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Gene expression imputation across multiple brain regions provides insights into schizophrenia risk.
Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardiñas AF, Rajagopal VM, Als TD, T Nguyen H, Girdhar K, Boocock J, Roussos P, Fromer M, Kramer R, Domenici E, Gamazon ER, Purcell S, CommonMind Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working Group, Demontis D, Børglum AD, Walters JTR, O'Donovan MC, Sullivan P, Owen MJ, Devlin B, Sieberts SK, Cox NJ, Im HK, Sklar P, Stahl EA
(2019) Nat Genet 51: 659-674
MeSH Terms: Brain, Case-Control Studies, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Schizophrenia, Transcriptome
Show Abstract · Added July 17, 2019
Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
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iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.
Park HJ, Lee SW, Im W, Kim M, Van Kaer L, Hong S
(2019) Mediators Inflamm 2019: 3540974
MeSH Terms: Animals, Brain, Cytokines, Disease Models, Animal, Disease Progression, Galactosylceramides, Genotype, Huntington Disease, Leukocytes, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 26, 2019
Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
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13 MeSH Terms
Linear Accelerator-Based Stereotactic Radiosurgery for Cranial Intraparenchymal Metastasis of a Malignant Peripheral Nerve Sheath Tumor: Case Report and Review of the Literature.
Fenlon JB, Khattab MH, Ferguson DC, Luo G, Keedy VL, Chambless LB, Kirschner AN
(2019) World Neurosurg 123: 123-127
MeSH Terms: Adult, Brain Neoplasms, Humans, Magnetic Resonance Imaging, Male, Nerve Sheath Neoplasms, Neurofibrosarcoma, Particle Accelerators, Positron-Emission Tomography, Radiosurgery
Show Abstract · Added April 2, 2019
BACKGROUND - Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive soft tissue sarcomas. MPNST intracranial metastasis is exceedingly rare with only 22 documented cases in the literature and, to our knowledge, only 1 case with intraparenchymal brain metastasis. Most have been managed surgically; however, 2 documented cases were treated with Gamma Knife radiosurgery. Excluding this case report, there are no other documented cases of linear accelerator-based stereotactic radiosurgery (SRS) to treat MPNST brain metastasis.
CASE DESCRIPTION - A 41-year-old man with MPNST of the lung initially underwent tumor resection. He developed multiple systemic metastases that were managed with directed radiation therapy. A parietal brain metastasis was treated with linear accelerator-based SRS. Following SRS therapy, the patient was treated with a tropomyosin receptor kinase inhibitor. Complete resolution of brain metastasis was seen on brain magnetic resonance imaging 5 months after treatment with SRS. At 11 months after SRS, there was no evidence of recurrence or progression of the intraparenchymal disease. The patient continued to have stable extracranial disease on his ninth cycle of systemic treatment.
CONCLUSIONS - This report provides important insights into efficacy of linear accelerator-based SRS to treat MPNST brain metastases.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Challenges in diffusion MRI tractography - Lessons learned from international benchmark competitions.
Schilling KG, Daducci A, Maier-Hein K, Poupon C, Houde JC, Nath V, Anderson AW, Landman BA, Descoteaux M
(2019) Magn Reson Imaging 57: 194-209
MeSH Terms: Algorithms, Benchmarking, Brain, Diffusion Tensor Imaging, Humans, Internationality, Neuroimaging, Reproducibility of Results
Show Abstract · Added March 26, 2019
Diffusion MRI (dMRI) fiber tractography has become a pillar of the neuroimaging community due to its ability to noninvasively map the structural connectivity of the brain. Despite widespread use in clinical and research domains, these methods suffer from several potential drawbacks or limitations. Thus, validating the accuracy and reproducibility of techniques is critical for sound scientific conclusions and effective clinical outcomes. Towards this end, a number of international benchmark competitions, or "challenges", has been organized by the diffusion MRI community in order to investigate the reliability of the tractography process by providing a platform to compare algorithms and results in a fair manner, and evaluate common and emerging algorithms in an effort to advance the state of the field. In this paper, we summarize the lessons from a decade of challenges in tractography, and give perspective on the past, present, and future "challenges" that the field of diffusion tractography faces.
Copyright © 2018 Elsevier Inc. All rights reserved.
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8 MeSH Terms
Deep Brain Stimulation Versus Peripheral Denervation for Cervical Dystonia: A Systematic Review and Meta-Analysis.
Ravindran K, Ganesh Kumar N, Englot DJ, Wilson TJ, Zuckerman SL
(2019) World Neurosurg 122: e940-e946
MeSH Terms: Deep Brain Stimulation, Denervation, Humans, Torticollis
Show Abstract · Added June 22, 2019
BACKGROUND - Cervical dystonia is a disabling medical condition that drastically decreases quality of life. Surgical treatment consists of peripheral nerve denervation procedures with or without myectomies or deep brain stimulation (DBS). The current objective was to compare the efficacy of peripheral denervation versus DBS in improving the severity of cervical dystonia through a systematic review and meta-analysis.
METHODS - A search of PubMed, MEDLINE, EMBASE, and Web of Science electronic databases was conducted in accordance with PRISMA guidelines. Preoperative and postoperative Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores were used to generate standardized mean differences and 95% confidence intervals (CIs), which were combined in a random-effects model. Both mean percentage and absolute reduction in TWSTRS scores were calculated. Absolute reduction was used for forest plots.
RESULTS - Eighteen studies met the inclusion criteria, comprising 870 patients with 180 (21%) undergoing DBS and 690 (79%) undergoing peripheral denervation procedures. The mean follow-up time was 31.5 months (range, 12-38 months). In assessing the efficacy of each intervention, forest plots revealed significant absolute reduction in total postoperative TWSTRS scores for both peripheral denervation (standardized mean difference 1.54; 95% CI 1.42-1.66) and DBS (standardized mean difference 2.07; 95% CI 1.43-2.71). On subgroup analysis, DBS therapy was significantly associated with improvement in postoperative TWSTRS severity (standardized mean difference 2.08; 95% CI 1.66-2.50) and disability (standardized mean difference 2.12; 95% CI 1.57-2.68) but not pain (standardized mean difference 1.18; 95% CI 0.80-1.55).
CONCLUSIONS - Both peripheral denervation and DBS are associated with a significant reduction in absolute TWSTRS total score, with no significant difference in the magnitude of reduction observed between the 2 treatments. Further comparative data are needed to better evaluate the long-term results of both interventions.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Limits to anatomical accuracy of diffusion tractography using modern approaches.
Schilling KG, Nath V, Hansen C, Parvathaneni P, Blaber J, Gao Y, Neher P, Aydogan DB, Shi Y, Ocampo-Pineda M, Schiavi S, Daducci A, Girard G, Barakovic M, Rafael-Patino J, Romascano D, Rensonnet G, Pizzolato M, Bates A, Fischi E, Thiran JP, Canales-Rodríguez EJ, Huang C, Zhu H, Zhong L, Cabeen R, Toga AW, Rheault F, Theaud G, Houde JC, Sidhu J, Chamberland M, Westin CF, Dyrby TB, Verma R, Rathi Y, Irfanoglu MO, Thomas C, Pierpaoli C, Descoteaux M, Anderson AW, Landman BA
(2019) Neuroimage 185: 1-11
MeSH Terms: Brain, Brain Mapping, Diffusion Tensor Imaging, Humans, Image Processing, Computer-Assisted, Neural Pathways
Show Abstract · Added March 26, 2019
Diffusion MRI fiber tractography is widely used to probe the structural connectivity of the brain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the 3-D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge at the ISBI 2018 conference. We made available three unique independent tractography validation datasets - a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography's inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.
Copyright © 2018 Elsevier Inc. All rights reserved.
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6 MeSH Terms
Anatomical accuracy of standard-practice tractography algorithms in the motor system - A histological validation in the squirrel monkey brain.
Schilling KG, Gao Y, Stepniewska I, Janve V, Landman BA, Anderson AW
(2019) Magn Reson Imaging 55: 7-25
MeSH Terms: Algorithms, Animals, Brain, Brain Mapping, Diffusion Tensor Imaging, Image Processing, Computer-Assisted, Models, Anatomic, Motor Cortex, Probability, Reproducibility of Results, Saimiri, Sensitivity and Specificity, Software, White Matter
Show Abstract · Added March 26, 2019
For two decades diffusion fiber tractography has been used to probe both the spatial extent of white matter pathways and the region to region connectivity of the brain. In both cases, anatomical accuracy of tractography is critical for sound scientific conclusions. Here we assess and validate the algorithms and tractography implementations that have been most widely used - often because of ease of use, algorithm simplicity, or availability offered in open source software. Comparing forty tractography results to a ground truth defined by histological tracers in the primary motor cortex on the same squirrel monkey brains, we assess tract fidelity on the scale of voxels as well as over larger spatial domains or regional connectivity. No algorithms are successful in all metrics, and, in fact, some implementations fail to reconstruct large portions of pathways or identify major points of connectivity. The accuracy is most dependent on reconstruction method and tracking algorithm, as well as the seed region and how this region is utilized. We also note a tremendous variability in the results, even though the same MR images act as inputs to all algorithms. In addition, anatomical accuracy is significantly decreased at increased distances from the seed. An analysis of the spatial errors in tractography reveals that many techniques have trouble properly leaving the gray matter, and many only reveal connectivity to adjacent regions of interest. These results show that the most commonly implemented algorithms have several shortcomings and limitations, and choices in implementations lead to very different results. This study should provide guidance for algorithm choices based on study requirements for sensitivity, specificity, or the need to identify particular connections, and should serve as a heuristic for future developments in tractography.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Resting-state white matter-cortical connectivity in non-human primate brain.
Wu TL, Wang F, Li M, Schilling KG, Gao Y, Anderson AW, Chen LM, Ding Z, Gore JC
(2019) Neuroimage 184: 45-55
MeSH Terms: Animals, Brain, Brain Mapping, Diffusion Tensor Imaging, Gray Matter, Magnetic Resonance Imaging, Neural Pathways, Saimiri, White Matter
Show Abstract · Added September 21, 2018
Numerous studies have used functional magnetic resonance imaging (fMRI) to characterize functional connectivity between cortical regions by analyzing correlations in blood oxygenation level dependent (BOLD) signals in a resting state. However, to date, there have been only a handful of studies reporting resting state BOLD signals in white matter. Nonetheless, a growing number of reports has emerged in recent years suggesting white matter BOLD signals can be reliably detected, though their biophysical origins remain unclear. Moreover, recent studies have identified robust correlations in a resting state between signals from cortex and specific white matter tracts. In order to further validate and interpret these findings, we studied a non-human primate model to investigate resting-state connectivity patterns between parcellated cortical volumes and specific white matter bundles. Our results show that resting-state connectivity patterns between white and gray matter structures are not randomly distributed but share notable similarities with diffusion- and histology-derived anatomic connectivities. This suggests that resting-state BOLD correlations between white matter fiber tracts and the gray matter regions to which they connect are directly related to the anatomic arrangement and density of WM fibers. We also measured how different levels of baseline neural activity, induced by varying levels of anesthesia, modulate these patterns. As anesthesia levels were raised, we observed weakened correlation coefficients between specific white matter tracts and gray matter regions while key features of the connectivity pattern remained similar. Overall, results from this study provide further evidence that neural activity is detectable by BOLD fMRI in both gray and white matter throughout the resting brain. The combined use of gray and white matter functional connectivity could also offer refined full-scale functional parcellation of the entire brain to characterize its functional architecture.
Published by Elsevier Inc.
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9 MeSH Terms
Neural representation of vowel formants in tonotopic auditory cortex.
Fisher JM, Dick FK, Levy DF, Wilson SM
(2018) Neuroimage 178: 574-582
MeSH Terms: Acoustic Stimulation, Adult, Auditory Cortex, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Male, Phonetics, Speech Perception
Show Abstract · Added March 26, 2019
Speech sounds are encoded by distributed patterns of activity in bilateral superior temporal cortex. However, it is unclear whether speech sounds are topographically represented in cortex, or which acoustic or phonetic dimensions might be spatially mapped. Here, using functional MRI, we investigated the potential spatial representation of vowels, which are largely distinguished from one another by the frequencies of their first and second formants, i.e. peaks in their frequency spectra. This allowed us to generate clear hypotheses about the representation of specific vowels in tonotopic regions of auditory cortex. We scanned participants as they listened to multiple natural tokens of the vowels [ɑ] and [i], which we selected because their first and second formants overlap minimally. Formant-based regions of interest were defined for each vowel based on spectral analysis of the vowel stimuli and independently acquired tonotopic maps for each participant. We found that perception of [ɑ] and [i] yielded differential activation of tonotopic regions corresponding to formants of [ɑ] and [i], such that each vowel was associated with increased signal in tonotopic regions corresponding to its own formants. This pattern was observed in Heschl's gyrus and the superior temporal gyrus, in both hemispheres, and for both the first and second formants. Using linear discriminant analysis of mean signal change in formant-based regions of interest, the identity of untrained vowels was predicted with ∼73% accuracy. Our findings show that cortical encoding of vowels is scaffolded on tonotopy, a fundamental organizing principle of auditory cortex that is not language-specific.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Acute effects of insulin on circulating natriuretic peptide levels in humans.
Bachmann KN, Deger SM, Alsouqi A, Huang S, Xu M, Ferguson JF, Su YR, Niswender KD, Ikizler TA, Wang TJ
(2018) PLoS One 13: e0196869
MeSH Terms: Adult, Aged, Atrial Natriuretic Factor, Female, Glucose Clamp Technique, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Natriuretic Peptide, Brain, Obesity, Peptide Fragments
Show Abstract · Added April 2, 2019
BACKGROUND - The natriuretic peptide hormones play an important role in salt and blood pressure regulation. In observational studies, obesity and insulin resistance have been consistently associated with lower concentrations of natriuretic peptides. It has been proposed that insulin influences natriuretic peptide production.
OBJECTIVE - We sought to determine the acute effects of insulin administration on natriuretic peptide concentrations.
METHODS - 31 men and women (11 lean, 10 overweight, and 10 obese), ages 30-70 years, without cardiovascular disease or overt diabetes underwent a hyperinsulinemic-euglycemic insulin clamp. Plasma concentrations of N-terminal pro atrial natriuretic peptide (NT-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured at baseline and steady-state (the final 30 minutes of the clamp protocol).
RESULTS - From baseline to steady-state, insulin levels increased from a mean level of 9.5 to 176.7 μU/ml (p<0.001). Over this period, circulating NT-proANP concentrations decreased by 9% (-1933 ng/L, p = 0.01). The changes in NT-proANP did not differ between lean, overweight, and obese individuals. Steady-state NT-proANP levels, adjusted for baseline, were lower in individuals with greater insulin resistance, independent of BMI. In contrast to NT-proANP, NT-proBNP levels did not change significantly during the clamp (p = 0.41).
CONCLUSION - Insulin administration was associated with a moderate decrease in circulating NT-proANP, but not NT-proBNP. The lowest NT-proANP concentrations were found in insulin-resistant individuals. Further investigations are warranted to elucidate potential mechanisms underlying the effects of insulin on the cardiac hormonal axis.
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