Faculty Bibliography
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school:SOM
Department/Unit:Neuroscience Institute
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13349
Differentiation of Jugular Foramen Paragangliomas versus Schwannomas Using Golden-Angle Radial Sparse Parallel Dynamic Contrast-Enhanced MRI
BACKGROUND AND PURPOSE:Accurate differentiation of paragangliomas and schwannomas in the jugular foramen has important clinical implications because treatment strategies may vary but differentiation is not always straightforward with conventional imaging. Our aim was to evaluate the accuracy of both qualitative and quantitative metrics derived from dynamic contrast-enhanced MR imaging using golden-angle radial sparse parallel MR imaging to differentiate paragangliomas and schwannomas in the jugular foramen. MATERIALS AND METHODS:test. A univariate logistic model was created with a binary output, paraganglioma or schwannoma, using a wash-in rate as a variable. Additionally, lesions were clustered on the basis of the wash-in rate and washout rate using a 3-nearest neighbors method. RESULTS:< .001). All 30 lesions were classified correctly by using a 3-nearest neighbors method. CONCLUSIONS:Paragangliomas at the jugular foramen can be reliably differentiated from schwannomas using golden-angle radial sparse parallel MR imaging-dynamic contrast-enhanced imaging when imaging characteristics cannot suffice.
PMID: 34503944
ISSN: 1936-959x
CID: 5033132
Reducing interaural tonotopic mismatch preserves binaural unmasking in cochlear implant simulations of single-sided deafness
Binaural unmasking, a key feature of normal binaural hearing, can refer to the improved intelligibility of masked speech by adding masking that facilitates perceived separation of target and masker. A question relevant for cochlear implant users with single-sided deafness (SSD-CI) is whether binaural unmasking can still be achieved if the additional masking is spectrally degraded and shifted. CIs restore some aspects of binaural hearing to these listeners, although binaural unmasking remains limited. Notably, these listeners may experience a mismatch between the frequency information perceived through the CI and that perceived by their normal hearing ear. Employing acoustic simulations of SSD-CI with normal hearing listeners, the present study confirms a previous simulation study that binaural unmasking is severely limited when interaural frequency mismatch between the input frequency range and simulated place of stimulation exceeds 1-2 mm. The present study also shows that binaural unmasking is largely retained when the input frequency range is adjusted to match simulated place of stimulation, even at the expense of removing low-frequency information. This result bears implications for the mechanisms driving the type of binaural unmasking of the present study and for mapping the frequency range of the CI speech processor in SSD-CI users.
PMID: 34717490
ISSN: 1520-8524
CID: 5037682
Journal of the American Academy of Child & Adolescent Psychiatry. 2021:Conference:(68th):S168-S169.DOI: 10.1016/j.jaac.2021.09.105
6.32 Assessing the Effect of Youth Involvement in Adverse Event Reporting during a Clinical Trial of Cannabidiol for Youth WITH AUTISM SPECTRUM DISORDER with Complex Verbal Language [Meeting Abstract]
Objectives: Clinical trials in youth with autism spectrum disorder (ASD) have typically neglected the voices of the youth themselves. Besides raising ethical questions, this may also affect the quality of the data obtained. We examined differences in adverse event (AE) reporting between parents and parent-child dyads in an open trial of cannabidiol (CBD). We hypothesized that including youth with ASD in AE reporting would increase the number of total and related AEs independently of response.
Method(s): Twelve youth (ages 7-14 years) with ASD (verbally fluent, IQ >= 80) completed a 6-week, Phase 2 open trial of 98% CBD (Epidiolex [V], 100 mg/mL) at 3 or 6 mg/kg/day; target N = 30. An individualized target symptom domain was identified at baseline by clinician consensus from informant report, rating scales, and clinical observation. Responders were defined by Clinical Global Impression Scale-Improvement (CGI-I) <= 2 in their target symptom domain. AEs were assessed by phone with parents (weeks 1, 3, 5) and via the UKU (Udvalg for Kliniske Under-sogelser) Side Effects Rating Scale administered by clinicians to dyads (weeks 2, 4, 6). Clinician consensus determined the relatedness of AEs to treatment. Disease-related events (DREs) were considered adverse if the severity or frequency increased. In this interim analysis, we identified response to treatment and AEs, contrasted AE rates (parents vs dyads), and examined the relationship between treatment response and AE profile.
Result(s): All 12 initial participants completed the trial; 4 responded (33%). Clinical Global Impression Scale-Severity (CGI-S) improved significantly from pre- (M = 4.83; SD = 0.39) to posttreatment (M = 3.92; SD = 0.90) (t11 = 3.53; p < 0.004). The most frequent AEs were tiredness (n = 5) and increased emotionality (n = 3). Of 47 total AEs, all were mild and 39 were first reported by dyads. Of 14 related AEs, 9 were first reported by dyads. One DRE occurred: increased severity of restricted, repetitive behaviors. The number of AEs reported by dyads (M = 3.25; SD = 3.14) compared to parents alone (M = 0.67; SD = 0.89) was significantly higher (t11 = 2.18; p = 0.017). Responders and nonresponders did not differ significantly in the number of total or related AEs.
Conclusion(s): This interim analysis suggests that including the input of children with ASD in AE reporting captures a fuller profile of total and related AEs without compromising the study integrity or results. ASD, OLT, R
Copyright
Method(s): Twelve youth (ages 7-14 years) with ASD (verbally fluent, IQ >= 80) completed a 6-week, Phase 2 open trial of 98% CBD (Epidiolex [V], 100 mg/mL) at 3 or 6 mg/kg/day; target N = 30. An individualized target symptom domain was identified at baseline by clinician consensus from informant report, rating scales, and clinical observation. Responders were defined by Clinical Global Impression Scale-Improvement (CGI-I) <= 2 in their target symptom domain. AEs were assessed by phone with parents (weeks 1, 3, 5) and via the UKU (Udvalg for Kliniske Under-sogelser) Side Effects Rating Scale administered by clinicians to dyads (weeks 2, 4, 6). Clinician consensus determined the relatedness of AEs to treatment. Disease-related events (DREs) were considered adverse if the severity or frequency increased. In this interim analysis, we identified response to treatment and AEs, contrasted AE rates (parents vs dyads), and examined the relationship between treatment response and AE profile.
Result(s): All 12 initial participants completed the trial; 4 responded (33%). Clinical Global Impression Scale-Severity (CGI-S) improved significantly from pre- (M = 4.83; SD = 0.39) to posttreatment (M = 3.92; SD = 0.90) (t
Conclusion(s): This interim analysis suggests that including the input of children with ASD in AE reporting captures a fuller profile of total and related AEs without compromising the study integrity or results. ASD, OLT, R
Copyright
EMBASE:2014994967
ISSN: 1527-5418
CID: 5024292
Urinary stone disease prevalence and associations in cystic fibrosis
Cystic fibrosis (CF) may predispose patients to urinary stone disease (USD), but reported prevalence of USD in patients with CF in previous small studies is variable. To date, analysis of risk factors for USD within the CF population has been limited. We studied 29,396 patients in the Cystic Fibrosis Foundation Patient Registry to calculate age and sex-stratified prevalence of USD. For adult patients, we examined age and multivariable-adjusted cross-sectional associations between demographic and clinical factors, CFTR mutation class, and prevalent USD. Prevalence of USD was 0.4% (95% CI 0.3-0.5%) under age 18 years, 3.1% (2.7-3.6%) at 18-24 years, 6.4% (5.8-7.1%) at 25-34 years, 7.5% (6.5-8.5%) at 35-44 years, and 6.7% (5.8-7.8%) at 45 years and older. Prevalence for women was higher than men at younger (< 45 years) but not older ages (P value for interaction < 0.0005). Multivariable odds of prevalent USD were significantly increased for severe CFTR mutations, OR 1.53 (1.14-2.06), diabetes, OR 1.24 (1.03-1.50), hypertension, OR 1.58 (1.29-1.93), and chronic macrolide therapy, OR 1.27 (1.07-1.52). BMI was not associated with USD. USD prevalence in CF is similar to that in the general population. With the exception of BMI, known risk factors for USD in the general population also appear to be important for patients with CF. We identified several novel associations in CF patients, including greater prevalence of USD in individuals with severe CFTR mutations and among young women.
PMID: 33547925
ISSN: 2194-7236
CID: 4789732
Journal of child psychology & psychiatry & allied disciplines. 2021:62(10):1202-1219.DOI: 10.1111/jcpp.13396
Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets
OBJECTIVE:Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS:We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS:There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION/CONCLUSIONS:Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
PMID: 33748971
ISSN: 1469-7610
CID: 4822272
A multimodal cell census and atlas of the mammalian primary motor cortex
Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1-5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
PMCID:8494634
PMID: 34616075
ISSN: 1476-4687
CID: 5136522
Neuroinflammatory astrocyte subtypes in the mouse brain
Astrocytes undergo an inflammatory transition after infections, acute injuries and chronic neurodegenerative diseases. How this transition is affected by time and sex, its heterogeneity at the single-cell level and how sub-states are spatially distributed in the brain remains unclear. In this study, we investigated transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus using the bacterial cell wall endotoxin lipopolysaccharide. We identified fast transcriptomic changes in astrocytes occurring within hours that drastically change over time. By sequencing ~80,000 astrocytes at single-cell resolution, we show that inflammation causes a widespread response with subtypes of astrocytes undergoing distinct inflammatory transitions with defined transcriptomic profiles. We also attribute key sub-states of inflammation-induced reactive astrocytes to specific brain regions using spatial transcriptomics and in situ hybridization. Together, our datasets provide a powerful resource for profiling astrocyte heterogeneity and will be useful for understanding the biological importance of regionally constrained reactive astrocyte sub-states.
PMID: 34413515
ISSN: 1546-1726
CID: 5006402
Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease
Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Ts65Dn mice had unique MSN BFCN transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamatergic, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate this interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.
PMID: 34263425
ISSN: 1559-1182
CID: 4937542
State-related neural influences on fMRI connectivity estimation
The spatiotemporal structure of functional magnetic resonance imaging (fMRI) signals has provided a valuable window into the network underpinnings of human brain function and dysfunction. Although some cross-regional temporal correlation patterns (functional connectivity; FC) exhibit a high degree of stability across individuals and species, there is growing acknowledgment that measures of FC can exhibit marked changes over a range of temporal scales. Further, FC can co-vary with experimental task demands and ongoing neural processes linked to arousal, consciousness and perception, cognitive and affective state, and brain-body interactions. The increased recognition that such interrelated neural processes modulate FC measurements has raised both challenges and new opportunities in using FC to investigate brain function. Here, we review recent advances in the quantification of neural effects that shape fMRI FC and discuss the broad implications of these findings in the design and analysis of fMRI studies. We also discuss how a more complete understanding of the neural factors that shape FC measurements can resolve apparent inconsistencies in the literature and lead to more interpretable conclusions from fMRI studies.
PMID: 34560268
ISSN: 1095-9572
CID: 5026912
Cathepsin S Evokes PAR2-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models
Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.
PMCID:8466361
PMID: 34572924
ISSN: 2072-6694
CID: 5012742
