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We seek to elucidate the underlying pathophysiology of injury sustained after mild traumatic brain injury (mTBI) using multi-shell diffusion magnetic resonance imaging, deriving compartment-specific white matter tract integrity (WMTI) metrics. WMTI allows a more biophysical interpretation of white matter (WM) changes by describing microstructural characteristics in both intra- and extra-axonal environments. Thirty-two patients with mTBI within 30 days of injury and 21 age- and sex-matched controls were imaged on a 3 Tesla magnetic resonance scanner. Multi-shell diffusion acquisition was performed with five b-values (250-2500 sec/mm2) along 6-60 diffusion encoding directions. Tract-based spatial statistics (TBSS) was used with family-wise error (FWE) correction for multiple comparisons. TBSS results demonstrated focally lower intra-axonal diffusivity (Daxon) in mTBI patients in the splenium of the corpus callosum (sCC; p < 0.05, FWE-corrected). The area under the curve value for Daxon was 0.76 with a low sensitivity of 46.9% but 100% specificity. These results indicate that Daxon may be a useful imaging biomarker highly specific for mTBI-related WM injury. The observed decrease in Daxon suggests restriction of the diffusion along the axons occurring shortly after injury.

Working memory is a complex cognitive process at the intersection of sensory processing, learning, and short-term memory and also has a general executive attention component. Impaired working memory is associated with a range of neurological and psychiatric disorders, but very little is known about how working memory relates to underlying white matter (WM) microstructure. In this study, we investigate the association between WM microstructure and performance on working memory tasks in healthy adults (right-handed, native English speakers). We combine compartment specific WM tract integrity (WMTI) metrics derived from multi-shell diffusion MRI as well as diffusion tensor/kurtosis imaging (DTI/DKI) metrics with Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) subtests tapping auditory working memory. WMTI is a novel tool that helps us describe the microstructural characteristics in both the intra- and extra-axonal environments of WM such as axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities, allowing a more biophysical interpretation of WM changes. We demonstrate significant positive correlations between AWF and letter-number sequencing (LNS), suggesting that higher AWF with better performance on complex, more demanding auditory working memory tasks goes along with greater axonal volume and greater myelination in specific regions, causing efficient and faster information process.

BackgroundIndividuals’ beliefs about the etiology of persistent physical symptoms (PPS) are linked to differences in coping style. However, it is unclear which attributions are related to greater expectations for improvement.Method and ResultsA cross-sectional regression analysis (N = 262) indicated that Veterans with Gulf War Illness (GWI) who attributed their GWI to behavior, (e.g., diet and exercise), had greater expectations for improvement (p = .001) than those who attributed their GWI to deployment, physical, or psychological causes (p values > .05).ConclusionsFindings support the possible clinical utility of exploring perceived contributing factors of PPS, which may increase perceptions that improvement of PPS is possible.Trial RegistrationClinicalTrials.gov Identifier: NCT02161133.

BackgroundMedically unexplained syndromes (MUS) are both prevalent and disabling. While illness beliefs and behaviors are thought to maintain MUS-related disability, little is known about which specific behavioral responses to MUS are related to disability or the way in which beliefs and behaviors interact to impact functioning. The purpose of the present study was to examine the relationship between illness beliefs and disability among patients with MUS, and assess the extent to which behaviors mediate this relationship.MethodsThe study examined data from the baseline assessment of a multi-site randomized controlled trial (RCT). Participants were 248 veterans with MUS. Illness beliefs, behavioral responses to illness, and disability were assessed through self-report questionnaire. Data were analyzed using mediation analysis.ResultsThreat-related beliefs predicted greater disability through decreased activity and increased practical support seeking. Protective beliefs predicted less disability through reductions in all-or-nothing behavior and limiting behavior.ConclusionsThese outcomes suggest that all-or-nothing behavior, limiting behavior, and practical support seeking are important in the perpetuation of disability among those with MUS. This has implications for improving MUS treatment by highlighting potential treatment targets.Trial RegistrationClinicalTrials.gov Identifier: NCT02161133

Few evidence-based treatments are available for Gulf War illness (GWI). Behavioral treatments that target factors known to maintain the disability from GWI, such as problem-solving impairment, may be beneficial. Problem-solving treatment (PST) targets problem-solving impairment and is an evidence-based treatment for other conditions. To examine the efficacy of PST to reduce disability, problem-solving impairment, and physical symptoms in GWI. This multicenter randomized clinical trial conducted in the US Department of Veterans Affairs compared PST with health education in a volunteer sample of 511 Gulf War veterans with GWI and disability (January 1, 2015, to September 1, 2019); outcomes were assessed at 12 weeks and 6 months. Statistical analysis was conducted between January 1, 2019, and December 31, 2020. Problem-solving treatment taught skills to improve problem-solving. Health education provided didactic health information. Both were delivered by telephone weekly for 12 weeks. The primary outcome was reduction from baseline to 12 weeks in self-report of disability (World Health Organization Disability Assessment Schedule). Secondary outcomes were reductions in self-report of problem-solving impairment and objective problem-solving. Exploratory outcomes were reductions in pain, pain disability, and fatigue. A total of 268 veterans (mean [SD] age, 52.9 [7.3] years; 88.4% male; 66.8% White) were randomized to PST (n = 135) or health education (n = 133). Most participants completed all 12 sessions of PST (114 of 135 [84.4%]) and health education (120 of 133 [90.2%]). No difference was found between groups in reductions in disability at the end of treatment. Results suggested that PST reduced problem-solving impairment (moderate effect, 0.42; P = .01) and disability at 6 months (moderate effect, 0.39; P = .06) compared with health education. In this randomized clinical trial of the efficacy of PST for GWI, no difference was found between groups in reduction in disability at 12 weeks. Problem-solving treatment had high adherence and reduced problem-solving impairment and potentially reduced disability at 6 months compared with health education. These findings should be confirmed in future studies. ClinicalTrials.gov Identifier: NCT02161133.

Social workers play an essential role in facilitating veterans’ reintegration into their communities and daily lives. Many veterans, particularly those who have been deployed, experience comorbid physical, psychological, and neurocognitive problems that significantly impact their health function in multiple domains. Veterans deployed to Operation Desert Shield/Operation Desert Storm have reported a wide range of persistent, diverse, medically unexplained symptoms that have come to be known as Gulf War Illness (GWI). These symptoms make it difficult for veterans to participate in daily activities, thereby impacting health function. There are few effective treatments to improve the health function for those with GWI. The goals of this article are to provide social workers with information about GWI, and describe how we modified an evidence-based treatment, problem-solving therapy, for veterans with GWI. This tailoring of an existing treatment may serve as a model for adapting evidence-based treatments for veterans and civilians with multiple chronic symptoms and other complex health concerns. Furthermore, the detailed description provided may facilitate dissemination of problem-solving therapy among social workers and trainees.

This article describes a study using heart rate variability (HRV) biofeedback to treat emotional dysregulation in 13 individuals with severe chronic brain injury. Measures included HRV indices, tests of attention and problem solving, and informant reports of behavioral regulation. Results demonstrated that individuals with severe brain injury were able to learn HRV biofeedback and increase coherence between the parasympathetic and sympathetic nervous systems. Individuals who attained the greatest coherence were rated as being able to best regulate their emotions and behavior.

The vertebrate pineal gland is dedicated to the production of the hormone melatonin, which increases at night to influence circadian and seasonal rhythms. This increase is associated with dramatic changes in the pineal transcriptome. Here, single-cell analysis of the rat pineal transcriptome was approached by sequencing mRNA from ~17,000 individual pineal cells, with the goals of profiling the cells that comprise the pineal gland and examining the proposal that there are two distinct populations of pinealocytes differentiated by the expression of Asmt, which encodes the enzyme that converts N-acetylserotonin to melatonin. In addition, this analysis provides evidence of cell-specific time-of-day dependent changes in gene expression. Nine transcriptomically distinct cell types were identified: ~90% were classified as melatonin-producing α- and β-pinealocytes (1:19 ratio). Non-pinealocytes included three astrocyte subtypes, two microglia subtypes, vascular and leptomeningeal cells, and endothelial cells. α-Pinealocytes were distinguished from β-pinealocytes by ~3-fold higher levels of Asmt transcripts. In addition, α-pinealocytes have transcriptomic differences that likely enhance melatonin formation by increasing the availability of the Asmt cofactor S-adenosylmethionine, resulting from increased production of a precursor of S-adenosylmethionine, ATP. These transcriptomic differences include ~2-fold higher levels of the ATP-generating oxidative phosphorylation transcriptome and ~8-fold lower levels of the ribosome transcriptome, which is expected to reduce the consumption of ATP by protein synthesis. These findings suggest that α-pinealocytes have a specialized role in the pineal gland: efficiently O-methylating the N-acetylserotonin produced and released by β-pinealocytes, thereby improving the overall efficiency of melatonin synthesis. We have also identified transcriptomic changes that occur between night and day in seven cell types, the majority of which occur in β-pinealocytes and to a lesser degree in α-pinealocytes; many of these changes were mimicked by adrenergic stimulation with isoproterenol. The cellular heterogeneity of the pineal gland as revealed by this study provides a new framework for understanding pineal cell biology at single-cell resolution.

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.