1996 — 2000 |
Black, Kevin J [⬀] |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
On-Off Mood Change in Parkinsons Disease |
0.936 |
2002 — 2004 |
Black, Kevin J [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dopamine D1 Effects On Blood Flow, Metabolism, and Bold
DESCRIPTION (provided by applicant): Dopamine D1 -like receptors (D1Rs) influence important neuronal circuits and have been associated with a number of physiological functions and illnesses, including working memory, Parkinson disease and substance abuse. However, they also mediate vascular effects. Consequently, they may disrupt the usual linkage of neuronal function to positron emission tomography (PET) or functional MRI (fMRI) neuroimaging methods. Blood oxygenation level dependent (BOLD) signals, for instance, are sensitive to variations in global cerebral blood flow. These effects are of significant concern for interpreting imaging studies in populations exposed to dopaminergic agonists or stimulants. In this RO1 application we propose to directly measure, using well-validated quantitative PET techniques, whether activation of dopamine D1 receptors in primates alters regional cerebral blood flow (rCBF) through direct vascular effects or, rather, via effects on neuronal work and metabolism We will also test whether the effects on rCBF are mediated specifically by D1 receptors. These results will be compared to pharmacological fMRI (phMRI) responses to the same D1R agonist. Although more sensitive MRI techniques have been used in nonhuman species, using contrast agents and/or high field strength, this application focuses on the physiology of those PET and phMRI techniques that are commonly applied in humans. Our experience with quantitative PET measurements, neuroimaging in nonhuman primates, and phMRI positions us to immediately address these questions. These results will inform interpretation of human neuroimaging studies in which dopamine D I receptors are affected. These results are also necessary for planning D DIR challenge phMRI studies in human disease or animal models. In this laboratory, potential applications would include longitudinal studies of treatment induced side effects *in Parkinson's disease or MPTP models, and pathophysiological studies in dopa-related dystonia or a nonhuman dystonia model.
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0.936 |
2002 — 2004 |
Black, Kevin J [⬀] |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Testing Dopaminergic Function Using Pharmacologic Fmri
technology /technique development; functional magnetic resonance imaging; brain imaging /visualization /scanning; apomorphine; dopamine; corpus striatum; bioimaging /biomedical imaging; clinical research; human subject;
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0.936 |
2006 — 2010 |
Black, Kevin J [⬀] |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dopaminergic Effects On Cortical Function in Tourette's
DESCRIPTION (provided by applicant): Chronic tic disorders including Tourette syndrome (TS) affect at least 2% of all school children and often persist into adulthood. Symptoms commonly interfere with education, employment, or social relationships, and in some individuals symptoms produce marked disability. Neuroleptics and other drugs reduce tic severity, but all TS treatment is empiric since the pathophysiology of tics is incompletely understood. However, a recent functional imaging study showed a medication- sensitive abnormality of brain function. A cognitive task involving working memory (WM) produced excessive activation of several brain regions, but the excessive activation normalized after administration of the dopamine precursor levodopa. This drug is well suited for neuroimaging studies as it is well tolerated in TS and (when given with carbidopa) essentially delivers dopamine to the brain only. The research proposed herein aims to clarify the cognitive task components and the clinical variables that combine to produce the abnormal responses to the WM task and levodopa. Adults with TS or chronic tic disorders, and matched controls, will be studied using functional MRI and WM tasks after levodopa or saline infusion on different days. Cognitive tasks will include parametric scaling of working memory load and matched spatial and verbal working memory tasks. Careful characterization of subjects will allow tests of how the imaging findings are affected by clinical variables such as comorbidity (e.g., ADHD, OCD), severity, or past medication exposure. Additionally, a mixed (pergolide) and D2-like-selective (pramipexole) dopamine receptor agonist, or placebo, will be given on separate scanning days with the same cognitive tasks to help determine the pharmacological mechanism of the levodopa effect. The significance of this research includes its potential to define an endophenotype for future developmental or genetic studies of TS.
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0.936 |
2009 — 2010 |
Black, Kevin J [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Quantitative Dopamine Receptor Pharmacodynamics From Fmri
DESCRIPTION (provided by applicant): This project will empirically test whether quantitative information about drug dose effects on brain function can be extracted from functional Magnetic Resonance Imaging (fMRI). We have developed a method for determining the ED50 - the drug dose required to produce 50 percent of the maximum effect - from data acquired from fMRI blood oxygen level dependent (BOLD) imaging. This method, quantitative pharmacodynamic imaging (QPDI), has been tested with encouraging results on simulated data, and on preliminary data from nonhuman primates. The proposed experiments will test the model with dopamine agonists (SKF82958, pramipexole). Dopamine is a critical neurotransmitter in the brain, and dopaminergic pathways are associated with movement disorders, mental illness and drug abuse. We will measure ED50 for two responses of the brain to the drugs: the effect of dopamine agonists on prolactin secretion will be determined from blood serum samples in the traditional manner (independent measurements for each dose of drug), while changes in brain hemodynamics will be measured in a single experiment using our new QPDI method and fMRI BOLD signal. This method has potentially wide application for testing the brain's response to pharmacological agents for use in scientific research and clinical medicine. PUBLIC HEALTH RELEVANCE: We propose to test a new method for obtaining quantitative pharmacodynamic information from functional magnetic resonance imaging with specific pharmacological agents in a living brain. This method could be used to diagnosis disorders and determine appropriate drug dosage, and could be invaluable for researching physiological mechanisms and developing new drugs for treating diseases.
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0.936 |
2010 — 2012 |
Black, Kevin J [⬀] |
K24Activity Code Description: To provide support for the clinicians to allow them protected time to devote to patient-oriented research and to act as mentors for beginning clinical investigators. |
Training New Investigators in Neuroimaging and in the Neuropsychiatry of Movement
DESCRIPTION (provided by applicant): This application for a Midcareer Investigator Award in Patient-Oriented Research (K24) is planned to allow the PI to devote 50% effort to the mentoring and research activities described. The PI is a board-certified neuropsychiatrist who completed a two-year movement disorders and neuroimaging fellowship after psychiatry residency. He has contributed new neuroimaging methods and applied them to neuropsychiatric aspects of Parkinson disease and TS. His current research includes studies in both these areas, but this application focuses on the PI's research into Tourette syndrome (TS). This includes ongoing neuroimaging studies funded by NIMH and the Tourette Syndrome Association, and new TS imaging studies are proposed for this application. The new studies build on the PI's past research, follow up on exciting leads from recently published TS research, and are planned to further develop a coordinated research program on TS in collaboration with colleagues from child neurology and child psychiatry. The PI has mentored over 40 young trainees over the years, many of them for brief summer or semester stints, but some for longer terms. In the past 3 years, 2 of the PI's longer-term clinical trainees (a psychiatry resident and a clinical neuropsychologist post-doc) have won the American Neuropsychiatric Association's Young Investigator Award for research done in his lab and for their overall career potential. The PI has now identified new M.D. research fellows and students whose training will be enhanced by additional time for the specific mentorship activities proposed herein. The institution is well known as a vibrant center for neuroscience research, and its recently awarded CTSA grant components will further support the training and research activities in this proposal. The department has committed to free the PI from his administrative duties with the medical school core psychiatry clerkship and from inpatient or consultation-liaison clinical duties in exchange for the mentorship and patient-oriented research opportunities that this K24 award will support. In short, the applicant's mentoring experience, research contributions, and near-future plans for research on TS have all arrived at the perfect moment for appropriate support from the K24. PUBLIC HEALTH RELEVANCE: The PI is a board-certified neuropsychiatrist who completed a two-year movement disorders and neuroimaging fellowship after psychiatry residency. This application focuses on the PI's research into Tourette syndrome (TS), including ongoing studies funded by NIMH and the Tourette Syndrome Association and new studies proposed for this application. This K24 award will allow the PI to devote substantially more time to mentoring additional new investigators in patient-oriented research, specifically clinical and neuroimaging investigations of Tourette syndrome (TS).
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0.936 |
2012 — 2013 |
Black, Kevin J [⬀] Hershey, Tamara G (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Testing the Phasic Dopamine Release Hypothesis in Tourette Syndrome: Pilot
DESCRIPTION (provided by applicant): Up to 20% of all children have tics at some time in their life, and about 3% of all children have a chronic tic disorder such as Tourette syndrome (TS), making tic disorders a subject of substantial public health interest. Despite steadily increasing research, no treatment for TS works for more than half those treated, and the cause and pathophysiology of TS are poorly understood. Based on the observation that dopamine D2 receptor antagonists significantly reduce tic severity, one longstanding hypothesis has been that tics may involve abnormalities in transient (phasic) dopamine release in the striatum, while baseline (tonic) dopamine release may be normal. Several experiments in the past 15 years attempted to address this hypothesis by measuring striatal dopamine release in TS in response to amphetamine. One could argue, however, that this assessed only maximal possible dopamine release under nonphysiological conditions. The present proposal represents the first step in a plan to directly test phasic dopamine release in TS by measuring striatal dopamine release in response to a cognitive task with and without exogenous levodopa. The proposal will exploit the newly developed Siemens PET-MRI scanner to acquire rCBF simultaneously with the receptor imaging. The applicants have preliminary data on most aspects of this approach, considered individually, but none for the combined approach. This application proposes to test the full protocol on a small group of TS and matched control subjects, in order to demonstrate feasibility and estimate variance for a planned R01 application. The planned R01-funded follow-up study would include sample sizes adequate to test the effects of psychiatric comorbidity, past treatment, and demographic variables. PUBLIC HEALTH RELEVANCE: About 20% of all children have tics-sudden, unwanted movements or noises-at some time in their life, and about 3% of all children have a chronic tic disorder such as Tourette syndrome (TS), in which quality of life is substantially reduced. Unfortunately, how the brain generates tics is still not clear. Experts have hypothesized that the brain messenger dopamine, while released normally most of the time in TS, is not released normally when the brain sends a quick burst signal related to learning or movement. This project will use a new, cutting-edge brain scanner and a new experimental design to directly test whether such transient dopamine release is normal in TS. The present application will support first studying a small group of people with and without TS to show that the project is feasible and to clarify how many people need to be tested in the planned conclusive follow-up study. This new approach is expected to prove or lay to rest one of the key current theories about the cause of tics in Tourette syndrome.
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0.936 |
2013 — 2014 |
Black, Kevin J [⬀] |
K24Activity Code Description: To provide support for the clinicians to allow them protected time to devote to patient-oriented research and to act as mentors for beginning clinical investigators. |
Training Investigators in Neuroimaging and Neuropsychiatry of Movement Disorders
DESCRIPTION (provided by applicant): This application for a Midcareer Investigator Award in Patient-Oriented Research (K24) is planned to allow the PI to devote 50% effort to the mentoring and research activities described. The PI is a board-certified neuropsychiatrist who completed a two-year movement disorders and neuroimaging fellowship after psychiatry residency. He has contributed new neuroimaging methods and applied them to neuropsychiatric aspects of Parkinson disease and TS. His current research includes studies in both these areas, but this application focuses on the PI's research into Tourette syndrome (TS). This includes ongoing neuroimaging studies funded by NIMH and the Tourette Syndrome Association, and new TS imaging studies are proposed for this application. The new studies build on the PI's past research, follow up on exciting leads from recently published TS research, and are planned to further develop a coordinated research program on TS in collaboration with colleagues from child neurology and child psychiatry. The PI has mentored over 40 young trainees over the years, many of them for brief summer or semester stints, but some for longer terms. In the past 3 years, 2 of the PI's longer-term clinical trainees (a psychiatry resident and a clinical neuropsychologist post-doc) have won the American Neuropsychiatric Association's Young Investigator Award for research done in his lab and for their overall career potential. The PI has now identified new M.D. research fellows and students whose training will be enhanced by additional time for the specific mentorship activities proposed herein. The institution is well known as a vibrant center for neuroscience research, and its recently awarded CTSA grant components will further support the training and research activities in this proposal. The department has committed to free the PI from his administrative duties with the medical school core psychiatry clerkship and from inpatient or consultation-liaison clinical duties in exchange for the mentorship and patient-oriented research opportunities that this K24 award will support. In short, the applicant's mentoring experience, research contributions, and near-future plans for research on TS have all arrived at the perfect moment for appropriate support from the K24.
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0.936 |
2015 — 2016 |
Black, Kevin J (co-PI) [⬀] Schlaggar, Bradley L [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Predicting Outcome in Children With New-Onset Tics Using Neuroimaging Data
? DESCRIPTION (provided by applicant): Childhood onset neuropsychiatric disorders are often debilitating and are increasing in prevalence. Tourette Syndrome/Chronic Tic Disorder (TS/CTD), we propose, has a course that lends itself especially well to discovering optimal strategies for early diagnosis and prevention of developmental disorders. Common clinical practice and epidemiological data suggest that a large fraction (10-25%) of all children manifest motor and/or vocal tics at some age. Yet only 1-3% of all children have tics for the full year required for diagnosis of TS/CTD. The objective of the proposed research is to understand the structural and functional neuroimaging features of children with new-onset tics (New Tics), as the neurobiology of this population has not been investigated. Studying children with New Tics should provide the most leverage in understanding why tics remit in some children but not others. This proposal compares neuroimaging features of New Tics to TS/CTD and to controls, implements machine-learning tools to predict whether children with New Tics will remit or develop TS/CTD, and utilizes longitudinal scans to identify within-subject changes that occur as tics remit or persist. The proposed study will apply resting-state functional connectivity MRI (rs fcMRI) and structural MRI methods to investigate children with New Tics. Neuroimaging will be conducted on children with current, new- onset tics, and comparisons will be made to existing MRI data from children with diagnosed TS/CTD and controls. Follow-up evaluation (1 year after tic onset) of New Tics will allow us to identify which children's tics remitted completely and whic were actually in the earliest stages of TS/CTD, thus sorting this group into Remitted Tics and Converted TS/CTD subgroups. Based on the epidemiological data, we expect most of New Tics subjects to fall in the Remitted Tics subgroup. Longitudinal scans of the New Tics children will enable us to assess within-subject changes that occur with remittance or persistence of tics. This study will also apply machine learning tools, specifically Support Vector Machines (SVMs), to characterize features that distinguish Remitted Tics and Existing TS/CTD groups. Those features will then be used to predict whether tics in the New Tics group will remit (Remitted Tics) or persist (Converted TS/CTD) on an individual patient basis. Thus, we will be poised to identify differences, and potentially early predictors, of remittance and TS/CTD. This study will provide innovative, important data on a common clinical presentation: the child with New Tics. Completing our aims successfully will allow individual prediction of remission or progression, or at least will allow a New Tics sample to be enriched for high risk of developing TS/CTD, which would make prevention studies for TS/CTD feasible. We will also gain insight into the neurobiology of New Tics. Finally, this study is an essential first step towards a definitive longitudinal study that can improve diagnostic accuracy and settle questions of cause and effect. With successful completion of our aims, similar methods can be applied to other childhood onset neuropsychiatric disorders, setting the stage for early treatment or prevention of chronicity.
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0.936 |
2017 — 2021 |
Black, Kevin J [⬀] Schlaggar, Bradley L (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The New Tics Study: a Novel Approach to Pathophysiology and Cause of Tic Disorders
Project Abstract At least 20% of all children have tics at some time in their life, making tic disorders a subject of substantial public health interest. However, only about 3% of all children have tics that last for a year or more. Thus chronic tic disorders, including Tourette syndrome, can be conceptualized as a two- step process: tics start, and then they fail to remit. By the numbers, the second part of this process is the more unusual and perhaps more closely related to disease, yet surprisingly, almost no research has examined this critical period after a first tic appears but before it is clear whether the child will go on to have a chronic tic disorder. Therefore prior research that has identified abnormalities of brain structure and function in children with TS generally does not clarify whether these abnormalities are related to tic appearance or to the more important process of tic disappearance. Furthermore, tic disappearance can be observed prospectively, allowing powerful within-subject analyses to test whether features of brain structure or function shortly after tic onset predict remission of tics before TS is diagnosable, and whether such features are state-related or more durable markers of vulnerability to tics. Colleagues in the TS field have agreed that such studies would be valuable, but have suspected that recruitment would be extremely difficult. However, we have now demonstrated enrollment of subjects with New Tics (defined as beginning within the previous 6 months, median 3.6 months) at a rate of 16 subjects per year when recruitment efforts were at their peak?though still on a shoestring budget without full staffing or media advertisements. We have implemented subject preparation and quality control methods that have allowed us to acquire structural and functional MRI data of high quality in many subjects. We now propose to enroll an additional 70 subjects with New Tics and characterize them carefully at baseline and at the 1-year anniversary of tic onset (when TS can first be diagnosed). Both time points will include clinical data, structural and functional MRI, and neuropsychological measures including ability to suppress tics. We expect that complete data will be available for 55-70 subjects (including those already collected), since MRI is sensitive to movement and we are selecting for subjects with tics and additional difficulty holding still (about half of children with tics also have ADHD). We will compare baseline data from this sample to matched tic-free control subjects, and to matched subjects who already have TS or a chronic tic disorder (leveraging existing data in our laboratories to provide some of the clinical and MRI data for these groups). Analyses will include tests of specific a priori hypotheses as well as machine learning analyses of the complete dataset. These comparisons will allow us to discover whether imaging differences in children with TS are present long before TS can be diagnosed, whether they fade when tics improve, and whether they predict outcome in children with new tics. Investigation of this ?pre-Tourette? population opens an entirely new window for etiologic discovery in tic disorders. It may also have important clinical consequences, if the results identify which newly- ticcing children are at highest risk for development of a chronic tic disorder.
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0.936 |