The proposed study will use dynamic molecular imaging to examine a novel hypothesis concerning nature of dysregulated dopamine neurotransmission in Tourette's syndrome (TS). It is known for several years that the dopamine system is dysregulated in TS, but the nature of dysregulation remains unclear because of contradictory evidence. Thus, symptomatic relief following administration of dopamine antagonists suggests hyperactivity of the dopamine system but the hyperactivity is not consistently supported by the data on receptor density, precursor and transporter uptake. Some of these data even suggest hypoactive dopamine. To reconcile contradictory data we hypothesize that the tonic pool of dopamine is attenuated in TS. It leads to compensatory enhancement of the phasic release. Increased phasic release is known to impair processing of the central inhibitory system, which in turn impairs the ability to inhibit unwanted response in TS patients. Consistent with this hypothesis, studies that have directly or indirectly measured the tonic pool have found reduced dopamine activity while those that have studied the phasic release have reported increased activity in TS. In the proposed study the validity of hypothesis will be examined by detecting, mapping and measuring the tonic and phasic release of dopamine in TS patients and matched healthy control volunteers using a recently developed dynamic molecular imaging technique. The tonic pool in the striatal and extrastriatal areas will be estimated by estimating the binding potentials (BP) of dopamine receptor ligands 11C-raclopride and 18F-fallypride respectively at rest. Comparison of the data acquired in the two groups will indicate whether the tonic pool is reduced in TS. For measurement of the phasic release, changes in the rate of ligand displacement (from receptor sites) and the ligand BP will be estimated during performance of a task that requires inhibition of an unwanted response (Eriksen's flanker task). During the task performance concentration of previously administered dopamine receptor ligand (11C-raclopride or 18F-fallypride) will be dynamically measured using a positron emission tomography (PET) camera. This measurement will be applied to newly developed receptor kinetic models to estimate values of the receptor kinetic parameters before and after task initiation. These measurements will help us detect, map and measure dopamine released during task performance. Comparison of the data acquired in TS patients and healthy control volunteers will indicate whether the phasic release is enhanced during response inhibition in TS. The study will advance our understanding of the nature of dysregulated dopamine neurotransmission in TS and demonstrate that the dynamic molecular imaging can be used to study dysregulated dopamine neurotransmission in neuropsychiatric conditions. Additionally, data acquired in the proposed experiments can be used to develop novel therapeutic strategies and targets for treatment and prevention of cognitive deficits in TS.

Public Health Relevance

The proposed study will examine an important hypothesis concerning pathophysiology of Tourette syndrome, which is a disabling condition. The results will allow better understanding of neurocognitive deficits and could lead to development of novel therapeutic strategies and targets for treatment and prevention of cognitive deficits in Tourette's patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073884-02
Application #
8550150
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gwinn, Katrina
Project Start
2012-09-30
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$561,125
Indirect Cost
$207,103
Name
State University of New York at Buffalo
Department
Psychiatry
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Steinberg, Bruce; Blum, Kenneth; McLaughlin, Thomas et al. (2016) Low-Resolution Electromagnetic Tomography (LORETA) of changed Brain Function Provoked by Pro-Dopamine Regulator (KB220z) in one Adult ADHD case. Open J Clin Med Case Rep 2:
Blum, Kenneth; Gold, Mark; Clark, H Westley et al. (2016) Should the United States Government Repeal Restrictions on Buprenorphine/Naloxone Treatment? Subst Use Misuse 51:1674-1679
Blum, K; Febo, M; Badgaiyan, R D (2016) Fifty Years in the Development of a Glutaminergic-Dopaminergic Optimization Complex (KB220) to Balance Brain Reward Circuitry in Reward Deficiency Syndrome: A Pictorial. Austin Addict Sci 1:
Braverman, Eric R; Blum, Kenneth; Hussman, Karl L et al. (2015) Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients. PLoS One 10:e0133609
Blum, Kenneth; Simpatico, Thomas; Badgaiyan, Rajendra D et al. (2015) Coupling Neurogenetics (GARSâ„¢) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms. J Reward Defic Syndr 1:75-80
Blum, Kenneth; Febo, Marcelo; Smith, David E et al. (2015) Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation. J Child Adolesc Psychopharmacol 25:286-92
Schoenthaler, Stephen J; Blum, Kenneth; Braverman, Eric R et al. (2015) NIDA-Drug Addiction Treatment Outcome Study (DATOS) Relapse as a Function of Spirituality/Religiosity. J Reward Defic Syndr 1:36-45
Blum, Kenneth; Thanos, Peter K; Badgaiyan, Rajendra D et al. (2015) Neurogenetics and gene therapy for reward deficiency syndrome: are we going to the Promised Land? Expert Opin Biol Ther 15:973-85
Badgaiyan, Rajendra D; Sinha, Sampada; Sajjad, Munawwar et al. (2015) Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder. PLoS One 10:e0137326
Blum, Kenneth; Hauser, Mary; Fratantonio, James et al. (2015) Molecular Genetic Testing in Pain and Addiction: Facts, Fiction and Clinical Utility. Addict Genet 2:1-5

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