Objectives: There is conflicting evidence regarding congruence between subjective cognitive decline and objective cognitive performance for individuals with a history of mild traumatic brain injury (mTBI). The current study investigated the congruity between subjective and objective cognition, particularly working memory, among veterans with an mTBI history, accounting for post-traumatic stress disorder (PTSD) and childhood trauma. Methods: Participants included 35 veterans with a history of mTBI sustained during deployment. Participants completed measures of subjective [i.e., Behavioral Inventory Rating of Executive Functioning (BRIEF)] and objective working memory (i.e., WAIS-IV working memory index). Congruity between subjective and objective working memory was examined using linear regression. Bonferroni-corrected correlations were run to explore relationships among working memory, psychiatric symptoms, mTBI severity, and childhood trauma. Results: Among Veterans with mTBI, subjective working memory and objective working memory performance were not significantly related (p > 0.05); however, the overall model was significant (p < 0.0001), and childhood trauma was a notable predictor (p = 0.02). Greater PTSD, depression, and sleep symptoms were significantly related to increased subjective working memory concerns, even after Bonferroni adjustments (ps < 0.0001). Better objective working memory was significantly related to a fewer number of childhood traumatic events; however, this did not sustain corrections. The majority of individuals (67%) endorsed significant working memory complaints, despite objectively performing within normal limits (within 1 SD and above). Conclusions: Subjective-objective working memory congruity among veterans with mTBI was limited. Subjective, but not objective, working memory concerns were associated with greater PTSD, depression, and sleep symptoms. Childhood trauma was a notable factor that contributed to both subjective and objective cognitive concerns. There remains clinical value in assessing subjective cognitive concerns given the strong relationships with psychiatric problems and, hence, a focus for intervention.

OBJECTIVE:To investigate the preliminary efficacy of a combined physical exercise + cognitive training intervention for older adults with amnestic mild cognitive impairment (aMCI). DESIGN:Randomized clinical trial. SETTING:Veteran Affairs Hospital, Palo Alto, CA. PARTICIPANTS:Sample included 72 community-dwelling volunteers (mean age 72.4 ± 9.5) diagnosed with aMCI. INTERVENTION:Participants were randomized to either a combined aerobic and resistance exercise + cognitive training (CARE+CT) or stretching exercise + CT (SE+CT). MEASUREMENTS:Primary outcomes included intervention specific assessments of word list and name-face recall. Secondary cognitive outcomes included standardized composite scores that reflect cognitive domains (e.g., learning and memory, executive function, processing speed, visuospatial ability, language). Secondary physiological outcomes included VO2 max and functional capacity (e.g., distance walked 6-minute walk test). APOE and BDNF were determined from whole blood samples. RESULTS:Controlling for age and employment status, linear mixed effects models revealed that all participants experienced significant improvement in the delayed recall of word list, learning and memory and executive function. Only the CARE+CT condition had significant improvement in processing speed and functional capacity. APOE4 status impacted cognitive benefits of those in the SE+CT condition. CONCLUSIONS:Results provide preliminary support for combined exercise and cognitive training interventions for older adults with aMCI. Further research is needed to understand the mechanisms involved as well as the impact of these interventions in diverse samples. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01962038.

Background: Brain-derived neurotrophic factor (BDNF) is implicated in neuronal and glial cell growth and dif-ferentiation, synaptic plasticity, and apoptotic mechanisms. A single-nucleotide polymorphism of the BDNF rs6265 gene may contribute to the pattern and magnitude of brain metabolite abnormalities apparent in those with an Alcohol Use Disorder (AUD). We predicted that methionine (Met) carriers would demonstrate lower magnetic resonance spectroscopy (MRS) measures of N-acetylaspartate level (NAA) and greater age-related decline in NAA than valine (Val) homozygotes.Methods: Veterans with AUD (n=95; 46 +/- 12 years of age, min = 25, max = 71) were recruited from VA Palo Alto residential treatment centers. Single voxel MRS, at 3 Tesla, was used to obtain NAA, choline (Cho) and creatine (Cr) containing compounds from the left dorsolateral prefrontal cortex (DLPFC). Metabolite spectra were fit with LC Model and NAA and Cho were standardized to total Cr level and NAA was also standardized to Cho.Results: Val/Met (n=35) showed markedly greater age-related decline in left DLPFC NAA/Cr level than Val/Val (n=60); no differences in mean metabolite levels were observed between Val/Met and Val/Val. Val/Met demonstrated greater frequency of history of MDD and higher frequency of cannabis use disorder over 12 months prior to study.Conclusions: The greater age-related decline in left DLPFC NAA/Cr and the higher frequency of MDD history and Cannabis Use disorder in BDNF rs6265 Met carriers with AUD are novel and may have implications for non-invasive brain stimulation targeting the left DLFPC and other psychosocial interventions typically utilized in the treatment of AUD.

Abstract Exercise shows immune benefits in older adults and can reduce the risk of late-life cognitive impairment and dementia. This study sought to explore the effects of high-intensity aquatic-based exercise on older adults with mild cognitive impairment (MCI), specifically by examining changes in inflammatory plasma protein concentrations and cognitive performance. A secondary data analysis was conducted on 20 healthy volunteers (mean age 68.2 ±7.75 years) who participated in 6 months of supervised aquatic exercise training. Participants completed a battery of neuropsychological assessments and whole blood draws at pre- and post-intervention. Plasma protein concentration levels were attained using the Olink Target96 Inflammation panel [Uppsala, Sweden]. Mixed effects models assessed the effects of protein concentration change scores on selected cognitive outcomes, while controlling for age. Results indicated that following the exercise intervention, significant changes in two inflammatory-related proteins (Extracellular newly identified receptor for advanced glycation end-products binding protein [EN-RAGE]; Interleukin-20 receptor subunit alpha [IL-20RA]) were associated with improved verbal memory and processing speed endpoints. Specifically, decreased EN-RAGE concentrations resulted in significantly improved delayed verbal memory scores (parameter estimate= -0.893, p= .023), while increased IL-20RA concentrations led to better task completion (parameter estimate= 2.145, p= .030). These findings demonstrate the cognitive benefits of aquatic-based exercise for older adults and those with MCI, and suggest these effects are mediated by alterations in pro- and anti-inflammatory protein markers such as EN-RAGE and IL-20RA. Larger studies are warranted to replicate these findings, and to further explore the role of activity-induced inflammatory changes on late-life brain health.

Objective:In the United States, Alzheimer’s disease (AD) is the most common cause of dementia and the seventh leading cause of death. Exercise has demonstrated health benefits in older adults and reduces the risk of developing AD. Exploring underlying biological mechanisms of exercise could aid in identifying therapeutic targets to prevent AD progression, especially for high-risk individuals such as those with Mild Cognitive Impairment (MCI). Many studies of dementia focus on memory; however, executive function and processing speed are also vulnerable to the neuropathology that causes AD. This exploratory study aimed to identify potential mechanisms by which physical activity can facilitate change in cognitive functioning in older adults. This was accomplished by investigating correlations between changes in neurology-related plasma proteins and changes in measures of executive function and processing speed after participation in a water-based exercise intervention.Participants and Methods:The sample included 20 older adults with amnestic MCI, ages 55-82 years (mean 68.15 ±7.75). Participants were predominately male (90%), White (70%), and non-Hispanic (85%), with more than high school education (95%). Participants engaged in supervised high-intensity water-based exercise three times per week for six months. Neuropsychological assessments and blood samples were assessed at baseline and after completion of the exercise intervention. Cognitive measures included: the Digit Span subtests from the Wechsler Adult Intelligence Scale, 4th Edition, Trail-Making Test (TMT), Stroop Color Word Test (SCWT), and the Symbol Digit Modalities Test (SDMT). Plasma protein levels were analyzed using the Olink Target 96 Neurology assay (Uppsala, Sweden), selected a priori for the established markers linked to neurobiological processes and diseases. Changes in cognitive measures and protein levels were assessed using paired-sample t-tests, and Pearson’s correlations were calculated for significant findings.Results:Participants’ cognitive performance significantly improved on the SCWT color trial (t = -2.19, p = 0.042) and SDMT (t = -2.17, p = .043). Significant decreases in plasma proteins levels were found for GDNF family receptor alpha-1 ([GFRA1]: t =2.05, p = 0.055), neuroblastoma suppressor tumorigenicity-1 ([NBL1]: t = 2.13, p= .046), and neuropilin-2 ([NRP2]: t = 2.61 p= 0.017). Correlational analyses showed reductions in NBL1 were significantly associated with changes in both SDMT (r = -.61, p = 0.006) and the color trial of SCWT (r = .48, p = .038), and NRP2 was significantly associated with improvement on the SDMT (r = -.46, p = 0.045). GFRA1 was not significantly associated with change on any cognitive measure.Conclusions:In a sample of older adults with MCI, participation in high-intensity water-based exercise led to significant improvements in cognitive function as well as changes in neurological plasma proteome. Improved outcomes in processing speed, attention, visuospatial scanning, and working memory were associated with changes in specific plasma protein concentrations. This highlights potential activity-dependent neurobiological mechanisms that may underlie the cognitive benefits derived from physical activity. Future studies should explore these findings in Randomized Control Trials with a comparative condition and larger sample size.

therapeutic intervention for withdrawal-related negative affect.

The multiple hypothesis testing problem is inherent in large-scale quantitative "omic" experiments such as mass spectrometry-based proteomics. Yet, tools for comparing the costs and benefits of different p-value correction methods under different experimental conditions are lacking. We performed thousands of simulations of omic experiments under a range of experimental conditions and applied correction using the Benjamini-Hochberg (BH), Bonferroni, and permutation-based false discovery proportion (FDP) estimation methods. The tremendous false discovery rate (FDR) benefit of correction was confirmed in a range of different contexts. No correction method can guarantee a low FDP in a single experiment, but the probability of a high FDP is small when a high number and proportion of corrected p-values are significant. On average, correction decreased sensitivity, but the sensitivity costs of BH and permutation were generally modest compared to the FDR benefits. In a given experiment, observed sensitivity was always maintained or decreased by BH and Bonferroni, whereas it was often increased by permutation. Overall, permutation had better FDR and sensitivity than BH. We show how increasing sample size, decreasing variability, or increasing effect size can enable the detection of all true changes while still correcting p-values, and we present basic guidelines for omic experimental design. Analysis of an experimental proteomic data set with defined changes corroborated these trends. We developed an R Shiny web application for further exploration and visualization of these models, which we call the Simulator of P-value Multiple Hypothesis Correction (SIMPLYCORRECT) and a high-performance R package, permFDP, for easy use of the permutation-based FDP estimation method.

Background: Brain stimulation is known to affect canonical pathways and proteins involved in memory. However, there are conflicting results on the ability of brain stimulation to improve to memory, which may be due to variations in timing of stimulation. Hypothesis: We hypothesized that repetitive transcranial magnetic stimulation (rTMS) given following a learning task and within the time period before retrieval could help improve memory. Methods: We implanted male B6129SF2/J mice (n = 32) with a cranial attachment to secure the rTMS coil so that the mice could be given consistent stimulation to the frontal area whilst freely moving. Mice then underwent the object recognition test sampling phase and given treatment +3, +24, +48 h following the test. Treatment consisted of 10 min 10 Hz rTMS stimulation (TMS, n = 10), sham treatment (SHAM, n = 11) or a control group which did not do the behavior test or receive rTMS (CONTROL n = 11). At +72 h mice were tested for their exploration of the novel vs familiar object. Results: At 72-h's, only the mice which received rTMS had greater exploration of the novel object than the familiar object. We further show that promoting synaptic GluR2 and maintaining synaptic connections in the perirhinal cortex and hippocampal CA1 are important for this effect. In addition, we found evidence that these changes were linked to CAMKII and CREB pathways in hippocampal neurons. Conclusion: By linking the known biological effects of rTMS to memory pathways we provide evidence that rTMS is effective in improving memory when given during the consolidation and maintenance phases.

Perfluoroalkyl acids (PFAAs) are man-made organic pollutants that are found ubiquitously in the environment and may impact human health. Here, we review the published literature concerning PFAA impacts on neurobiological, neuroendocrine, and neurobehavioral outcomes. We find that there are many mechanisms through which PFAAs may enter the brain and interact with biochemical endpoints to impact neurological function. These results are supported by epidemiological evidence in humans and experimental evidence in animals that demonstrate numerous and varied PFAA impacts on the nervous system. However, the methods commonly used in animal models of PFAA exposure result in durations of exposure and serum PFAA concentrations in blood that may not appropriately mimic human absorption, distribution, metabolism, and excretion. If animal models lack validity, confidence in mechanistic inferences regarding PFAA exposure and brain function is reduced, limiting these studies’ utility. Finally, we end by suggesting some potential impacts of PFAA exposure in human neurological health and disease states whose associations may not readily present themselves in the epidemiological literature.

Perfluoroalkyl acids (PFAAs) are man-made organic pollutants that are found ubiquitously in the environment and may impact human health. Here, we review the published literature concerning PFAA impacts on neurobiological, neuroendocrine, and neurobehavioral outcomes. We find that there are many mechanisms through which PFAAs may enter the brain and interact with biochemical endpoints to impact neurological function. These results are supported by epidemiological evidence in humans and experimental evidence in animals that demonstrate numerous and varied PFAA impacts on the nervous system. However, the methods commonly used in animal models of PFAA exposure result in durations of exposure and serum PFAA concentrations in blood that may not appropriately mimic human absorption, distribution, metabolism, and excretion. If animal models lack validity, confidence in mechanistic inferences regarding PFAA exposure and brain function is reduced, limiting these studies’ utility. Finally, we end by suggesting some potential impacts of PFAA exposure in human neurological health and disease states whose associations may not readily present themselves in the epidemiological literature.

Background: Patients with uncomplicated cases of concussion are thought to fully recover within several months as symptoms resolve.However, at the group level, undergraduates reporting a history of concussion (mean: 4.14 years post-injury) show lasting deficits in visual working memory performance.To clarify what predicts long-term visual working memory outcomes given heterogeneous performance across group members, we investigated factors surrounding the injury, including gender, number of mild traumatic brain injuries, time since mild traumatic brain injury (mTBI), loss of consciousness (LOC) (yes, no), and mTBI etiology (non-sport, team sport, high impact sport, and individual sport).We also collected low-density resting state electroencephalogram to test whether spectral power was correlated with performance.Aim: The purpose of this study was to identify predictors for poor visual working memory outcomes in current undergraduates with a history of concussion.Methods: Participants provided a brief history of their injury and symptoms.Participants also completed an experimental visual working memory task.Finally, low-density resting-state electroencephalogram was collected. Results:The key observation was that LOC at the time of injury predicted superior visual working memory years later.In contrast, visual working memory performance was not predicted by other factors, including etiology, high impact sports, or electroencephalogram spectral power.Conclusions: Visual working memory deficits are apparent at the group level in current undergraduates with a history of concussion.LOC at the time of concussion predicts less impaired visual working memory performance, whereas no significant links were associated with other factors.One interpretation is that after LOC, patients are more likely to seek medical advice than without LOC.Relevance for patients: Concussion is a head injury associated with future cognitive changes in some people.Concussion should be taken seriously, and medical treatment sought whenever a head injury occurs.

Abstract Background Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer’s disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. Methods/design In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. Discussion The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. Trial registration Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. Protocol version This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

Many returning OEF/OIF Veterans with concussion histories report cognitive problems that may last for months or even years. Co-morbid conditions such as post traumatic stress disorder (PTSD) and depression may prolong the symptoms of TBI resulting in lowered attention, processing speed, learning and memory. This study evaluated the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a promising therapeutic treatment for executive function (EF) deficits seen in mild to moderate Traumatic Brain Injury (TBI) Veterans.

Evaluation of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) in Veterans offers unique clinical trial challenges. Here we describe a randomized, double-blinded, intent-to-treat, two-arm, superiority parallel design, a multicenter study funded by the Cooperative Studies Program (CSP No. 556) of the US Department of Veterans Affairs.

Sex differences in procedural skill learning have not been well characterized. Skill learning is an important area to explore in clinical settings that involve rehabilitation and deficit remediation, especially for returning Veterans that have a range of co-morbid conditions (traumatic brain injury, posttraumatic stress disorder, and depression) and possess impairments in multiple domains. Sixty-five (55 males, 10 females) Veterans completed two procedural learning tasks and answered self-report questionnaires. Participants’ performance and total learning slope were analyzed to determine sex differences in learning. Our results revealed sex differences in both tasks demonstrating females tend to perform better than males with a large effect size for these mean differences. While females performed better on the procedural learning tasks compared to males, their rate of learning was equivalent. Skill learning is an important requisite for rehabilitation, as skill learning is necessary to perform daily activities in new settings. Ultimately, these results provide insight into skill learning in Veterans with a range of co-morbid conditions and provide support for further investigation of sex differences in procedural learning.