESULTS: Greater substance use was significantly associated with lower hippocampal volume for women but not men. The same pattern was observed for alcohol, cannabis, and nicotine. CTC analyses provided evidence that hippocampal effects likely reflected familial risk and the consequence of substance use in general and alcohol and nicotine in particular; cannabis effects were in the expected direction but not significant. Within-pair mediation analyses suggested that the effect of alcohol use on the hippocampus may reflect, in part, comorbid nicotine use. CONCLUSIONS: The observed hippocampal volume deviations in women likely reflected substance-related premorbid familial risk and the consequences of smoking and, to a lesser degree, drinking. Findings contribute to a growing body of work suggesting heightened risk among women toward experiencing deleterious effects of substance exposure on the still-developing young adult hippocampus.

Pubertal timing and adolescent outcomes: investigating explanations for associations with a genetically informed design.

BACKGROUND: Psychopathology and risky behaviors increase during adolescence, and understanding which adolescents are most at risk informs prevention and intervention efforts. Pubertal timing relative to same-sex, same-age peers is a known correlate of adolescent outcomes among both boys and girls. However, it remains unclear whether this relation is better explained by a plausible causal process or unobserved familial liability. METHODS: We extended previous research by examining associations between pubertal timing in early adolescence (age 14) and outcomes in later adolescence (age 17) in a community sample of 2,510 twins (49% boys, 51% girls). RESULTS: Earlier pubertal timing was associated with more substance use, risk behavior, internalizing and externalizing problems, and peer problems in later adolescence; these effects were small, consistent with previous literature. Follow-up co-twin control analyses indicated that within-twin-pair differences in pubertal timing were not associated with within-twin-pair differences in most adolescent outcomes after accounting for shared familial liability, suggesting that earlier pubertal timing and adolescent outcomes both reflect familial risk factors. Biometric models indicated that associations between earlier pubertal timing and negative adolescent outcomes were largely attributable to shared genetic liability. CONCLUSIONS: Although earlier pubertal timing was associated with negative adolescent outcomes, our results suggests that these associations did not appear to be caused by earlier pubertal timing but were likely caused by shared genetic influences.

Parietal P3 and midfrontal theta prospectively predict the development of adolescent alcohol use.

BACKGROUND: Subclinical adolescent alcohol use is highly prevalent and may have deleterious effects on important psychosocial and brain outcomes. Prior research has focused on identifying endophenotypes of pathological drinking, and the predictors of normative drinking remain understudied. This study investigated the incremental predictive value of two potential psychophysiological endophenotypes, P3 amplitude (an index of decision making) and midfrontal theta power (a correlate of attentional control), for prospectively predicting the expression and initiation of alcohol use emerging in adolescence. METHODS: A large (N = 594) epidemiological sample was prospectively assessed at ages 11/14/17. Alcohol/substance use was assessed at all ages via a computerized self-report inventory. EEG was recorded at age-14 during a visual oddball task to elicit P3 and theta. RESULTS: Reduced target-related P3 and theta at age-14 prospectively predicted drinking at age-17 independent of one another. Among alcohol-naive individuals at age-14, attenuated P3 and theta increased the odds of new-onset alcohol behaviors 3 years later. Importantly, the endophenotypes provided significant incremental predictive power of future non-clinical alcohol use beyond relevant risk factors (prior alcohol use; tobacco/illicit drug initiation; parental alcohol use disorder). CONCLUSIONS: The current report is the first of our knowledge to demonstrate that deviations in parietal P3 and midfrontal theta prospectively predict the emergence of normative/non-pathological drinking. P3 and theta provide modest yet significant explanatory variance beyond prominent self-report and familial risk measures. Findings offer strong evidence supporting the predictive utility of P3 and theta as candidate endophenotypes for adolescent drinking.

Using multivariate endophenotypes to identify psychophysiological mechanisms associated with polygenic scores for substance use, schizophrenia, and education attainment.

BACKGROUND: To better characterize brain-based mechanisms of polygenic liability for psychopathology and psychological traits, we extended our previous report (Liu et al. Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci. Psychological Medicine, 2017), focused solely on schizophrenia, to test the association between multivariate psychophysiological candidate endophenotypes (including novel measures of θ/δ oscillatory activity) and a range of polygenic scores (PGSs), namely alcohol/cannabis/nicotine use, an updated schizophrenia PGS (containing 52 more genome-wide significant loci than the PGS used in our previous report) and educational attainment. METHOD: A large community-based twin/family sample (N = 4893) was genome-wide genotyped and imputed. PGSs were constructed for alcohol use, regular smoking initiation, lifetime cannabis use, schizophrenia, and educational attainment. Eleven endophenotypes were assessed: visual oddball task event-related electroencephalogram (EEG) measures (target-related parietal P3 amplitude, frontal θ, and parietal δ energy/inter-trial phase clustering), band-limited resting-state EEG power, antisaccade error rate. Principal component analysis exploited covariation among endophenotypes to extract a smaller number of meaningful dimensions/components for statistical analysis. RESULTS: Endophenotypes were heritable. PGSs showed expected intercorrelations (e.g. schizophrenia PGS correlated positively with alcohol/nicotine/cannabis PGSs). Schizophrenia PGS was negatively associated with an event-related P3/δ component [ß = -0.032, nonparametric bootstrap 95% confidence interval (CI) -0.059 to -0.003]. A prefrontal control component (event-related θ/antisaccade errors) was negatively associated with alcohol (ß = -0.034, 95% CI -0.063 to -0.006) and regular smoking PGSs (ß = -0.032, 95% CI -0.061 to -0.005) and positively associated with educational attainment PGS (ß = 0.031, 95% CI 0.003-0.058). CONCLUSIONS: Evidence suggests that multivariate endophenotypes of decision-making (P3/δ) and cognitive/attentional control (θ/antisaccade error) relate to alcohol/nicotine, schizophrenia, and educational attainment PGSs and represent promising targets for future research.

Impact of alcohol use on EEG dynamics of response inhibition: a cotwin control analysis.

Research indicates that alcohol misuse is associated with behavioral disinhibition, but the neurophysiological mechanisms governing this relationship remain largely unknown. Recent work suggests that successful inhibition and cognitive control involve electrophysiological theta-band dynamics, including medial frontal cortex (MFC) power enhancement and functional connectivity between the MFC and dorsal prefrontal cortex (dPFC) regions, which may be disrupted by alcohol misuse. In addition, research suggests that, compared to men, women are at heightened risk of experiencing the negative physical and neurocognitive correlates of drinking. The present study tested the hypothesis that alcohol misuse has a deleterious effect on theta-band response inhibition EEG dynamics in a sample of 300 24-year-old same-sex twins. A cotwin control (CTC) design was used to disentangle premorbid risk for alcohol use from the causal effects of alcohol exposure. Drinking was negatively associated with theta-band MFC power and MFC-dPFC connectivity during response inhibition, and this effect was stronger among women. The CTC analysis suggested that, for women, reduced nogo-related theta-band MFC power and MFC-dPFC connectivity were both consistent with the potential deleterious causal effects of alcohol exposure. These findings suggest that diminished theta-band MFC power and MFC-dPFC connectivity may be neurophysiological mechanisms underlying alcohol-related disinhibition. Although preliminary, these results suggest that normative levels of alcohol use during emerging adulthood have potential sex-specific causal effects on response inhibition EEG dynamics, and thus have potentially significant public health implications.

Rapid dynamics of electrophysiological connectome states are heritable.

Time-varying changes in whole-brain connectivity patterns, or connectome state dynamics, are a prominent feature of brain activity with broad functional implications. While infra-slow (<0.1Hz) connectome dynamics have been extensively studied with fMRI, rapid dynamics highly relevant for cognition are poorly understood. Here, we asked whether rapid electrophysiological connectome dynamics constitute subject-specific brain traits and to what extent they are under genetic influence. Using source-localized EEG connectomes during resting-state (N=928, 473 females), we quantified heritability of multivariate (multi-state) features describing temporal or spatial characteristics of connectome dynamics. States switched rapidly every ~60-500ms. Temporal features were heritable, particularly, Fractional Occupancy (in theta, alpha, beta, and gamma bands) and Transition Probability (in theta, alpha, and gamma bands), representing the duration spent in each state and the frequency of state switches, respectively. Genetic effects explained a substantial proportion of phenotypic variance of these features: Fractional Occupancy in beta (44.3%) and gamma (39.8%) bands and Transition Probability in theta (38.4%), alpha (63.3%), beta (22.6%), and gamma (40%) bands. However, we found no evidence for heritability of spatial features, specifically states' Modularity and connectivity pattern. We conclude that genetic effects strongly shape individuals' connectome dynamics at rapid timescales, specifically states' overall occurrence and sequencing.

Cognitive abilities are associated with rapid dynamics of electrophysiological connectome states.

Time-varying changes in whole-brain connectivity patterns, or connectome state dynamics, hold significant implications for cognition. However, connectome dynamics at fast (> 1Hz) timescales highly relevant to cognition are poorly understood due to the dominance of inherently slow fMRI in connectome studies. Here, we investigated the behavioral significance of rapid electrophysiological connectome dynamics using source-localized EEG connectomes during resting-state (N=926, 473 females). We focused on dynamic connectome features pertinent to individual differences, specifically those with established heritability: Fractional Occupancy (i.e., the overall duration spent in each recurrent connectome state) in beta and gamma bands, and Transition Probability (i.e., the frequency of state switches) in theta, alpha, beta, and gamma bands. Canonical correlation analysis found a significant relationship between the heritable phenotypes of sub-second connectome dynamics and cognition. Specifically, principal components of Transition Probabilities in alpha (followed by theta and gamma bands) and a cognitive factor representing visuospatial processing (followed by verbal and auditory working memory) most notably contributed to the relationship. We conclude that the specific order in which rapid connectome states are sequenced shapes individuals' cognitive abilities and traits. Such sub-second connectome dynamics may inform about behavioral function and dysfunction and serve as endophenotypes for cognitive abilities.

Longitudinal stability and change in time-frequency measures from an oddball task during adolescence and early adulthood.

Time-frequency representations of electroencephalographic signals lend themselves to a granular analysis of cognitive and psychological processes. Characterizing developmental trajectories of time-frequency measures can thus inform us about the development of the processes involved as well as correlated traits and behaviors. We decomposed electroencephalographic (EEG) activity in a large sample of individuals (N = 1692; 917 females), assessed at approximately 3-year intervals from the age of 11 to their mid-20s. Participants completed an oddball task that elicits a robust P3 response. Principal component analysis served to identify the primary dimensions of time-frequency energy. Component loadings were virtually identical across assessment waves. A common and stable set of time-frequency dynamics thus characterized EEG activity throughout this age range. Trajectories of changes in component scores suggest that aspects of brain development reflected in these components comprise two distinct phases, with marked decreases in component amplitude throughout much of adolescence followed by smaller yet significant rates of decreases into early adulthood. Although the structure of time-frequency activity was stable throughout adolescence and early adulthood, we observed subtle change in component loadings as well. Our findings suggest that striking developmental change in event-related potentials emerges through a gradual change in the magnitude and timing of a stable set of dimensions of time-frequency activity, illustrating the usefulness of time-frequency representations of EEG signals and longitudinal designs for understanding brain development. In addition, we provide proof of concept that trajectories of time-frequency activity can serve as potential endophenotypes for childhood externalizing psychopathology and alcohol use in adolescence and early adulthood.

Higher hospitalization and mortality rates among SARS-CoV-2-infected persons in rural America.

PURPOSE: Rural communities are among the most underserved and resource-scarce populations in the United States. However, there are limited data on COVID-19 outcomes in rural America. This study aims to compare hospitalization rates and inpatient mortality among SARS-CoV-2-infected persons stratified by residential rurality. METHODS: This retrospective cohort study from the National COVID Cohort Collaborative (N3C) assesses 1,033,229 patients from 44 US hospital systems diagnosed with SARS-CoV-2 infection between January 2020 and June 2021. Primary outcomes were hospitalization and all-cause inpatient mortality. Secondary outcomes were utilization of supplemental oxygen, invasive mechanical ventilation, vasopressor support, extracorporeal membrane oxygenation, and incidence of major adverse cardiovascular events or hospital readmission. The analytic approach estimates 90-day survival in hospitalized patients and associations between rurality, hospitalization, and inpatient adverse events while controlling for major risk factors using Kaplan-Meier survival estimates and mixed-effects logistic regression. FINDINGS: Of 1,033,229 diagnosed COVID-19 patients included, 186,882 required hospitalization. After adjusting for demographic differences and comorbidities, urban-adjacent and nonurban-adjacent rural dwellers with COVID-19 were more likely to be hospitalized (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI], 1.16-1.21 and aOR 1.29, CI 1.24-1.1.34) and to die or be transferred to hospice (aOR 1.36, CI 1.29-1.43 and 1.37, CI 1.26-1.50), respectively. All secondary outcomes were more likely among rural patients. CONCLUSIONS: Hospitalization, inpatient mortality, and other adverse outcomes are higher among rural persons with COVID-19, even after adjusting for demographic differences and comorbidities. Further research is needed to understand the factors that drive health disparities in rural populations.

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection? A population-level view in the EHR-based RECOVER program.

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies.