Linked Exposures Across Databases: an exposure common data elements aggregation framework to facilitate clinical exposure review.

Understanding the health outcomes of military exposures is of critical importance for Veterans, their health care team, and national leaders. Approximately 43% of Veterans report military exposure concerns to their VA providers. Understanding the causal influences of environmental exposures on health is a complex exposure science task and often requires interpreting multiple data sources; particularly when exposure pathways and multi-exposure interactions are ill-defined, as is the case for complex and emerging military service exposures. Thus, there is a need to standardize clinically meaningful exposure metrics from different data sources to guide clinicians and researchers with a consistent model for investigating and communicating exposure risk profiles. The Linked Exposures Across Databases (LEAD) framework provides a unifying model for characterizing exposures from different exposure databases with a focus on providing clinically relevant exposure metrics. Application of LEAD is demonstrated through comparison of different military exposure data sources: Veteran Military Occupational and Environmental Exposure Assessment Tool (VMOAT), Individual Longitudinal Exposure Record (ILER) database, and a military incident report database, the Explosive Ordnance Disposal Information Management System (EODIMS). This cohesive method for evaluating military exposures leverages established information with new sources of data and has the potential to influence how military exposure data is integrated into exposure health care and investigational models.

Stroke Incidence in Patients With Hypertension According to Cardiorespiratory Fitness.

BACKGROUND: Hypertension and physical inactivity are risk factors for stroke. The effect of cardiorespiratory fitness (CRF) on stroke risk in patients with hypertension has not been assessed. We evaluated stroke incidence in patients with hypertension according to CRF and changes in CRF. METHODS: We included 483 379 patients with hypertension (mean age±SD; 59.4±9.0 years) and no evidence of unstable cardiovascular disease as indicated by a standardized exercise treadmill test. Patients were assigned to 5 age- and sex-specific CRF categories based on peak metabolic equivalents achieved at the initial exercise treadmill test and in 4 categories based on metabolic equivalent changes over time (n=110 576). Multivariable Cox models, adjusted for age, and comorbidities were used to estimate hazard ratios and 95% CIs for stroke risk. RESULTS: During a median follow-up of 10.6 (interquartile range, 6.6-14.6) years, 15 925 patients developed stroke with an average yearly rate of 3.1 events/1000 person-years. Stroke risk declined progressively with higher CRF and was 55% lower for the High-fit individuals (hazard ratio, 0.45 [95% CI, 0.42-0.48]) compared with the Least-fit. Similar associations were observed across the race, sex, and age spectra. Poor CRF was the strongest predictor of stroke risk of all comorbidities studied (hazard ratio, 2.24 [95% CI, 2.10-2.40]). Changes in CRF reflected inverse and proportional changes in stroke risk. CONCLUSIONS: Poor CRF carried a greater risk than any of the cardiac risk factors in patients with hypertension, regardless of age, race, or sex. The lower stroke risk associated with improved CRF suggests that increasing physical activity, even later in life, may reduce stroke risk.

Long-Term Mortality Risk According to Cardiorespiratory Fitness in Patients Undergoing Coronary Artery Bypass Graft Surgery.

The aim of this study was to evaluate the association between cardiorespiratory fitness (CRF) and long-term survival in United States (US) Veterans undergoing CABG. We identified 14,550 US Veterans who underwent CABG at least six months after completing a symptom-limited exercise treadmill test (ETT) with no evidence of cardiovascular disease. During a mean follow-up period of 10.0 ± 5.4 years, 6502 (43.0%) died. To assess the association between CRF and risk of mortality, we formed the following five fitness categories based on peak workload achieved (metabolic equivalents or METs) prior to CABG: Least-Fit (4.3 ± 1.0 METs (n = 4722)), Low-Fit (6.8 ± 0.9 METs (n = 3788)), Moderate-Fit (8.3 ± 1.1 METs (n = 2608)), Fit (10.2 ± 0.8 METs (n = 2613)), and High-Fit (13.0 ± 1.5 METs (n = 819)). Cox proportional hazard models were used to calculate risk across CRF categories. The models were adjusted for age, body mass index, race, cardiovascular disease, percutaneous coronary intervention prior to ETT, cardiovascular medications, and cardiovascular disease risk factors. P-values < 0.05 using two-sided tests were considered statistically significant. The association between cardiorespiratory fitness and mortality was inverse and graded. For every 1-MET increase in exercise capacity, the mortality risk was 11% lower (HR = 0.89; CI: 0.88-0.90; p < 0.001). When compared to the Least-Fit category (referent), mortality risk was 22% lower in Low-Fit individuals (HR = 0.78; CI: 0.73-0.82; p < 0.001), 31% lower in Moderate-Fit individuals (HR = 0.69; CI: 0.64-0.74; p < 0.001), 52% lower in Fit individuals (HR = 0.48; CI: 0.44-0.52; p < 0.001), and 66% lower in High-Fit individuals (HR = 0.34; CI: 0.29-0.40; p < 0.001). Cardiorespiratory fitness is inversely and independently associated with long-term mortality after CABG in Veterans referred for exercise testing.

The Association between Cardiorespiratory Fitness and the Risk of Breast Cancer in Women.

INTRODUCTION: Studies have shown an inverse association between the risk of breast cancer in women and physical activity. However, information on the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized test and the risk of developing breast cancer is limited. PURPOSE: To examine the CRF-breast cancer risk association in healthy females. METHODS: This retrospective study was derived from the Exercise Testing and Health Outcomes Study cohort ( n = 750,302). Female participants ( n = 44,463; mean age ± SD; 55.1 ± 8.9 yr) who completed an exercise treadmill test evaluation (Bruce protocol) at the Veterans Affairs Medical Centers nationwide from 1999 to 2020 were studied. The cohort was stratified into four age-specific CRF categories (Least-fit, Low-fit, Moderate-fit, and Fit), based on the peak METs achieved during the exercise treadmill test. RESULTS: During 438,613 person-years of observation, 994 women developed breast cancer. After controlling for covariates, the risk of breast cancer was inversely related to exercise capacity. For each 1-MET increase in CRF, the risk of cancer was 7% lower (HR, 0.93; 95% CI, 0.90-0.95; P < 0.001). When risk was assessed across CRF categories with the Least-fit group as the referent, the risk was 18% lower for Low-fit women (HR, 0.82; 95% CI, 0.70-0.96; P = 0.013), 31% for Moderate-fit (HR, 0.69; 95% CI, 0.58-0.82; P < 0.001), and 40% for Fit (HR, 0.60; 95% CI, 0.47-0.75; P < 0.001). CONCLUSIONS: We observed an inverse and graded association between CRF and breast cancer risk in women. Thus, encouraging women to improve CRF may help attenuate the risk of developing breast cancer.

Progression to Insulin Therapy in Patients With Type 2 Diabetes According to Cardiorespiratory Fitness, Body Mass Index, and Statin Therapy.

OBJECTIVE: To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and progression to insulin therapy in type 2 diabetes mellitus (T2DM). METHODS: Participants were patients with T2DM (mean age, 62.7±8.4 years; men, 178,992; women, 8360) not treated with insulin, with no evidence of uncontrolled cardiovascular disease, who completed an exercise treadmill test between October 1, 1999, and September 3, 2020. Of these, 158,578 were treated with statins and 28,774 were not. We established 5 age-specific CRF categories according to peak metabolic equivalents of task achieved during an exercise treadmill test. RESULTS: During a median follow-up period of 9.0 years, 51,182 patients progressed to insulin therapy with an average annual incidence rate of 28.4 events/1000 person-years. The adjusted progression rate was 27% higher in statin-treated patients (hazard ratio [HR], 1.27; 95% CI, 1.24 to 1.31), related directly to BMI and inversely related to CRF. A progressively higher rate was noted in statin-treated vs non-statin-treated patients within all BMI categories, ranging from 23% for normal weight to 90% for those with BMI of 35 kg/m2 and higher. The statin-CRF interaction revealed 43% higher rate in the least-fit statin-treated patients (HR, 1.43; 95% CI, 1.35 to 1.51) and a progressive decline with increased CRF to 30% lower risk in highly fit statin-treated patients (HR, 0.70; 95% CI, 0.66 to 0.75). CONCLUSION: In patients with T2DM, the statin-related progression to insulin therapy was associated with relatively low CRF and high BMI levels. The progression rate was mitigated by increased CRF regardless of BMI. Clinicians should foster regular exercise for patients with T2DM to enhance CRF and to lessen the rate of progression to insulin therapy.

Cardiorespiratory fitness and risk of heart failure with preserved ejection fraction.

AIMS: Preventive strategies for heart failure with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence. METHODS AND RESULTS: We assessed CRF in US Veterans (624 551 men; mean age 61.2 ± 9.7 years and 43 179 women; mean age 55.0 ± 8.9 years) by a standardized ETT performed between 1999 and 2020 across US Veterans Affairs Medical Centers. All had no evidence of heart failure or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age- and gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations (n = 139 434) ≥1.0 year apart. During a median follow-up of 10.1 years (interquartile range 6.0-14.3 years), providing 6 879 229 person-years, there were 16 493 HFpEF events with an average annual rate of 2.4 events per 1000 person-years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% confidence interval [CI] 0.46-0.51) compared with least fit (≤4.9 METs; referent). Being unfit carried the highest risk (HR 2.88, 95% CI 2.67-3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57-0.71), compared to those who remained unfit. CONCLUSIONS: Higher CRF levels are independently associated with lower HFpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF.

Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease.

BACKGROUND: The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF assessment. The impact of CRF change on mortality risk is not well-defined. OBJECTIVES: This study sought to evaluate changes in CRF and all-cause mortality. METHODS: We assessed 93,060 participants aged 30-95 years (mean 61.3 ± 9.8 years). All completed 2 symptom-limited exercise treadmill tests, 1 or more years apart (mean 5.8 ± 3.7 years) with no evidence of overt cardiovascular disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change) observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-cause mortality. RESULTS: During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF ≥1.0 MET were associated with inverse and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% increase (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD. CONCLUSIONS: Changes in CRF reflected inverse and proportional changes in mortality risk for those with and without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health significance.

A Cross-sectional Cohort Study to Assess Long-term Neurocognitive and Psychiatric Symptoms of Mefloquine Use in Veterans.

INTRODUCTION: To evaluate the associations between neurocognitive and psychiatric health outcomes with mefloquine or any antimalarial exposure. MATERIALS AND METHODS: Medical records were systematically reviewed to identify veterans that indicated antimalarial medication use. Linear regression was performed to examine associations between mefloquine/antimalarial exposure and health outcomes. The mefloquine-exposed group was further compared with normative populations for the same health outcomes. RESULTS: In the adjusted models, no significant differences were noted between the two exposure groups and the unexposed group for any of the health measures (P-value > 0.05). When compared to normative population samples, the mefloquine-exposed group had poorer health and greater neurobehavioral symptom severity or cognitive complaints. CONCLUSION: This study suggests that mefloquine use by veterans referred for intensive evaluation of their military deployment exposures and health was not associated with increased, long-term, neurocognitive/psychiatric symptoms compared to unexposed veterans.

Aftereffects of frontoparietal theta tACS on verbal working memory: Behavioral and neurophysiological analysis.

Verbal working memory is supported by a left-lateralized frontoparietal theta oscillatory (4-8 Hz) network. We tested whether stimulating the left frontoparietal network at theta frequency during verbal working memory can produce observable after-stimulation effects in behavior and neurophysiology. Weak theta-band alternating 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 (within-subject) 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 and EEG data from the post-stimulation session, we report two main observations. First, in-phase stimulation improved task performance in subjects with higher working memory capacity (WMC) under higher memory load (load 6). Second, in-phase stimulation enhanced frontoparietal theta synchrony during working memory retention 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. These observations suggest that (1) in-phase theta transcranial alternating current stimulation (tACS) during verbal working memory can result in observable behavioral and neurophysiological consequences post stimulation, (2) the short-term plasticity effects are state- and individual-dependent, and (3) enhanced executive control underlies improved behavioral performance.

Cardiorespiratory Fitness and Mortality Risk Across the Spectra of Age, Race, and Sex.

BACKGROUND: 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. OBJECTIVES: The aim of this study was to evaluate the association of CRF and mortality risk across the spectra of age, race, and sex. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lower cortical volume is associated with poor sleep quality after traumatic brain injury.

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.

Compounding Effects of Traumatic Brain Injury, Military Status, and Other Factors on Pittsburgh Sleep Quality Index: A Meta-analysis.

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.

The Microstructure of Attentional Control in the Dorsal Attention Network.

The top-down control of attention involves command signals arising chiefly in the dorsal attention network (DAN) in frontal and parietal cortex and propagating to sensory cortex to enable the selective processing of incoming stimuli based on their behavioral relevance. Consistent with this view, the DAN is active during preparatory (anticipatory) attention for relevant events and objects, which, in vision, may be defined by different stimulus attributes including their spatial location, color, motion, or form. How this network is organized to support different forms of preparatory attention to different stimulus attributes remains unclear. We propose that, within the DAN, there exist functional microstructures (patterns of activity) specific for controlling attention based on the specific information to be attended. To test this, we contrasted preparatory attention to stimulus location (spatial attention) and to stimulus color (feature attention), and used multivoxel pattern analysis to characterize the corresponding patterns of activity within the DAN. We observed different multivoxel patterns of BOLD activation within the DAN for the control of spatial attention (attending left vs. right) and feature attention (attending red vs. green). These patterns of activity for spatial and feature attentional control showed limited overlap with each other within the DAN. Our findings thus support a model in which the DAN has different functional microstructures for distinctive forms of top-down control of visual attention.

Exercise blood pressure, cardiorespiratory fitness and mortality risk.

OBJECTIVE: To assess the cardiorespiratory fitness (CRF) impact on the association between exercise blood pressure (BP) and mortality risk. PATIENTS AND METHODS: 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) achieved <50% (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. RESULTS: Mortality risk was significantly elevated only in Unfit individuals with SBP-Reserve ≤52 mmHg compared to those with SBP-Reserve >52 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-Reserve >52 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-Reserve >52 mmHg. CONCLUSION: 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 SBP >52 mmHg beyond resting levels.

Working Memory Capacity Is Negatively Associated with Memory Load Modulation of Alpha Oscillations in Retention of Verbal Working Memory.

Working memory capacity (WMC) measures the amount of information that can be maintained online in the face of distraction. Past work has shown that the efficiency with which the frontostriatal circuit filters out task-irrelevant distracting information is positively correlated with WMC. Recent work has demonstrated a role of posterior alpha oscillations (8-13 Hz) in providing a sensory gating mechanism. We investigated the relationship between memory load modulation of alpha power and WMC in two verbal working memory experiments. In both experiments, we found that posterior alpha power increased with memory load during memory, in agreement with previous reports. Across individuals, the degree of alpha power modulation by memory load was negatively associated with WMC, namely, the higher the WMC, the less alpha power was modulated by memory load. After the administration of topiramate, a drug known to affect alpha oscillations and have a negative impact on working memory function, the negative correlation between memory load modulation of alpha power and WMC was no longer statistically significant but still somewhat detectable. These results suggest that (1) individuals with low WMC demonstrate stronger alpha power modulation by memory load, reflecting possibly an increased reliance on sensory gating to suppress task-irrelevant information in these individuals, in contrast to their high WMC counterparts who rely more on frontal areas to perform this function and (2) this negative association between memory load modulation of alpha oscillations and WMC is vulnerable to drug-related cognitive disruption.

Neural mechanisms of internal distraction suppression in visual attention.

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.

Compensatory Neural Responses to Cognitive Fatigue in Young and Older Adults.

Prolonged performance of a demanding cognitive task induces cognitive fatigue. We examined the behavioral and neural responses to fatigue-induced cognitive impairments in young and older adults. Particular emphasis was placed on whether the brain exhibited compensatory neural activity in response to cognitive fatigue. High-density EEG was recorded from a young (n = 16; 18-33 years of age) and an older (n = 18; 60-87 years of age) cohort who performed a Stroop task continuously for ∼2 h with no breaks. In the young cohort, behavioral performance declined as the experiment progressed, reflecting the deleterious effects of cognitive fatigue. Neurophysiologically, in addition to declining neural activity as cognitive fatigue developed, there is also evidence of region- and time-specific increase in neural activity, suggesting neural compensation. The compensatory activities followed patterns paralleling that of posterior-anterior shift in aging (PASA) and early to late shift in aging (ELSA) observed in cognitive aging and helped to moderate fatigue-induced behavioral deterioration. In the older cohort, behavioral performance did not decline as the experiment progressed, and neural activity either declined or stayed unchanged, showing no evidence of neural compensation, in contrast to the young. These results suggest that young and older adults coped with cognitive fatigue differently by exhibiting differential responses as a function of time-on-task at both the behavioral level and the neural level.

Task-Based Cognitive Fatigability for Older Adults and Validation of Mental Fatigability Subscore of Pittsburgh Fatigability Scale.

Cognitive fatigue and cognitive fatigability are distinct constructs. Cognitive fatigue reflects perception of cognitive fatigue outside of the context of activity level and duration and can be reliably assessed via established instruments such as the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). In contrast, cognitive fatigability reflects change in fatigue levels quantified within the context of the level and duration of cognitive activity, and currently there are no reliable measures of cognitive fatigability. A recently published scale, the Pittsburgh Fatigability Scale (PFS), attempts to remedy this problem with a focus on the aged population. While the physical fatigability subscore of PFS has been validated using physical activity derived measures, the mental fatigability subscore of PFS remains to be tested against equivalent measures derived from cognitive activities. To this end, we recruited 35 older, healthy adult participants (mean age 73.77 ± 5.9) to complete the PFS as well as a prolonged continuous performance of a Stroop task (>2 h). Task-based assessments included time-on-task changes in self-reported fatigue scores (every 20 min), reaction time, and pupil diameter. Defining subjective fatigability, behavioral fatigability, and physiologic/autonomic fatigability to be the slope of change over time-on-task in the above three assessed variables, we found that the PFS mental subscore was not correlated with any of the three task-based fatigability measures. Instead, the PFS mental subscore was correlated with trait level fatigue measures FSS (ρ = 0.63, p < 0.001), and MFIS cognitive subsection (ρ = 0.36, p = 0.03). This finding suggested that the PFS mental fatigability subscore may not be an adequate measure of how fatigued one becomes after a given amount of mental work. Further development efforts are needed to create a self-report scale that reliably captures cognitive fatigability in older adults.

The frequency of alpha oscillations: Task-dependent modulation and its functional significance.

Power (amplitude) and frequency are two important characteristics of EEG alpha oscillations (8-12 Hz). There is an extensive literature showing that alpha power can be modulated in a goal-oriented manner to either enhance or suppress sensory information processing. Only a few studies to date have examined the task-dependent modulation of alpha frequency. Instead, alpha frequency is often viewed as a trait variable, and used to characterize individual differences in cognitive functioning. We performed two experiments to examine the task-dependent modulation of alpha frequency and its functional significance. In the first experiment, high-density EEG was recorded from 21 participants performing a Sternberg working memory task. The results showed that: (1) during memory encoding, alpha frequency decreased with increasing memory load, whereas during memory retention and retrieval, alpha frequency increased with increasing memory load, (2) higher alpha frequency prior to the onset of probe was associated with longer reaction time, and (3) higher alpha frequency prior to the onset of cue or probe was associated with weaker early cue-evoked or probe-evoked neural responses. In the second experiment, simultaneous EEG-fMRI was recorded from 59 participants during resting state. An EEG-informed fMRI analysis revealed that the spontaneous fluctuations of alpha frequency, but not alpha power, were inversely associated with BOLD activity in the visual cortex. Taken together, these findings suggest that alpha frequency is task-dependent, may serve as an indicator of cortical excitability, and along with alpha power, provides more comprehensive indexing of sensory gating.

Brain's compensatory response to drug-induced cognitive impairment.

INTRODUCTION: Topiramate (TPM), a frequently prescribed antiseizure 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. RESULTS: Comparing TPM with baseline we found the following results. (a) TPM administration led to declines in behavioral performance. (b) Fronto-central event-related potentials (ERP) 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. (c) 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. (d) 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. (e) 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. Placebo-TPM comparison yielded similar effects albeit with generally reduced significance and effect sizes. CONCLUSION: Our findings support the hypothesis that TPM impairs the primary task network by reducing its efficiency, which triggers compensatory recruitment of additional resources to maintain task performance.