Functional connectivity and alterations in baseline brain state in humans

This work examines the influence of changes in baseline activity on the intrinsic functional connectivity fMRI (fc-fMRI) in humans. Baseline brain activity was altered by inducing anesthesia (sevoflurane end-tidal concentration 1%) in human volunteers and fc-fMRI maps between the pre-anesthetized and anesthetized conditions were compared across different brain networks. We particularly focused on low-level sensory areas (primary somatosensory, visual, and auditory cortices), the thalamus, and pain (insula), memory (hippocampus) circuits, and the default mode network (DMN), the latter three to examine higher-order brain regions. The results indicate that, while fc-fMRI patterns did not significantly differ (p<0.005; 20-voxel cluster threshold) in sensory cortex and in the DMN between the pre- and anesthetized conditions, fc-fMRI in high-order cognitive regions (i.e. memory and pain circuits) was significantly altered by anesthesia. These findings provide further evidence that fc-fMRI reflects intrinsic brain properties, while also demonstrating that 0.5 MAC sevoflurane anesthesia preferentially modulates higher-order connections

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

Background: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world\u27s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P \u3c 10-30) and African American (P \u3c .0005) participants in CSP #572. Conclusions: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations

Tick Transmission of \u3ci\u3eBorrelia burgdorferi\u3c/i\u3e to the Murine Host is not Influenced by Environmentally Acquired Midgut Microbiota

Background Ixodes scapularis is the predominant tick vector of Borrelia burgdorferi, the agent of Lyme disease, in the USA. Molecular interactions between the tick and B. burgdorferi orchestrate the migration of spirochetes from the midgut to the salivary glands—critical steps that precede transmission to the vertebrate host. Over the last decade, research efforts have invoked a potential role for the tick microbiome in modulating tick-pathogen interactions. Results Using multiple strategies to perturb the microbiome composition of B. burgdorferi-infected nymphal ticks, we observe that changes in the microbiome composition do not significantly influence B. burgdorferi migration from the midgut, invasion of salivary glands, or transmission to the murine host. We also show that within 24 and 48 h of the onset of tick feeding, B. burgdorferi spirochetes are within the peritrophic matrix and epithelial cells of the midgut in preparation for exit from the midgut. Conclusions This study highlights two aspects of tick-spirochete interactions: (1) environmental bacteria associated with the tick do not influence spirochete transmission to the mammalian host and (2) the spirochete may utilize an intracellular exit route during migration from the midgut to the salivary glands, a strategy that may allow the spirochete to distance itself from microbiota in the midgut lumen effectively. This may explain in part, the inability of environment-acquired midgut microbiota to significantly influence spirochete transmission. Unraveling a molecular understanding of this exit strategy will be critical to gain new insights into the biology of the spirochete and the tick

Monte Carlo Simulation of Transmission Studies using a Planar Sources with a Parallel Collimator and a Line Source with a Fan-Beam Collimators

A knowledge of the distribution of the attenuation coefficient is generally required for a successful correction of attenuation in nonhomogeneous regions. This can be accomplished by performing transmission measurement with either parallel or fan-bean collimation. The Monte Carlo method makes it possible to fully evaluate the results of such a correction. This study shows results from such simulations for both parallel and fan-beam transmission imaging. Also, examples of the effect of down-scatter from an emission 99mTc radionuclide into the energy window for a transmission 153Gd radionuclide are shown

Cooperative studies Program (CSP) #572: A study of serious mental illness in veterans as a pathway to personalized medicine in schizophrenia and bipolar illness

Personalization of psychiatric treatment includes treatment of symptoms, cognition and functional deficits, suicide, and medical co-morbidities. VA Collaborative Study 572 examined a large sample of male and female veterans with schizophrenia (n = 3,942) and with bipolar disorder (n = 5,414) with phenotyping and genomic analyses. We present the results to date and future directions. All veterans received a structured diagnostic interview and assessments of suicidal ideation and behavior, PTSD, and health. Veterans with schizophrenia were assessed for negative symptoms and lifetime depression. All were assessed with a cognitive and functional capacity assessment. Data for genome wide association studies were collected. Controls came from the VA Million Veteran Program. Suicidal ideation or behavior was present in 66%. Cognitive and functional deficits were consistent with previous studies. 40% of the veterans with schizophrenia had a lifetime major depressive episode and PTSD was present in over 30%. Polygenic risk score (PRS) analyses indicated that cognitive and functional deficits overlapped with PRS for cognition, education, and intelligence in the general population and PRS for suicidal ideation and behavior correlated with previous PRS for depression and suicidal ideation and behavior, as did the PRS for PTSD. Results to date provide directions for personalization of treatment in SMI, veterans with SMI, and veterans in general. The results of the genomic analyses suggest that cognitive deficits in SMI may be associated with general population features. Upcoming genomic analyses will reexamine the issues above, as well as genomic factors associated with smoking, substance abuse, negative symptoms, and treatment response

Suicidal ideation, behavior, and mortality in male and female US veterans with severe mental illness

•This research evaluated a large study population of US veterans—including a representative proportion of female veterans—with severe mental illness (SMI), and used a structured clinical interview to confirm diagnosis, which is more reliable than a clinical diagnosis.•Factors associated with suicidal behavior and death by suicide among men and women veterans with severe mental illness have similarities and differences from patterns in the general population.•Although suicide-specific mortality involved relatively few events over the six years these occurrences were an order of magnitude more frequent compared to the U.S. general population and also compared to the overall veteran population.•Female veterans with SMI had more suicide attempts than would be expected based on general population standards.•Findings from this study may have health-policy implications, including for targeted prevention strategies. We compared male and female American veterans with schizophrenia or bipolar disorder regarding clinical characteristics associated with lifetime suicidal ideation and behavior. Subsequent mortality, including death by suicide, was also assessed. Data from questionnaires and face-to-face evaluations were collected during 2011–2014 from 8,049 male and 1,290 female veterans with schizophrenia or bipolar disorder. In addition to comparing male-female characteristics, Cox regression models—adjusted for demographic information, medical-psychiatric comorbidities, and self-reported suicidal ideation and behavior—were used to examine gender differences in associations of putative risk factors with suicide-specific and all-cause mortality during up to six years of follow-up. Women overall were younger, more likely to report a history of suicidal behavior, less likely to be substance abusers, and had lower overall mortality during follow-up. Among women only, psychiatric comorbidity was paradoxically associated with lower all-cause mortality (hazard ratio [HR]=0.53, 95% CI, 0.29–0.96, p = 0.037 for 1 disorder vs. none; HR=0.44, 95% CI, 0.25–0.77, p = 0.004 for ≥2 disorders vs. none). Suicide-specific mortality involved relatively few events, but crude rates were an order of magnitude higher than in the U.S. general and overall veteran populations. Incomplete cause-of-death information and low statistical power for male-female comparisons regarding mortality. Female veterans with SMI differed from females in the general population by having a higher risk of suicide attempts. They also had more lifetime suicide attempts than male veterans with same diagnoses. These differences should inform public policy and clinical planning

Utilizing patient data from the veterans administration electronic health record to support web-based clinical decision support: informatics challenges and issues from three clinical domains

Abstract Background The US Veterans Administration (VA) has developed a robust and mature computational infrastructure in support of its electronic health record (EHR). Web technology offers a powerful set of tools for structuring clinical decision support (CDS) around clinical care. This paper describes informatics challenges and design issues that were confronted in the process of building three Web-based CDS systems in the context of the VA EHR. Methods Over the course of several years, we implemented three Web-based CDS systems that extract patient data from the VA EHR environment to provide patient-specific CDS. These were 1) the VACS (Veterans Aging Cohort Study) Index Calculator which estimates prognosis for HIV+ patients, 2) Neuropath/CDS which assists in the medical management of patients with neuropathic pain, and 3) TRIM (Tool to Reduce Inappropriate Medications) which identifies potentially inappropriate medications in older adults and provides recommendations for improving the medication regimen. Results The paper provides an overview of the VA EHR environment and discusses specific informatics issues/challenges that arose in the context of each of the three Web-based CDS systems. We discuss specific informatics methods and provide details of approaches that may be useful within this setting. Conclusions Informatics issues and challenges relating to data access and data availability arose because of the particular architecture of the national VA infrastructure and the need to link to that infrastructure from local Web-based CDS systems. Idiosyncrasies of VA patient data, especially the medication data, also posed challenges. Other issues related to specific functional needs of individual CDS systems. The goal of this paper is to describe these issues so that our experience may serve as a useful foundation to assist others who wish to build such systems in the future

Variation in orbitofrontal cortex volume: relation to sex, emotion regulation and affect

Sex differences in brain structure have been examined extensively but are not completely understood, especially in relation to possible functional correlates. Our two aims in this study were to investigate sex differences in brain structure, and to investigate a possible relation between orbitofrontal cortex subregions and affective individual differences. We used tensor-based morphometry to estimate local brain volume from MPRAGE images in 117 healthy right-handed adults (58 female), age 18–40 years. We entered estimates of local brain volume as the dependent variable in a GLM, controlling for age, intelligence and whole-brain volume. Men had larger left planum temporale. Women had larger ventromedial prefrontal cortex (vmPFC), right lateral orbitofrontal (rlOFC), cerebellum, and bilateral basal ganglia and nearby white matter. vmPFC but not rlOFC volume covaried with self-reported emotion regulation strategies (reappraisal, suppression), expressivity of positive emotions (but not of negative), strength of emotional impulses, and cognitive but not somatic anxiety. vmPFC volume statistically mediated sex differences in emotion suppression. The results confirm prior reports of sex differences in orbitofrontal cortex structure, and are the first to show that normal variation in vmPFC volume is systematically related to emotion regulation and affective individual differences

Impact of genotyping errors on statistical power of association tests in genomic analyses: A case study

A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available. In this article, we investigate the impact of variant calling errors on the statistical power to identify associations between single nucleotides and disease, and on associations between multiple rare variants and disease. Both differential and nondifferential genotyping errors are considered. Our results show that the power of burden tests for rare variants is strongly influenced by the specificity in variant calling, but is rather robust with regard to sensitivity. By using the variant calling accuracies estimated from a substudy of a Cooperative Studies Program project conducted by the Department of Veterans Affairs, we show that the power of association tests is mostly retained with commonly adopted variant calling pipelines. An R package, GWAS.PC, is provided to accommodate power analysis that takes account of genotyping errors (http://zhaocenter.org/software/)