Durham, NC, United States
Durham, NC, United States

Time filter

Source Type

Li Q.,Duke University | Ha T.S.,University of Texas Southwestern Medical Center | Okuwa S.,Duke University | Wang Y.,Duke University | And 5 more authors.
Current Biology | Year: 2013

Background Sensory neuron diversity ensures optimal detection of the external world and is a hallmark of sensory systems. An extreme example is the olfactory system, as individual olfactory receptor neurons (ORNs) adopt unique sensory identities by typically expressing a single receptor gene from a large genomic repertoire. In Drosophila, about 50 different ORN classes are generated from a field of precursor cells, giving rise to spatially restricted and distinct clusters of ORNs on the olfactory appendages. Developmental strategies spawning ORN diversity from an initially homogeneous population of precursors are largely unknown. Results Here we unravel the nested and binary logic of the combinatorial code that patterns the decision landscape of precursor states underlying ORN diversity in the Drosophila olfactory system. The transcription factor Rotund (Rn) is a critical component of this code that is expressed in a subset of ORN precursors. Addition of Rn to preexisting transcription factors that assign zonal identities to precursors on the antenna subdivides each zone and almost exponentially increases ORN diversity by branching off novel precursor fates from default ones within each zone. In rn mutants, rn-positive ORN classes are converted to rn-negative ones in a zone-specific manner. Conclusions We provide a model describing how nested and binary changes in combinations of transcription factors could coordinate and pattern a large number of distinct precursor identities within a population to modulate the level of ORN diversity during development and evolution. © 2013 Elsevier Ltd.


Balasubramaniam M.,Duke University | Telles S.,Indian Council of Medical Research Center for Advanced Research | Doraiswamy P.M.,Duke University | Doraiswamy P.M.,Duke Institute for Brain science
Frontiers in Psychiatry | Year: 2013

Background: The demand for clinically efficacious, safe, patient acceptable, and cost-effective forms of treatment for mental illness is growing. Several studies have demonstrated benefit from yoga in specific psychiatric symptoms and a general sense of well-being. Objective: To systematically examine the evidence for efficacy of yoga in the treatment of selected major psychiatric disorders. Methods: Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases, MEDLINE, EMBASE, and PsycINFO, were performed through April 2011 and an updated in June 2011 using the keywords yoga AND psychiatry OR depression OR anxiety OR schizophrenia OR cognition OR memory OR attention AND randomized controlled trial (RCT). Studies with yoga as the independent variable and one of the above mentioned terms as the dependent variable were included and exclusion criteria were applied. Results:The search yielded a total of 124 trials, of which 16 met rigorous criteria for the final review. Grade B evidence supporting a potential acute benefit for yoga exists in depression (four RCTs), as an adjunct to pharmacotherapy in schizophrenia (three RCTs), in children with ADHD (two RCTs), and Grade C evidence in sleep complaints (three RCTs). RCTs in cognitive disorders and eating disorders yielded conflicting results. No studies looked at primary prevention, relapse prevention, or comparative effectiveness versus pharmacotherapy. Conclusion:There is emerging evidence from randomized trials to support popular beliefs about yoga for depression, sleep disorders, and as an augmentation therapy. Limitations of literature include inability to do double-blind studies, multiplicity of comparisons within small studies, and lack of replication. Biomarker and neuroimaging studies, those comparing yoga with standard pharmaco and psychotherapies, and studies of long-term efficacy are needed to fully translate the promise of yoga for enhancing mental health. © 2013 Balasubramaniam, Telles and Doraiswamy.


Vaewpanich J.,Mahidol University | Reuter-Rice K.,Duke University | Reuter-Rice K.,Duke Institute for Brain science
Epilepsy and Behavior | Year: 2016

Background Traumatic brain injury (TBI) is a major cause of pediatric morbidity and mortality. Secondary injury that occurs as a result of a direct impact plays a crucial role in patient prognosis. The guidelines for the management of severe TBI target treatment of secondary injury. Posttraumatic seizure, one of the secondary injury sequelae, contributes to further damage to the injured brain. Continuous electroencephalography (cEEG) helps detect both clinical and subclinical seizure, which aids early detection and prompt treatment. Objective The aim of this study was to examine the relationship between cEEG findings in pediatric traumatic brain injury and neurocognitive/functional outcomes. Methods This study focuses on a subgroup of a larger prospective parent study that examined children admitted to a level-1 trauma hospital. The subgroup included sixteen children admitted to the pediatric intensive care unit (PICU) who received cEEG monitoring. Characteristics included demographics, cEEG reports, and antiseizure medication. We also examined outcome scores at the time of discharge and 4–6 weeks postdischarge using the Glasgow Outcome Scale — Extended Pediatrics and center-based speech pathology neurocognitive/functional evaluation scores. Results Sixteen patients were included in this study. Patients with severe TBI made up the majority of those that received cEEG monitoring. Nonaccidental trauma was the most frequent TBI etiology (75%), and subdural hematoma was the most common lesion diagnosed by CT scan (75%). Fifteen patients received antiseizure medication, and levetiracetam was the medication of choice. Four patients (25%) developed seizures during PICU admission, and 3 patients had subclinical seizures that were detected by cEEG. One of these patients also had both a clinical and subclinical seizure. Nonaccidental trauma was an etiology of TBI in all patients with seizures. Characteristics of a nonreactive pattern, severe/burst suppression, and lack of sleep architecture, on cEEG, were associated with poor neurocognitive/functional outcome. Conclusion Continuous electroencephalography demonstrated a pattern that associated seizures and poor outcomes in patients with moderate to severe traumatic brain injury, particularly in a subgroup of patients with nonaccidental trauma. Best practice should include institution-based TBI cEEG protocols, which may detect seizure activity early and promote outcomes. Future studies should include examination of individual cEEG characteristics to help improve outcomes in pediatric TBI. © 2016 Elsevier Inc.


Neavin D.,Molecular Therapeutics | Neavin D.,Rochester College | Kaddurah-Daouk R.,Duke Institute for Brain science | Weinshilboum R.,Molecular Therapeutics
Metabolomics | Year: 2016

Introduction: The initial decades of the twenty-first century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single metabolites and single genetic polymorphisms to the study of hundreds or thousands of metabolites and millions of genomic variants in a single cell or subject. It is now possible to merge and integrate large data sets generated by the use of different “-omics” techniques to increase our understanding of the molecular basis for variation in disease risk and/or drug response phenotypes. Objectives: This “Brief Review” will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy. Methods: Studies that used pharmacometabolomics to inform and guide pharmacogenomics were reviewed. Clinical studies that were used as the basis for pharmacometabolomics-informed pharmacogenomic studies, published in five independent manuscripts, are described briefly. Results: Within these five manuscripts, both pharmacokinetic and pharmacodynamic metabolomics approaches were used. Candidate gene and genome-wide approaches that were used in concert with these metabolomic data identified novel metabolite-gene relationships that were associated with drug response phenotypes in these pharmacometabolomics-informed pharmacogenomics studies. Conclusion: This “Brief Review” outlines the emerging discipline of pharmacometabolomics-informed pharmacogenomics in which metabolic profiles are associated with both clinical phenotypes and genetic variants to identify novel genetic variants associated with drug response phenotypes based on metabolic profiles. © 2016, Springer Science+Business Media New York.


Zannas A.S.,Duke University | Okuno Y.,Kyoto University | Doraiswamy P.M.,Duke University | Doraiswamy P.M.,Duke Institute for Brain science
Pharmacotherapy | Year: 2014

Study Objectives: Case reports suggest a relationship between cholinesterase inhibitors (ChEIs) and Pisa syndrome (PS), also known as pleurothotonus, a form of dystonia, but this relationship has not been systematically examined. Our objective was to estimate the adjusted reporting ratios of PS with donepezil, rivastigmine, and galantamine in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. DESIGN: Retrospective analysis of adverse event reports in the FAERS database. PATIENTS: Patients with drug-related adverse events in the FAERS database. MEASUREMENTS AND MAIN RESULTS: The Gamma Poisson Shrinker algorithm was used to estimate the empirical Bayes geometric mean (EBGM) along with the lower and upper 90% confidence interval (CI) limits (EB05 and EB95, respectively), as measures of the adjusted reporting ratio of PS in patients taking ChEIs. EB05 < 2.0 was used as the cutoff for significance for the signals. The EBGM (EB05) was 37.9 (30) for all ChEIs, 25.6 (17.6) for donepezil, 76.4 (50.3) for galantamine, and 33.7 (21.2) for rivastigmine. All adverse event signals were strongly significant based on the a priori set EB05 cutoff. The female:male ratio in the reported cases was 2:1. No significant signals were found between ChEIs and other dystonias. About half of the ChEI users were also taking concomitant antipsychotics. CONCLUSION: Although FAERS data cannot establish causality due to reporting biases, our findings support a potential dopaminergic-cholinergic imbalance as an underlying mechanism for PS and may help increase clinician awareness, early identification, and treatment of ChEI-related dystonias. KEY WORDS cholinesterase inhibitors, dystonia, Pisa syndrome, pleurothotonus. © 2013 Pharmacotherapy Publications, Inc.


Boyd J.L.,Duke University | Skove S.L.,Duke University | Rouanet J.P.,Duke University | Pilaz L.-J.,Duke University | And 5 more authors.
Current Biology | Year: 2015

The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [1-5]. Although these evolutionary changes most likely contributed to the origin of distinctively human cognitive faculties, their genetic basis remains almost entirely unknown. Highly conserved non-coding regions showing rapid sequence changes along the human lineage are candidate loci for the development and evolution of uniquely human traits. Several studies have identified human-accelerated enhancers [6-14], but none have linked an expression difference to a specific organismal trait. Here we report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size [15, 16]. Using transgenic mice, we demonstrate dramatic differences in human and chimpanzee HARE5 activity, with human HARE5 driving early and robust expression at the onset of corticogenesis. Similar to HARE5 activity, FZD8 is expressed in neural progenitors of the developing neocortex [17-19]. Chromosome conformation capture assays reveal that HARE5 physically and specifically contacts the core Fzd8 promoter in the mouse embryonic neocortex. To assess the phenotypic consequences of HARE5 activity, we generated transgenic mice in which Fzd8 expression is under control of orthologous enhancers (Pt-HARE5::Fzd8 and Hs-HARE5::Fzd8). In comparison to Pt-HARE5::Fzd8, Hs-HARE5::Fzd8 mice showed marked acceleration of neural progenitor cell cycle and increased brain size. Changes in HARE5 function unique to humans thus alter the cell-cycle dynamics of a critical population of stem cells during corticogenesis and may underlie some distinctive anatomical features of the human brain. © 2015 Elsevier Ltd All rights reserved.


Zannas A.S.,Duke University | Doraiswamy P.M.,Duke University | Doraiswamy P.M.,Duke Institute for Brain science | Shpanskaya K.S.,Duke Institute for Brain science | And 4 more authors.
Neurocase | Year: 2014

18F-florbetapir positron emission tomography (PET) imaging of the brain is now approved by the Food and Drug Administration (FDA) approved for estimation of β-amyloid neuritic plaque density when evaluating patients with cognitive impairment. However, its impact on clinical decision-making is not known. We present 11 cases (age range 67-84) of cognitively impaired subjects in whom clinician surveys were done before and after PET scanning to document the theoretical impact of amyloid imaging on the diagnosis and treatment plan of cognitively impaired subjects. Subjects have been clinically followed for about 5 months after the PET scan. Negative scans occurred in five cases, leading to a change in diagnosis for four patients and a change in treatment plan for two of these cases. Positive scans occurred in six cases, leading to a change in diagnosis for four patients and a change in treatment plan for three of these cases. Following the scan, only one case had indeterminate diagnosis. Our series suggests that both positive and negative florbetapir PET scans may enhance diagnostic certainty and impact clinical decision-making. Controlled longitudinal studies are needed to confirm our data and determine best practices. © 2013 © 2013 Taylor & Francis.


Tur-Kaspa I.,Institute for Human Reproduction | Tur-Kaspa I.,University of Chicago | Jeelani R.,Wayne State University | Doraiswamy P.M.,Duke Institute for Brain science
Nature Reviews Neurology | Year: 2014

Preimplantation genetic diagnosis (PGD) is an option for couples at risk of having offspring with an inherited debilitating or fatal neurological disorder who wish to conceive a healthy child. PGD has been carried out for conditions with various modes of inheritance, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal or mitochondrial disorders, and for susceptibility genes for cancers with nervous system involvement. Most couples at risk of transmitting a genetic mutation would opt for PGD over prenatal testing and possible termination of a pregnancy. The aim of this Perspectives article is to assist neurologists in counselling and treating patients who wish to explore the option of PGD to enable conception of an unaffected child. PGD can be accomplished for most disorders in which the genetic basis is known, and we argue that it is time for clinicians and neurological societies to consider the evidence and to formulate guidelines for the responsible integration of PGD into modern preventative neurology. © 2014 Macmillan Publishers Limited.


PubMed | Mahidol University and Duke Institute for Brain science
Type: | Journal: Epilepsy & behavior : E&B | Year: 2016

Traumatic brain injury (TBI) is a major cause of pediatric morbidity and mortality. Secondary injury that occurs as a result of a direct impact plays a crucial role in patient prognosis. The guidelines for the management of severe TBI target treatment of secondary injury. Posttraumatic seizure, one of the secondary injury sequelae, contributes to further damage to the injured brain. Continuous electroencephalography (cEEG) helps detect both clinical and subclinical seizure, which aids early detection and prompt treatment.The aim of this study was to examine the relationship between cEEG findings in pediatric traumatic brain injury and neurocognitive/functional outcomes.This study focuses on a subgroup of a larger prospective parent study that examined children admitted to a level-1 trauma hospital. The subgroup included sixteen children admitted to the pediatric intensive care unit (PICU) who received cEEG monitoring. Characteristics included demographics, cEEG reports, and antiseizure medication. We also examined outcome scores at the time of discharge and 4-6weeks postdischarge using the Glasgow Outcome Scale - Extended Pediatrics and center-based speech pathology neurocognitive/functional evaluation scores.Sixteen patients were included in this study. Patients with severe TBI made up the majority of those that received cEEG monitoring. Nonaccidental trauma was the most frequent TBI etiology (75%), and subdural hematoma was the most common lesion diagnosed by CT scan (75%). Fifteen patients received antiseizure medication, and levetiracetam was the medication of choice. Four patients (25%) developed seizures during PICU admission, and 3 patients had subclinical seizures that were detected by cEEG. One of these patients also had both a clinical and subclinical seizure. Nonaccidental trauma was an etiology of TBI in all patients with seizures. Characteristics of a nonreactive pattern, severe/burst suppression, and lack of sleep architecture, on cEEG, were associated with poor neurocognitive/functional outcome.Continuous electroencephalography demonstrated a pattern that associated seizures and poor outcomes in patients with moderate to severe traumatic brain injury, particularly in a subgroup of patients with nonaccidental trauma. Best practice should include institution-based TBI cEEG protocols, which may detect seizure activity early and promote outcomes. Future studies should include examination of individual cEEG characteristics to help improve outcomes in pediatric TBI.


PubMed | Duke Institute for Brain science and Molecular Therapeutics
Type: Journal Article | Journal: Metabolomics : Official journal of the Metabolomic Society | Year: 2016

The initial decades of the 21This Brief Review will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy.Studies that used pharmacometabolomics to inform and guide pharmacogenomics were reviewed. Clinical studies that were used as the basis for pharmacometabolomics-informed pharmacogenomic studies, published in five independent manuscripts, are described briefly.Within these five manuscripts, both pharmacokinetic and pharmacodynamic metabolomics approaches were used. Candidate gene and genome-wide approaches that were used in concert with these metabolomic data identified novel metabolite-gene relationships that were associated with drug response phenotypes in these pharmacometabolomics-informed pharmacogenomics studies.This Brief Review outlines the emerging discipline of pharmacometabolomics-informed pharmacogenomics in which metabolic profiles are associated with both clinical phenotypes and genetic variants to identify novel genetic variants associated with drug response phenotypes based on metabolic profiles.

Loading Duke Institute for Brain science collaborators
Loading Duke Institute for Brain science collaborators