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Cardiorespiratory fitness (CRF) is inversely associated with all-cause mortality. However, the association of CRF and mortality risk for different races, women, and elderly individuals has not been fully assessed.The aim of this study was to evaluate the association of CRF and mortality risk across the spectra of age, race, and sex.A total of 750,302 U.S. veterans aged 30 to 95 years (mean age 61.3 ± 9.8 years) were studied, including septuagenarians (n = 110,637), octogenarians (n = 26,989), African Americans (n = 142,798), Hispanics (n = 35,197), Native Americans (n = 16,050), and women (n = 45,232). Age- and sex-specific CRF categories (quintiles and 98th percentile) were established objectively on the basis of peak METs achieved during a standardized exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for mortality across the CRF categories.During follow-up (median 10.2 years, 7,803,861 person-years of observation), 174,807 subjects died, averaging 22.4 events per 1,000 person-years. The adjusted association of CRF and mortality risk was inverse and graded across the age spectrum, sex, and race. The lowest mortality risk was observed at approximately 14.0 METs for men (HR: 0.24; 95% CI: 0.23-0.25) and women (HR: 0.23; 95% CI: 0.17-0.29), with no evidence of an increase in risk with extremely high CRF. The risk for least fit individuals (20th percentile) was 4-fold higher (HR: 4.09; 95% CI: 3.90-4.20) compared with extremely fit individuals.The association of CRF and mortality risk across the age spectrum (including septuagenarians and octogenarians), men, women, and all races was inverse, independent, and graded. No increased risk was observed with extreme fitness. Being unfit carried a greater risk than any of the cardiac risk factors examined.

Introduction Traumatic brain injury (TBI) or concussion is a known risk factor for multiple adverse health outcomes, including disturbed sleep. Although prior studies show adverse effects of TBI on sleep quality, its compounding effect with other factors on sleep is unknown. This meta-analysis aimed to quantify the effects of TBI on subjective sleep quality in the context of military status and other demographic factors. Materials and Methods A programmatic search of PubMed database from inception to June 2020 was conducted to identify studies that compared subjective sleep quality measured using Pittsburgh Sleep Quality Index (PSQI) in individuals with TBI relative to a control group. The meta-analysis included group-wise standard mean difference (SMD) and 95% CI. Pooled means and SDs were obtained for TBI and non-TBI groups with and without military service, and meta-regression was conducted to test for group effects. Exploratory analysis was performed to test for the effect of TBI, non-head injury, military status, sex, and age on sleep quality across studies. Results Twenty-six articles were included, resulting in a combined total of 5,366 individuals (2,387 TBI and 2,979 controls). Overall, individuals with TBI self-reported poorer sleep quality compared to controls (SMD = 0.63, 95% CI: 0.45 to 0.80). Subgroup analysis revealed differences in the overall effect of TBI on PSQI, with a large effect observed in the civilian subgroup (SMD: 0.80, 95% CI: 0.57 to 1.03) and a medium effect in the civilian subgroup with orthopedic injuries (SMD: 0.40, 95% CI: 0.13 to 0.65) and military/veteran subgroup (SMD: 0.43, 95% CI: 0.14 to 0.71). Exploratory analysis revealed that age and history of military service significantly impacted global PSQI scores. Conclusions Poor sleep quality in TBI cohorts may be due to the influence of multiple factors. Military/veteran samples had poorer sleep quality compared to civilians even in the absence of TBI, possibly reflecting unique stressors associated with prior military experiences and the sequelae of these stressors or other physical and/or psychological traumas that combine to heightened vulnerability. These findings suggest that military service members and veterans with TBI are particularly at a higher risk of poor sleep and its associated adverse health outcomes. Additional research is needed to identify potential exposures that may further heighten vulnerability toward poorer sleep quality in those with TBI across both civilian and military/veteran populations.

To assess the cardiorespiratory fitness (CRF) impact on the association between exercise blood pressure (BP) and mortality risk.We assessed CRF in 15,004 US Veterans (mean age 57.5 ± 11.2 years) who completed a standardized treadmill test between January 1, 1988 and July 28, 2017 and had no evidence of ischemia. They were classified as Unfit or Fit according to the age-specific metabolic equivalents (METs) achieved50% (6.2 ± 1.6 METs; n = 8440) or ≥ 50% (10.5 ± 2.4 METs; n = 6264). To account for the impact of resting systolic BP (SBP) on outcomes, we calculated the difference (Peak SBP-Resting SBP) and termed it SBP-Reserve. We noted a significant increase in mortality associated with SBP-Reserve ≤52 mmHg and stratified the cohort accordingly (SBP-Reserve ≤52 mmHg and 52 mmHg). We applied multivariable Cox models to estimate hazard ratios (HR) and 95% confidence interval (CIs) for outcomes.Mortality risk was significantly elevated only in Unfit individuals with SBP-Reserve ≤52 mmHg compared to those with SBP-Reserve52 mmHg (HR = 1.35; CI: 1.24-1.46; P 0.001). We then assessed the CRF and SBP-Reserve interaction on mortality risk with Fit individuals with SBP-Reserve52 mmHg serving as the referent. Mortality risk was 92% higher (HR = 1.92%; 95% CI: 1.77-2.09; P 0.001) in Unfit individuals with SBP-Reserve ≤52 mmHg and 47% higher (HR = 1.47; 95% CI: 1.33-1.62; P 0.001) in those with SBP-Reserve52 mmHg.Low CRF was associated with increased mortality risk regardless of peak exercise SBP. The risk was substantially higher in individuals unable to augment their exercise SBP52 mmHg beyond resting levels.

Traumatic brain injury (TBI) is known to be associated with poor sleep. In this report, we aimed to identify associations between differences in cortical volume and sleep quality post-TBI. MRI anatomical scans from 88 cases with TBI were analyzed in this report. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Voxel Based Morphometry (VBM), was used to obtain statistical maps of the association between PSQI and cortical volume in gray matter and white matter voxels. Higher PSQI total scores (poor sleep quality) were strongly associated with smaller gray matter volume in the cerebellum. White matter volume was not associated with total PSQI. The sleep disturbance subcomponent showed a significant association with gray and white matter volumes in the cerebellum. Although not significant, cortical areas such as the cingulate and medial frontal regions were associated with sleep quality. The cerebellum with higher contribution to motor and autonomic systems was associated strongly with poor sleep quality. Additionally, regions that play critical roles in inhibitory brain function and suppress mind wandering (i.e., default mode network including medial frontal and cingulate regions) were associated (although to a lesser extent) with sleep. Our findings suggest that poor sleep quality following TBI is significantly associated with lower cerebellar volume, with trending relationships in regions associated with inhibitory function.

When performing a demanding cognitive task, internal distraction in the form of task-irrelevant thoughts and mind wandering can shift our attention away from the task, negatively affecting task performance. Behaviorally, individuals with higher executive function indexed by higher working memory capacity (WMC) exhibit less mind wandering during cognitive tasks, but the underlying neural mechanisms are unknown. To address this problem, we recorded functional magnetic resonance imaging (fMRI) data from subjects performing a cued visual attention task, and assessed their WMC in a separate experiment. Applying machine learning and time-series analysis techniques, we showed that (1) higher WMC individuals experienced lower internal distraction through stronger suppression of posterior cingulate cortex (PCC) activity, (2) higher WMC individuals had better neural representations of attended information as evidenced by higher multivoxel decoding accuracy of cue-related activities in the dorsal attention network (DAN), (3) the positive relationship between WMC and DAN decoding accuracy was mediated by suppression of PCC activity, (4) the dorsal anterior cingulate (dACC) was a source of top-down signals that regulate PCC activity as evidenced by the negative association between Granger-causal influence dACC→PCC and PCC activity levels, and (5) higher WMC individuals exhibiting stronger dACC→PCC Granger-causal influence. These results shed light on the neural mechanisms underlying the executive suppression of internal distraction in tasks requiring externally oriented attention and provide an explanation of the individual differences in such suppression.

Left-lateralized frontoparietal theta oscillations are thought to play an important role in verbal working memory. We causally tested this idea by stimulating the frontoparietal theta network at individual theta frequencies (4 to 8 Hz) during verbal working memory and observing the subsequent behavioral and neurophysiological effects. Weak electric currents were delivered via two 4×1 HD electrode arrays centered at F3 and P3. Three stimulation configurations, including in-phase, anti-phase, or sham, were tested on three different days in a cross-over design. On each test day, the subject underwent three experimental sessions: pre-, during- and post-stimulation sessions. In all sessions, the subject performed a Sternberg verbal working memory task with three levels of memory load (load 2, 4 and 6), imposing three levels of cognitive demand. Analyzing behavioral, EEG, and pupillometry data from the post-stimulation sessions, we report three results. First, in-phase stimulation improved task performance only in subjects with higher working memory capacity (WMC) and under higher memory load (load 6). Second, in-phase stimulation enhanced frontoparietal theta synchrony during working memory retention only in subjects with higher WMC under higher memory loads (load 4 and load 6), and the enhanced frontoparietal theta synchronization is mainly driven by enhanced frontal→parietal theta Granger causality. Third, the pupil diameter was not different irrespective of whether the preceding stimulation was in-phase, anti-phase, or sham. These findings suggest that theta tACS effects on verbal working memory were load- and subject-dependent, rooted in tACS-induced changes in frontoparietal network interactions, and not driven by changes in arousal levels.

Background: Most studies that have evaluated the association between exercise capacity and the risk of all-cause mortality have focused on middle-aged Caucasian populations. We assessed the risk associated with fitness in male and female participants 30-95 years of age and of different ethnicities. Methods:In this retrospective cohort study, we included male and female US Veterans who completed an exercise treadmill test (ETT) between 1999-2020. We assigned participants to one of ten age-specific fitness categories (deciles) based on peak metabolic equivalents (METs) achieved during the ETT. The primary endpoint was all-cause mortality assessed from Veterans Affairs medical records up to Dec 31, 2020. We compared fitness categories with Cox proportional hazard model adjusted for age, body-mass index, ethnic origin, sex, cardiovascular disease, cardiovascular risk factors and medications. Findings: We assessed 750,302 US male and female US Veterans nationwide, ages 30-95 years (mean age 61.3 years, SD 9.8 years). During a median follow-up of 9.8 years (IQR 5.6-14.0), 164,288 died with an average yearly mortality rate of 22 deaths per1,000 person-years. The association between cardiorespiratory fitness (CRF) and mortality risk was independent, inverse, and graded for all ages, ethnicities, and gender. Compared to the least fit group within each age category, mortality risk was 50% lower at peak exercise capacities of approximately 10.0 METs for those 30-49 years, 8.0 METs for septuagenarians, and 7.0 METs for octogenarians. The lowest mortality risk was observed at approximately 14.0 METs with no additional decline or increase in risk beyond this level. Being unfit, defined having exercise capacity below the median ( 2 times higher mortality risk compared to being fit (≥8.5 METs), and was higher than the risk of the traditional cardiac risk factors examined. Interpretation: Higher CRF is independently associated with lower mortality risk for all ages, ethnicities, and gender. Exercise capacity

Topiramate (TPM), a frequently prescribed anti-seizure medication, can cause severe cognitive side effects. Though these side effects have been studied behaviorally, the underlying neural mechanisms are unknown. In a double-blind, randomized, placebo-controlled, crossover study of TPM’s impact on cognition, nine healthy volunteers completed three study sessions: a no-drug baseline session and two sessions during which they received either TPM or placebo. Electroencephalogram was recorded during each session while subjects performed a working-memory task with three memory loads. Comparing TPM with baseline we found the following results. (1) TPM administration led to declines in behavioral performance. (2) Fronto-central event-related potentials (ERPs) elicited by probe-stimuli, representing the primary task network activity, showed strong memory load modulations at baseline, but the magnitude of these load-dependent modulations was significantly reduced during TPM session, suggesting drug-induced impairments of the primary task network. (3) ERP responses over bilateral fronto-temporal electrodes, which were not load-sensitive at baseline, showed significant memory load modulations after TPM administration, suggesting the drug-related recruitment of additional neural resources. (4) At fronto-central scalp sites, there was significant increase in response amplitude for low memory load during TPM session compared to baseline, and the amplitude increase was dependent on TPM plasma concentration, suggesting that the primary task network became less efficient under TPM impact. (5) At bilateral fronto-temporal electrodes, there were no ERP differences when comparing low memory load trials, but TPM administration led to an increase in ERP responses to high load, the magnitude of which was positively correlated with task performance, suggesting that the recruited neural resources were beneficial for task performance (compensatory). Placebo-TPM comparison yielded similar effects albeit with generally reduced significance and effect sizes. Our findings support the hypothesis that TPM impairs the primary task network by reducing its efficiency, triggering compensatory recruitment of additional resources to maintain task performance.

Prolonged continuous performance of a cognitively demanding task induces cognitive fatigue and is associated with a time-related deterioration of objective performance, the degree of which is referred to cognitive fatigability. Although the neural underpinnings of cognitive fatigue are poorly understood, prior studies report changes in neural activity consistent with deterioration of task-related networks over time. While compensatory brain activity is reported to maintain motor task performance in the face of motor fatigue and cognitive performance in the face of other stressors (e.g., aging) and structural changes, there are no studies to date demonstrating compensatory activity for cognitive fatigue. High-density electroencephalography was recorded from human subjects during a 160 min continuous performance of a cognitive control task. While most time-varying neural activity showed a linear decline over time, we identified an evoked potential over the anterior frontal region which demonstrated an inverted U-shaped time-on-task profile. This evoked brain activity peaked between 60 and 100 min into the task and was positively associated with better behavioral performance only during this interval. Following the peak and during subsequent decline of this anterior frontal activity, the rate of performance decline also accelerated. These findings demonstrate that this anterior frontal brain activity, which is not part of the primary task-related activity at baseline, is recruited to compensate for fatigue-induced impairments in the primary task-related network, and that this compensation terminates as cognitive fatigue further progresses. These findings may be relevant to understanding individual differences in cognitive fatigability and developing interventions for clinical conditions afflicted by fatigue.SIGNIFICANCE STATEMENTFatigue refers to changes in objective performance and subjective effort induced by continuous task performance. We examined the neural underpinnings of cognitive fatigue in humans using a prolonged continuous performance task and high-density electroencephalography with the goal of determining whether compensatory processes exist to maintain performance in the face of fatigue. We identified brain activity demonstrating an inverted U-shaped time-on-task profile. This brain activity showed features consistent with a compensatory role including: peaking between 60 and 100 min into the task, a positive association with behavioral performance only during this interval, and accelerated performance decline following its peak. These findings may be relevant to understanding individual differences in cognitive fatigue and developing interventions for clinical conditions afflicted by fatigue.

OBJECTIVES/SPECIFIC AIMS: Identify objective neurological substrates of cognitive fatigue in Parkinson’s disease and in aging. METHODS/STUDY POPULATION: Structural and diffusion MRI. Behavioral assessments for aged adults and Parkinson’s disease. RESULTS/ANTICIPATED RESULTS: Gray and white matter deficits that correlate with deficits in the basal ganglia for fatigued Parkinson’s disease patients Versus anterior cingulate cortex in healthy aged adults with fatigue. DISCUSSION/SIGNIFICANCE OF IMPACT: Over 50% of patients with Parkison’s disease and 38% of healthy older adults suffer from cognitive fatigue. However, diagnostics are limited to subjective surveys and there are no treatments for either population. Therefore, objective measures are greatly needed for better diagnosis and development of treatment targets.