NIH Toolbox Research Articles

Base rates of healthy community-dwelling adults meeting criteria for traumatic encephalopathy syndrome and levels of chronic traumatic encephalopathy certainty

Objective: The National Institute of Neurological Disorders and Stroke (NINDS) recently revised criteria for Traumatic Encephalopathy Syndrome (TES) (Katz et al.), aiming to improve the specificity of former TES criteria (Montenigro et al.) and adding methods to gauge certainty of underlying Chronic Traumatic Encephalopathy (CTE). This study examined base rates of Montenigro et al. and Katz et al. TES criteria in healthy community-dwelling adults. Method: Participants consisted of healthy adults (n = 835; M = 48.1 ± 18.2 years-old, range = 18–85; 37.1% male; 64.1% White) without known history of neurotrauma or psychiatric or neurological conditions. The former and current TES criteria were operationalized using the NIH Toolbox Cognition, Motor, and Emotion batteries and PROMIS-29. Results: Per Katz et al. criteria, 36.9% had symptoms Suggestive of CTE (i.e. either cognitive impairment or neurobehavioral dysregulation), 4.1% had Possible CTE (i.e. requiring cognitive impairment and two additional criteria), and 0.8% had Probable CTE (i.e. requiring cognitive impairment and three additional criteria). The requirement of cognitive impairment for Possible CTE certainty decreased the base rate of Possible CTE tenfold from Montenigro et al. criteria (40.1%). Conclusion: The Katz et al. criteria were met less frequently by healthy adults than the Montenigro et al. criteria. Requiring cognitive impairment and more supportive TES features when gauging CTE certainty may reduce false-positive diagnoses. This finding supports the role of neuropsychologists in the diagnosis and monitoring of patients in TES research studies. To assess specificity, future research should examine base rates of Katz et al. criteria in other psychiatric and neurological conditions.

Residual and enduring effects of cannabis use on cognitive and psychomotor function: A study of adults during unrestricted cannabis use, short-term abstinence, and protracted abstinence.

The impact of cannabis on cognitive and psychomotor function is important to understand, given the role of the endocannabinoid system in these critical processes. The literature has shown robust acute negative effects of cannabis on cognition and psychomotor skills during intoxication, and to a lesser degree, persisting effects following short-term abstinence up to 4 weeks. However, whether these decrements resolve after long-term cessation of use remains unclear. We evaluated cognitive and psychomotor function in 31 adults with current cannabis use during unrestricted use (UNR) and after a 3-day abstinence (RES), 23 adults with former cannabis use (> 90 days abstinent; FU), and 58 nonusing controls (CON) using the cognition and motor batteries of the National Institutes of Health Toolbox. Linear mixed models showed no significant differences in cognitive and motor performance between UNR, RES, and FU groups. Group effects emerged such that CON outperformed UNR on the Oral Reading Recognition Test, and CON outperformed both UNR and RES on the Picture Vocabulary Test. In terms of psychomotor function, FU, RES, and UNR performed better than CON on the Grip Strength Test. In this comprehensive examination of cognitive and psychomotor performance in adults with cannabis use with 3 days to > 90 days of abstinence, our results indicated that the cognitive impacts of chronic, heavy cannabis use are observable during short-term abstinence but remit after > 90 days of abstinence. This highlights widespread impacts of cannabis use abstinence across cognitive and psychomotor domains. Future studies are needed to evaluate whether these effects are also observable with use reduction, as opposed to abstinence. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Curcumin Supplementation and Vascular and Cognitive Function in Chronic Kidney Disease: A Randomized Controlled Trial.

Chronic kidney disease (CKD) increases the risk of cardiovascular disease and cognitive impairment. Curcumin is a polyphenol that improves vascular and cognitive function in older adults; however, its effects on vascular and cognitive function in patients with CKD are unknown. We hypothesized that curcumin supplementation would improve vascular and cognitive function in patients with CKD. Eighty-eight adults diagnosed with stage 3b or 4 CKD (aged 66 ± 8 years, 75% male) participated in a 12-month, randomized, double-blind, placebo-controlled study to test the effects of curcumin (Longvida®, 2000 mg/day) on vascular and cognitive function. Our primary outcome was brachial artery flow-mediated dilation (FMD). Our secondary outcomes were nitroglycerin-mediated dilation, carotid-femoral pulse wave velocity (cfPWV), and cognitive function assessed via the NIH Toolbox Cognition Battery. At baseline, the mean estimated glomerular filtration rate was 34.7 ± 10.8, and the median albumin/creatinine ratio was 81.9 (9.7, 417.3). A total of 44% of participants had diabetes. Compared with placebo, 12 months of curcumin did not improve FMD (median change from baseline was -0.7 (-2.1, 1.1) and -0.1 (-1.5, 1.5) for curcumin and placebo, respectively, with p = 0.69). Similarly, there were no changes in nitroglycerin-mediated dilation, cfPWV, or cognitive outcomes. These results do not support chronic curcumin supplementation to improve vascular and cognitive function in patients with CKD.

Mobile toolbox (MTB) remote measures of executive function and processing speed: development and validation.

The ability to remotely monitor cognitive skills is increasing with the ubiquity of smartphones. The Mobile Toolbox (MTB) is a new measurement system that includes measures assessing Executive Functioning (EF) and Processing Speed (PS): Arrow Matching, Shape-Color Sorting, and Number-Symbol Match. The purpose of this study was to assess their psychometric properties. MTB measures were developed for smartphone administration based on constructs measured in the NIH Toolbox® (NIHTB). Psychometric properties of the resulting measures were evaluated in three studies with participants ages 18 to 90. In Study 1 (N = 92), participants completed MTB measures in the lab and were administered both equivalent NIH TB measures and other external measures of similar cognitive constructs. In Study 2 (N = 1,021), participants completed the equivalent NIHTB measures in the lab and then took the MTB measures on their own, remotely. In Study 3 (N = 168), participants completed MTB measures twice remotely, two weeks apart. All three measures exhibited very high internal consistency and strong test-retest reliability, as well as moderately high correlations with comparable NIHTB tests and moderate correlations with external measures of similar constructs. Phone operating system (iOS vs. Android) had a significant impact on performance for Arrow Matching and Shape-Color Sorting, but no impact on either validity or reliability. Results support the reliability and convergent validity of MTB EF and PS measures for use across the adult lifespan in remote, self-administered designs.

Feasibility and success of a non-sedated brain MRI training protocol in 7-year-old children from rural and semi-rural Colombia.

Brain magnetic resonance imaging (MRI) is a crucial tool for clinical evaluation of the brain and neuroscience research. Obtaining successful non-sedated MRI in children who live in resource-limited settings may be an additional challenge. To present a feasibility study of a novel, low-cost MRI training protocol used in a clinical research study in a rural/semi-rural region of Colombia and to examine neurodevelopmental factors associated with successful scans. Fifty-seven typically developing Colombian children underwent a training protocol and non-sedated brain MRI at age 7. Group training utilized a customized booklet, an MRI toy set, and a simple mock scanner. Children attended MRI visits in small groups of two to three. Resting-state functional and structural images were acquired on a 1.5-Tesla scanner with a protocol duration of 30-40minutes. MRI success was defined as the completion of all sequences and no more than mild motion artifact. Associations between the Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Movement Assessment Battery for Children (MABC), Behavioral Rating Inventory of Executive Function (BRIEF), Child Behavior Checklist (CBCL), and Adaptive Behavior Assessment System (ABAS) scores and MRI success were analyzed. Mean (SD) age at first MRI attempt was 7.2 (0.2) years (median 7.2 years, interquartile range 7.1-7.3 years). Twenty-six (45.6%) participants were male. Fifty-one (89.5%) children were successful across two attempts; 44 (77.2%) were successful on their first attempt. Six (10.5%) were unsuccessful due to refusal or excessive motion. Age, sex, and scores across all neurodevelopmental assessments (MABC, TVIP, ABAS, BRIEF, CBCL, NIH Toolbox Flanker, NIH Toolbox Pattern Comparison, WPPSI) were not associated with likelihood of MRI success (P=0.18, 0.19, 0.38, 0.92, 0.84, 0.80, 1.00, 0.16, 0.75, 0.86, respectively). This cohort of children from a rural/semi-rural region of Colombia demonstrated comparable MRI success rates to other published cohorts after completing a low-cost MRI familiarization training protocol suitable for low-resource settings. Achieving non-sedated MRI success in children in low-resource and international settings is important for the continuing diversification of pediatric research studies.

Altered gyrification in chemotherapy-treated older long-term breast cancer survivors.

The purpose of this prospective longitudinal study was to evaluate the changes in brain surface gyrification in older long-term breast cancer survivors 5-15 years after chemotherapy treatment. Older breast cancer survivors aged ≥ 65 years treated with chemotherapy (C+) or without chemotherapy (C-) 5-15 years prior and age- and sex-matched healthy controls (HC) were recruited (time point 1 (TP1)) and followed up for 2 years (time point 2 (TP2)). Study assessments for both time points included neuropsychological (NP) testing with the NIH Toolbox cognition battery and cortical gyrification analysis based on brain MRI. The study cohort with data for both TP1 and TP2 consisted of the following: 10 participants for the C+ group, 12 participants for the C- group, and 13 participants for the HC group. The C+ group had increased gyrification in six local gyral regions including the right fusiform, paracentral, precuneus, superior, middle temporal gyri and left pars opercularis gyrus, and it had decreased gyrification in two local gyral regions from TP1 to TP2 (p<.05, Bonferroni corrected). The C- and HC groups showed decreased gyrification only (p<.05, Bonferroni corrected). In the C+ group, changes in right paracentral gyrification and crystalized composite scores were negatively correlated (R=-0.76, p=.01). Altered gyrification could be the neural correlate of cognitive changes in older chemotherapy-treated long-term breast cancer survivors.

Identification of amnestic mild cognitive impairment among Black and White community-dwelling older adults using NIH Toolbox Cognition tablet battery.

Identify which NIH Toolbox Cognition Battery (NIHTB-CB) subtest(s) best differentiate healthy controls (HC) from those with amnestic mild cognitive impairment (aMCI) and compare the discriminant accuracy between a model using a priori "Norm Adjusted" scores versus "Unadjusted" standard scores with age, sex, race/ethnicity, and education controlled for within the model. Racial differences were also examined. Participants were Black/African American (B/AA) and White consensus-confirmed (HC = 96; aMCI = 62) adults 60-85 years old that completed the NIHTB-CB for tablet. Discriminant function analysis (DFA) was used in the Total Sample and separately for B/AA (n = 80) and White participants (n = 78). Picture Sequence Memory (an episodic memory task) was the highest loading coefficient across all DFA models. When stratified by race, differences were noted in the pattern of the highest loading coefficients within the DFAs. However, the overall discriminant accuracy of the DFA models in identifying HCs and those with aMCI did not differ significantly by race (B/AA, White) or model/score type (Norm Adjusted versus Unadjusted). Racial differences were noted despite the use of normalized scores or demographic covariates-highlighting the importance of including underrepresented groups in research. While the models were fairly accurate at identifying consensus-confirmed HCs, the models proved less accurate at identifying White participants with an aMCI diagnosis. In clinical settings, further work is needed to optimize computerized batteries and the use of NIHTB-CB norm adjusted scores is recommended. In research settings, demographically corrected scores or within model correction is suggested.

Association between twin status with cognitive, behavioral development and brain structure in early adolescence: a retrospective cohort analysis based on the Adolescent Brain Cognitive Development Study.

Twin births are related with maternal and fetal adverse outcomes. Little was known about the comparability of the cognitive, behavioral development and brain structure between twins and singletons in early adolescence. This retrospective cohort study was based on data from the United States population-based, prospective, longitudinal observational Adolescent Brain Cognitive Development study. Children with complete twin status information were enrolled, and the exposure variable was twin status. Primary outcomes were cognitive, behavioral development and brain structure in early adolescence. Cognitive and behavioral outcomes were assessed by using the NIH Toolbox and Child Behavioral Checklist, respectively. Brain structure was evaluated by the cortical thickness, area, and volume extracted from the magnetic resonance imaging (MRI) data. Subgroup analyses were conducted by prematurity, birth weight, with sibling, genetic profiles, and twin types (zygosity). From 1st September 2016 to 15th November 2018, 11545 children (9477 singletons and 2068 twins) aged 9-10years were enrolled. Twins showed mildly lower cognitive performance (|t|> 5.104, P-values < 0.001, False Discovery Rate [FDR] < 0.001), better behavioral outcome (|t|> 2.441, P-values < 0.015, FDR < 0.042), such as lower scores for multiple psychiatric disorders and behavioral issues, and smaller cortical volume (t = - 3.854, P-values < 0.001, FDR < 0.001) and cortical area (t = - 3.872, P-values < 0.001, FDR < 0.001). The observed differences still held when stratified for prematurity, birth weight, presence of siblings, genetic profiles, and twin types (zygosity). Furthermore, analyses on the two-year follow-up data showed consistent results with baseline data. Twin status is associated with lower cognitive and better behavioral development in early adolescence accompanied by altered brain structure. Clinicians should be aware of the possible difference when generalizing results from adolescent twin samples to singletons.

The NIH Infant and Toddler Toolbox: A new standardized tool for assessing neurodevelopment in children ages 1-42 months.

The progress of developmental research demands reliable measurement techniques, yet inconsistency persist across laboratories, subfields, and settings. To address this, the NIH Toolbox for Neurological and Behavioral Function (NIHTB)® has been extended to create a universal assessment for developmental and pediatric communities: The NIH Infant and Toddler ("Baby") Toolbox. Currently undergoing norming in a sample of 2550 children demographically representative of the 2020 U.S. census, the Baby Toolbox is slated for release in late 2024. This paper introduces the Baby Toolbox, details its objectives, development, and technological innovations, describes plans for reliability and norming, and invites researchers to consider the Baby Toolbox in the future studies. Ultimately, this initiative stands to enhance cross-study comparability and advance comprehensive developmental evaluation.

Effects of Aerobic Exercise on Brain Age and Health in Middle-Aged and Older Adults: A Single-Arm Pilot Clinical Trial.

Sleep disturbances are prevalent among elderly individuals. While polysomnography (PSG) serves as the gold standard for sleep monitoring, its extensive setup and data analysis procedures impose significant costs and time constraints, thereby restricting the long-term application within the general public. Our laboratory introduced an innovative biomarker, utilizing artificial intelligence algorithms applied to PSG data to estimate brain age (BA), a metric validated in cohorts with cognitive impairments. Nevertheless, the potential of exercise, which has been a recognized means of enhancing sleep quality in middle-aged and older adults to reduce BA, remains undetermined. We conducted an exploratory study to evaluate whether 12 weeks of moderate-intensity exercise can improve cognitive function, sleep quality, and the brain age index (BAI), a biomarker computed from overnight sleep electroencephalogram (EEG), in physically inactive middle-aged and older adults. Home wearable devices were used to monitor heart rate and overnight sleep EEG over this period. The NIH Toolbox Cognition Battery, in-lab overnight polysomnography, cardiopulmonary exercise testing, and a multiplex cytokines assay were employed to compare pre- and post-exercise brain health, exercise capacity, and plasma proteins. In total, 26 participants completed the initial assessment and exercise program, and 24 completed all procedures. Data are presented as mean [lower 95% CI of mean, upper 95% CI of mean]. Participants significantly increased maximal oxygen consumption (Pre: 21.11 [18.98, 23.23], Post 22.39 [20.09, 24.68], mL/kg/min; effect size: -0.33) and decreased resting heart rate (Pre: 66.66 [63.62, 67.38], Post: 65.13 [64.25, 66.93], bpm; effect size: -0.02) and sleeping heart rate (Pre: 64.55 [61.87, 667.23], Post: 62.93 [60.78, 65.09], bpm; effect size: -0.15). Total cognitive performance (Pre: 111.1 [107.6, 114.6], Post: 115.2 [111.9, 118.5]; effect size: 0.49) was significantly improved. No significant differences were seen in BAI or measures of sleep macro- and micro-architecture. Plasma IL-4 (Pre: 0.24 [0.18, 0.3], Post: 0.33 [0.24, 0.42], pg/mL; effect size: 0.49) was elevated, while IL-8 (Pre: 5.5 [4.45, 6.55], Post: 4.3 [3.66, 5], pg/mL; effect size: -0.57) was reduced. Cognitive function was improved by a 12-week moderate-intensity exercise program in physically inactive middle-aged and older adults, as were aerobic fitness (VO2max) and plasma cytokine profiles. However, we found no measurable effects on sleep architecture or BAI. It remains to be seen whether a study with a larger sample size and more intensive or more prolonged exercise exposure can demonstrate a beneficial effect on sleep quality and brain age.

Controlling false discovery rate for mediator selection in high-dimensional data.

The need to select mediators from a high dimensional data source, such as neuroimaging data and genetic data, arises in much scientific research. In this work, we formulate a multiple-hypothesis testing framework for mediator selection from a high-dimensional candidate set, and propose a method, which extends the recent development in false discovery rate (FDR)-controlled variable selection with knockoff to select mediators with FDR control. We show that the proposed method and algorithm achieved finite sample FDR control. We present extensive simulation results to demonstrate the power and finite sample performance compared with the existing method. Lastly, we demonstrate the method for analyzing the Adolescent Brain Cognitive Development (ABCD) study, in which the proposed method selects several resting-state functional magnetic resonance imaging connectivity markers as mediators for the relationship between adverse childhood events and the crystallized composite score in the NIH toolbox.

Post-Pandemic Evaluation: Impact of Covid-19 Pandemic on Medical Students’ Mental Health, Self-Esteem, Social Interactions, and Academic Progression in Malaysia

Covid-19 pandemic has brought drastic and unprecedented challenges to the medical education and medical students, affecting them physically, mentally and emotionally. While progressing through the post-pandemic recovery phase, it is crucial to comprehensively evaluate the pandemic’s consequences and tackle the underlying problems. To investigate the impact of Covid-19 pandemic on medical students’ mental health, social well-being, and academic progression. A cross-sectional study was carried out with voluntary sampling of students from both government and private medical schools in Malaysia. A self-administered online survey form containing three validated psychological tools was distributed (Hospital Anxiety and Depression Scale HADS, Rosenberg Self-esteem Scale, NIH Toolbox Social Relationship Scales). There were also questions regarding the challenges faced by medical students and their academic performance during Covid-19 pandemic. Scores of each questionnaire were tabulated, analyzed and interpreted according to their specific cut-points. Two hundred and thirteen responses were received. 89.2% (n = 190) were domestic students while 10.8% (n = 23) were international students. Out of 32 medical universities in Malaysia, the participants were from 19 of them (9 public and 10 private universities). About half of the participants had contracted Covid-19 infection during the study period (n = 124, 58.2%). Majority had chosen “Lack of on-campus learning and training session causing incompetency” as the most relevant impact of Covid-19 on their academic progression (n = 85, 39.9%). Above 90% of participants passed their Final Academic Assessment in 2020 (91.5%) and 2021 (93.9%). About half of them (n = 86, 40.4%) were having symptoms considerable of anxiety while only 19.2% (n = 41) were having symptoms considerable of depression. Majority had normal self-esteem (n = 177, 83.1%). For social relationship, around two-third of them had great social support and companionship. However, more than half had social distress. The median for the period of time having absolute online classes, absolute physical classes and hybrid classes were 18, 4, and 9 months, respectively. Having absolute online classes of &gt;18 months was associated significantly with higher perceived hostility (16.49vs. 14.47, p = .012). In addition, being infected with Covid-19 was associated significantly with higher self-esteem (26.88vs. 25.85, p = .009). Large proportion of students were affected by Covid-19 pandemic. Absolute online classes has huge impact on emotions of medical students especially from the aspect of perceived hostility. Hence, implementation of online medical education during Covid-19 era requires modifications and improvements.

Comparing the stability and reproducibility of brain-behavior relationships found using canonical correlation analysis and partial least squares within the ABCD sample.

Canonical correlation analysis (CCA) and partial least squares correlation (PLS) detect linear associations between two data matrices by computing latent variables (LVs) having maximal correlation (CCA) or covariance (PLS). This study compared the similarity and generalizability of CCA- and PLS-derived brain-behavior relationships. Data were accessed from the baseline Adolescent Brain Cognitive Development (ABCD) dataset (N > 9,000, 9-11 years). The brain matrix consisted of cortical thickness estimates from the Desikan-Killiany atlas. Two phenotypic scales were examined separately as the behavioral matrix; the Child Behavioral Checklist (CBCL) subscale scores and NIH Toolbox performance scores. Resampling methods were used to assess significance and generalizability of LVs. LV1 for the CBCL brain relationships was found to be significant, yet not consistently stable or reproducible, across CCA and PLS models (singular value: CCA = .13, PLS = .39, p < .001). LV1 for the NIH brain relationships showed similar relationships between CCA and PLS and was found to be stable and reproducible (singular value: CCA = .21, PLS = .43, p < .001). The current study suggests that stability and reproducibility of brain-behavior relationships identified by CCA and PLS are influenced by the statistical characteristics of the phenotypic measure used when applied to a large population-based pediatric sample.

Developmental associations between cognition and adaptive behavior in intellectual and developmental disability

BackgroundIntellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM–5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD.MethodsThree groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (mage = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization).ResultsOver a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model.ConclusionsThe present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, “real life” meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

Prevalence of detectable HIV-DNA and HIV-RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy.

Central nervous system (CNS) HIV infection can impact cognition and may be an obstacle to cure in adolescents and young adults with perinatal HIV (AYAPHIV). IMPAACT2015 enrolled AYAPHIV on suppressive antiretroviral therapy (ART) with cognitive impairment to detect and quantify HIV in blood and cerebrospinal fluid (CSF). IMPAACT2015 was a U.S.-based multi-site, exploratory, observational study. Cognitive impairment was defined as NIH Toolbox Fluid Cognition Composite score (FCCS) more than 1 standard deviation below age-adjusted normative group mean. Cell-free HIV-RNA and cell-associated HIV pol/gag -DNA and 10 biomarkers of inflammation/neuronal injury were measured in paired CSF and blood. ART exposure concentrations were quantified in hair. Among 24 participants, 20 had successful CSF collection and 18 also met viral suppression criteria. Nine of 18 (50%) were female sex-at-birth, and 14 of 18 (78%) were black. Median (range) age was 20 years (13-27), time on ART was 18.3 years (8.0-25.5), and FCCS was 68 (53-80). HIV-DNA was detected in PBMCs from all participants. In CSF, two of 18 (11%, 95% CI: 1.4-34.7%) participants had detectable cell-free HIV-RNA, while HIV gag or pol -DNA was detectable in 13 of 18 (72%, 95% confidence interval: 47-90). Detectable HIV-DNA in CSF was associated with male sex-at-birth ( P = 0.051), lower CD4 + cell count at enrollment ( P = 0.016), and higher PBMC HIV pol -DNA copies ( P = 0.058). Hair antiretroviral concentrations and biomarkers were not associated with CSF HIV-DNA detection. We found that a high proportion of AYAPHIV with neurocognitive impairment had CSF cells harboring HIV-DNA during long-term virologic suppression. This evidence of persistent HIV-DNA in CSF suggests that the CNS should be considered in treatment and cure studies.

Emotional Awareness and Expression Therapy vs Cognitive Behavioral Therapy for Chronic Pain in Older Veterans

Chronic pain is common and disabling in older adults, and psychological interventions are indicated. However, the gold standard approach, cognitive-behavioral therapy (CBT), produces only modest benefits, and more powerful options are needed. To evaluate whether emotional awareness and expression therapy (EAET) is superior to CBT for treatment of chronic pain among predominantly male older veterans and whether higher baseline depression, anxiety, or posttraumatic stress disorder (PTSD) symptoms-key targets of EAET-moderate treatment response. This 2-arm randomized clinical trial was conducted from May 16, 2019, to September 14, 2023, in the US Department of Veterans Affairs Greater Los Angeles Healthcare System. The trial included a racially and ethnically diverse group of veterans aged 60 to 95 years with at least 3 months of musculoskeletal pain. Emotional awareness and expression therapy or CBT, conducted concurrently, each presented as one 90-minute individual session followed by eight 90-minute group sessions. The primary outcome was Brief Pain Inventory pain severity (range, 0 to 10) from baseline to posttreatment (week 10, primary end point) and 6-month follow-up. Secondary outcomes included Patient Reported Outcomes Institute Measurement System Anxiety, Depression, Fatigue, General Life Satisfaction (NIH Toolbox), Pain Interference, and Sleep Disturbance Short Forms, Patient Global Impression of Change (PGIC), and Satisfaction with Therapy and Therapist Scale-Revised. A subset of participants completed the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). All analyses were for the intention-to-treat population and included all randomized participants. Among 126 randomized participants (66 in the EAET group and 60 in the CBT group; mean [SD] age, 71.9 [5.9] years; 116 [92%] male), 111 (88%) completed posttreatment, and 104 (82%) completed the 6-month follow-up. The EAET was superior to CBT for the primary outcome of reduction in pain severity at posttreatment (estimate, -1.59 [95% CI, -2.35 to -0.83]; P < .001) and follow-up (estimate, -1.01 [95% CI, -1.78 to -0.24]; P = .01). A greater percentage of participants in EAET vs CBT had clinically significant (at least 30%) pain reduction (63% vs 17%; odds ratio, 21.54 [95% CI, 4.66-99.56]; P < .001) at posttreatment. In addition, EAET was superior to CBT on 50% pain reduction (35% vs 7%; odds ratio, 11.77 [95% CI, 2.38-58.25]; P = .002), anxiety (estimate, -2.49 [95% CI, -4.30 to -0.68]; P = .006), depression (estimate, -3.06 [95% CI, -5.88 to -0.25]; P = .03), general life satisfaction (estimate, 1.23 [95% CI, 0.36-2.10]; P = .005), PTSD symptoms (estimate, -4.39 [95% CI, -8.44 to -0.34]; P = .03), PGIC score (estimate, 1.46 [95% CI, 0.77-2.15]; P < .001), and global treatment satisfaction (estimate, 0.28 [95% CI, 0.12-0.45]; P < .001) at posttreatment. Higher baseline depression (estimate, -1.55 [95% CI, -0.37 to 2.73]; P < .001), anxiety (estimate, -1.53 [95% CI, -2.19 to -0.88]; P < .001), and PTSD symptoms (estimate, -1.69 [95% CI, -2.96 to -0.42]; P = .009) moderated greater reduction in pain severity after EAET but not CBT. The results of this randomized clinical trial suggest that EAET may be a preferred intervention for medically and psychiatrically complex patients with pain. The societal burden of chronic pain could be improved by further incorporating the principles of EAET into mainstream clinical pain medicine. ClinicalTrials.gov Identifier: NCT03918642.

Correlation Between VOC and Cognitive Function Using the NIH ToolBox in SCD

Correlation Between VOC and Cognitive Function Using the NIH ToolBox in SCD

Prenatal and childhood air pollution exposure, cellular immune biomarkers, and brain connectivity in early adolescents

IntroductionAmbient air pollution is a neurotoxicant with hypothesized immune-related mechanisms. Adolescent brain structural and functional connectivity may be especially vulnerable to ambient pollution due to the refinement of large-scale brain networks during this period, which vary by sex and have important implications for cognitive, behavioral, and emotional functioning. In the current study we explored associations between air pollutants, immune markers, and structural and functional connectivity in early adolescence by leveraging cross-sectional sex-stratified data from the Adolescent Brain Cognitive Development℠ Study®. MethodsPollutant concentrations of fine particulate matter, nitrogen dioxide, and ozone were assigned to each child's primary residential address during the prenatal period and childhood (9-10 years-old) using an ensemble-based modeling approach. Data collected at 11-13 years-old included resting-state functional connectivity of the default mode, frontoparietal, and salience networks and limbic regions of interest, intracellular directional and isotropic diffusion of available white matter tracts, and markers of cellular immune activation. Using partial least squares correlation, a multivariate data-driven method that identifies important variables within latent dimensions, we investigated associations between 1) pollutants and structural and functional connectivity, 2) pollutants and immune markers, and 3) immune markers and structural and functional connectivity, in each sex separately. ResultsAir pollution exposure was related to white matter intracellular directional and isotropic diffusion at ages 11–13 years, but the direction of associations varied by sex. There were no associations between pollutants and resting-state functional connectivity at ages 11–13 years. Childhood exposure to nitrogen dioxide was negatively correlated with white blood cell count in males. Immune biomarkers were positively correlated with white matter intracellular directional diffusion in females and both white matter intracellular directional and isotropic diffusion in males. Lastly, there was a reliable negative correlation between lymphocyte-to-monocyte ratio and default mode network resting-state functional connectivity in females, as well as a compromised immune marker profile associated with lower resting-state functional connectivity between the salience network and the left hippocampus in males. In post-hoc exploratory analyses, we found that the PLSC-identified white matter tracts and resting-state networks related to processing speed and cognitive control performance from the NIH Toolbox. ConclusionsWe identified novel links between childhood nitrogen dioxide and cellular immune activation in males, and brain network connectivity and immune markers in both sexes. Future research should explore the potentially mediating role of immune activity in how pollutants affect neurological outcomes as well as the potential consequences of immune-related patterns of brain connectivity in service of improved brain health for all.

Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Testing the structural disconnection hypothesis: Myelin content correlates with memory in healthy aging

IntroductionThe "structural disconnection" hypothesis of cognitive aging suggests that deterioration of white matter (WM), especially myelin, results in cognitive decline, yet in vivo evidence is inconclusive. MethodsWe examined age differences in WM microstructure using Myelin Water Imaging and Diffusion Tensor Imaging in 141 healthy participants (age 20–79). We used the Virginia Cognitive Aging Project and the NIH Toolbox® to generate composites for memory, processing speed, and executive function. ResultsVoxel-wise analyses showed that lower myelin water fraction (MWF), predominantly in prefrontal WM, genu of the corpus callosum, and posterior limb of the internal capsule was associated with reduced memory performance after controlling for age, sex, and education. In structural equation modeling, MWF in the prefrontal white matter and genu of the corpus callosum significantly mediated the effect of age on memory, whereas fractional anisotropy (FA) did not. DiscussionOur findings support the disconnection hypothesis, showing that myelin decline contributes to age-related memory loss and opens avenues for interventions targeting myelin health.