The clinical diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) affects 5-10% of school-age children, many of whom receive suboptimal or no treatment. At the same time there is increasing concern regarding potential over-diagnosis and unnecessary treatment. This application is to establish an interdisciplinary inter-institutional network focused on testing the specific hypotheses that (1) ADHD results from dysregulation by the cerebellar vermis of brainstem catecholaminergic nuclei, which negatively affect striatal and prefrontal cortical functioning; and (2) that abnormalities in neocerebellar mediated temporal processing result in cascaded deficits in executive function and in excessive behavioral variability.
The specific aims are to (1) form an interdisciplinary inter-institutional network; (2) conduct pilot studies in rats to establish the regional localization of dopamine relative to norepinephrine in cerebellum; determine the effects of stimulants administered locally into cerebellar """"""""hot spots"""""""" on striatal and prefrontal dopamine levels using microdialysis; examine whether low oral doses of stimulants will improve prefrontal behavioral performance; if so, whether those improvements can be blocked by prefrontally administered antagonists; and whether stimulants administered locally into vermis produce enhancements in prefrontal function; and (3) to conduct an FMRI study in adolescents with ADHD and matched controls using a reward anticipation task that activates nucleus accumbens, cerebellar vermis, and prefrontal cortex in adults; and to refine for FMRI a time perception task on which subjects with ADHD perform abnormally. The ultimate aim of this proposal is to test putative links between basic science observations and aspects of the ADHD phenotype so as to initiate the process of evolving diagnostic criteria grounded in etiological and mechanistic constructs. Because of the extensive heterogeneity within current populations defined by syndromal presentations, we anticipate that pursuing a """"""""bottom-up"""""""" (instead of """"""""top-down"""""""") approach is more likely to lead to objective quantitative criteria that could be used to derive neurobiologically meaningful subtypes of ADHD. Eventually, such advances in nosology will lead to improved matches between treatment options and the underlying disorder(s).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH066393-02
Application #
6659919
Study Section
Special Emphasis Panel (ZMH1-CRB-J (01))
Program Officer
James, Regina Smith
Project Start
2002-09-12
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$253,444
Indirect Cost
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kelly, Clare; Uddin, Lucina Q; Shehzad, Zarrar et al. (2010) Broca's region: linking human brain functional connectivity data and non-human primate tracing anatomy studies. Eur J Neurosci 32:383-98
Uddin, Lucina Q; Kelly, A M; Biswal, Bharat B et al. (2009) Functional connectivity of default mode network components: correlation, anticorrelation, and causality. Hum Brain Mapp 30:625-37
Toplak, Maggie E; Bucciarelli, Stefania M; Jain, Umesh et al. (2009) Executive functions: performance-based measures and the behavior rating inventory of executive function (BRIEF) in adolescents with attention deficit/hyperactivity disorder (ADHD). Child Neuropsychol 15:53-72
Castellanos, F Xavier; Kelly, Clare; Milham, Michael P (2009) The restless brain: attention-deficit hyperactivity disorder, resting-state functional connectivity, and intrasubject variability. Can J Psychiatry 54:665-72
Thomas, Theresa Currier; Grandy, David K; Gerhardt, Greg A et al. (2009) Decreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum. Neuropsychopharmacology 34:436-45
Castellanos, F Xavier; Margulies, Daniel S; Kelly, Clare et al. (2008) Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 63:332-7
Uddin, Lucina Q; Mooshagian, Eric; Zaidel, Eran et al. (2008) Residual functional connectivity in the split-brain revealed with resting-state functional MRI. Neuroreport 19:703-9
Uddin, Lucina Q; Kelly, A M Clare; Biswal, Bharat B et al. (2008) Network homogeneity reveals decreased integrity of default-mode network in ADHD. J Neurosci Methods 169:249-54
Kelly, A M Clare; Uddin, Lucina Q; Biswal, Bharat B et al. (2008) Competition between functional brain networks mediates behavioral variability. Neuroimage 39:527-37
Thomas, Theresa Currier; Kruzich, Paul J; Joyce, B Matthew et al. (2007) Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release. J Neurosci Methods 166:306-14

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