Biology subjects

Bradley, B.

Publications and source records attributed to Bradley, B..

8 recordsLinked to original sources

bioRxiv2023

Neurophysiological Changes Associated with Vibroacoustically-augmented Breath-focused Mindfulness for Dissociation: Targeting Interoception and Attention

BackgroundDissociative symptoms can emerge after trauma and interfere with attentional control and interoception, both of which are barriers to mind-body interventions such as breath-focused mindfulness (BFM). To overcome these barriers, we tested the use of an exteroceptive augmentation to BFM, using vibrations equivalent to the amplitude of the auditory waveform of the actual breath, delivered via a wearable subwoofer in real time (VBFM). We tested whether this device enhanced interoceptive processes, attentional control and autonomic regulation in trauma-exposed women with dissociative symptoms. Method65 women, majority (82%) Black American, aged 18-65 completed self-report measures of interoception and 6 BFM sessions, during which electrocardiographic recordings were taken to derive high-frequency heart rate variability (HRV) estimates. A subset (n=31) of participants completed functional MRI at pre- and post-intervention, during which they were administered an affective attentional control task. ResultsCompared to those who received BFM only, women who received VBFM demonstrated greater increases in interoception, particularly their ability to trust body signals, increased sustained attention, and as well as increased connectivity between nodes of emotion processing and interoceptive networks. Intervention condition moderated the relationship between interoception change and dissociation change, as well as the relationship between dissociation and HRV change. ConclusionsVibration feedback during breath focus yielded greater improvements in interoception, sustained attention and increased connectivity of emotion processing and interoceptive networks. Augmenting BFM with vibration appears to have considerable effects on interoception, attention and autonomic regulation; it could be used as a monotherapy or to address trauma treatment barriers.

neuroscience↗

bioRxiv2021

A Kernel Method for Dissecting Genetic Signals in Tests of High-Dimensional Phenotypes

Genomewide association studies increasingly employ multivariate tests of multiple correlated phenotypes to exploit likely pleiotropy to improve power. Typical multivariate methods produce a global p-value of association between a variant (or set of variants) and multiple phenotypes. When the global test is significant, subsequent interest then focuses on dissecting the signal and, in particular, delineating the set of phenotypes where the genetic variant(s) have a direct effect from the remaining phenotypes where the genetic variant(s) possess either indirect or no effect. While existing techniques like mediation models can be utilized for this purpose, they generally cannot handle high-dimensional phenotypic and genotypic data. To assist in filling this important gap, we propose a modification of a kernel distance-covariance framework for gene mapping of multiple variants with multiple phenotypes to test instead whether the association between the variants and a group of phenotypes is driven through a direct association with just a subset of the phenotypes. We use simulated data to show that our new method controls for type I error and is powerful to detect a variety of models demonstrating different patterns of direct and indirect effects. We further illustrate our method using GWAS data from the Grady Trauma Project and show that an existing signal between genetic variants in the ZHX2 gene and 21 items within the Beck Depression Inventory appears to be due to a direct effect of these variants on only 3 of these items. Our approach scales to genomewide analysis, and is applicable to high-dimensional correlated phenotypes.

genomics↗

bioRxiv2019

Sensitive detection of highly fragmented cytomegalovirus nucleic acid in human cfDNA

Congenital human cytomegalovirus (CMV) infections are the leading cause of newborn hearing and central nervous system impairments worldwide. Currently, routine prenatal screening for congenital CMV is not performed in the United States and confirmation in suspected perinatal cases requires invasive sampling by amniocentesis. We hypothesized that detection of CMV from maternal cell-free DNA (cfDNA) plasma could provide a non-invasive indicator of congenital CMV infection. We analyzed sequence data from 2,208 individuals undergoing routine non-invasive prenatal aneuploidy screening at the University of Washington. CMV reads were identified in 117 (5.3%) samples. Positive samples were stratified based on CMV reads per million sample reads (RPM), resulting in ten samples being classified as strong positive (RPM > 0.3) and 107 as intermediate positive (0.01<RPM<0.3). Subsequent qPCR testing identified CMV in 9/10 strong positive samples and 2/32 intermediate positive samples. Median cfDNA insert size derived from CMV was significantly shorter than cfDNA derived from human chromosomes (103 vs 172 bp, p<0.0001), corresponding to the 3rd percentile of human cfDNA insert size. In addition, CMV cfDNA fragment lengths were distributed over a wider range than human cfDNA reads. These studies reveal the highly fragmented nature of CMV cfDNA and offer precise measurements of its length: these features likely explain discrepancies in serum CMV viral loads measurements determined by different qPCR assays, despite widespread efforts to standardize results. More work is required to determine how detection of CMV from maternal cfDNA can be best used as tool for congenital CMV screening or diagnosis.

microbiology↗

bioRxiv2019

Genomic Influences on Self-Reported Childhood Maltreatment

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to 1) identify genetic variation associated with reported childhood maltreatment, 2) calculate the relevant SNP-based heritability estimates, and 3) quantify the genetic overlap of reported childhood maltreatment with mental and physical health-related phenotypes. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n=124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder working group (PGC-PTSD) (n=26,290). Heritability estimations for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression (LDSR). Two genome-wide significant loci associated with childhood maltreatment, located on chromosomes 3p13 (rs142346759, beta=0.015, p=4.35x10-8, FOXP1) and 7q31.1 (rs10262462, beta=-0.016, p=3.24x10-8, FOXP2), were identified in the discovery dataset but were not replicated in the PGC-PTSD sample. SNP-based heritability for childhood maltreatment was estimated to be [~]6%. Childhood maltreatment was most significantly genetically correlated with depressive symptoms (rg=0.70, p=4.65x10-40). This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. FOXP genes could influence traits such as depression and thereby be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with various psychiatric disorders, may ultimately be useful in in developing targeted treatment and prevention strategies.

genomics↗

bioRxiv2018

Epigenetic derepression of FKBP5 by aging and stress contributes to NF-kB-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are poorly understood. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress exposure along the lifespan could confer disease risk by epigenetically deregulating molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with mechanistic in vitro investigations, we found that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n=3,131), aging and stress-related phenotypes were synergistically associated with epigenetic derepression of FKBP5. These age/stress-related epigenetic effects were recapitulated in an in vitro model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-{kappa}B-related gene networks. Accordingly, experiments in immune cells showed that FKBP5 overexpression promotes inflammation by strengthening the interactions of NF-{kappa}B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-{kappa}B. Further, the age/stress-related epigenetic signature enhanced FKBP5 responsivity to NF-{kappa}B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that FKBP5-NF-{kappa}B signaling mediates inflammation associated with aging and stress, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.\n\nSignificanceDiseases of the aging are the leading cause of morbidity and mortality. Elucidating the molecular mechanisms through which modifiable factors, such as psychosocial stress, confer risk for aging-related disease can have profound implications. Here, by combining studies in humans with experiments in cells, we find that aging and stress synergize to epigenetically derepress FKBP5, a protein implicated in stress physiology. Higher FKBP5 promotes inflammation by activating the master immune regulator NF-{kappa}B, whereas opposing FKBP5 - either genetically or pharmacologically- prevents the effects on NF-{kappa}B. Further, the age/stress-related epigenetic signature of FKBP5 is associated with history of myocardial infarction, a disease state linked to inflammation. These findings provide molecular insights into stress-related disease and may point to novel biomarker and treatment possibilities.

genomics↗

bioRxiv2018

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinsons Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

genetics↗

bioRxiv2018

Powerful and Efficient Strategies for Genetic Association Testing of Symptom and Questionnaire Data in Psychiatric Genetic Studies

Genetic studies of psychiatric disorders often deal with phenotypes that are not directly measurable. Instead, researchers rely on multivariate symptom data from questionnaires and surveys like the PTSD Symptom Scale (PSS) and Beck Depression Inventory (BDI) to indirectly assess a latent phenotype of interest. Researchers subsequently collapse such multivariate questionnaire data into a univariate outcome to represent a surrogate for the latent phenotype. However, when a causal variant is only associated with a subset of collapsed symptoms, the effect will be challenging to detect using the univariate outcome. We describe a more powerful strategy for genetic association testing in this situation that jointly analyzes the original multivariate symptom data collectively using a statistical framework that compares similarity in multivariate symptom-scale data from questionnaires to similarity in common genetic variants across a gene. We use simulated data to demonstrate this strategy provides substantially increased power over standard approaches that collapse questionnaire data into a single surrogate outcome. We also illustrate our approach using GWAS data from the Grady Trauma Project and identify genes associated with BDI not identified using standard univariate techniques. The approach is computationally efficient, scales to genome-wide studies, and is applicable to correlated symptom data of arbitrary dimension (thereby aligning with National Institute of Mental Healths Research Domain Criteria).

genetics↗

bioRxiv2017

1/f neural noise is a better predictor of schizophrenia than neural oscillations

Diagnosis and symptom severity in schizophrenia are associated with irregularities across neural oscillatory frequency bands, including theta, alpha, beta, and gamma. However, electroencephalographic signals consist of both periodic and aperiodic activity characterized by the (1/fX) shape in the power spectrum. In this paper we investigated oscillatory and aperiodic activity differences between patients with schizophrenia and healthy controls during a target detection task. Separation into periodic and aperiodic components revealed that the steepness of the power spectrum better predicted group status than traditional band-limited oscillatory power in a classification analysis. Aperiodic activity also outperformed the predictions made using participants behavioral responses. Additionally, the differences in aperiodic activity were highly consistent across all electrodes. In sum, compared to oscillations the aperiodic activity appears to be a more accurate and more robust way to differentiate patients with schizophrenia from healthy controls. Significance statementUnderstanding the neurobiological origins of schizophrenia and identifying reliable and consistent biomarkers are of critical importance to improving treatment of that disease. Numerous studies have reported disruptions to neural oscillations in patients with schizophrenia. This has, in part, led to schizophrenia being characterized as a disease of disrupted neural coordination, reflected by changes in frequency band power. We report however that changes in the aperiodic signal can also predict clinical status. Unlike band-limited power though, aperiodic activity predicts status better than participants own behavioral performance and acts as a consistent predictor across all electrodes. Alterations in the aperiodic signal are consistent with well-established inhibitory neuron dysfunctions associated with schizophrenia, allowing for a direct link between noninvasive EEG and chronic, widespread, neurobiological deficits.

neuroscience↗