Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood behavioral diagnosis. In addition, its symptoms of inattention and impulsivity occur pervasively in many genetic and acquired neurological and psychiatric diseases. Despite the short-term efficacy of psychostimulants to treat core ADHD symptoms in childhood, adult outcomes include high rates of academic underachievement, mental illness, substance abuse, and criminal activity. A critical obstacle to improving long term ADHD treatment outcomes is the lack of quantitative markers which correlate with symptoms and reveal neurobiological mechanisms in ways that could point toward more accurate prognosis and more effective future treatments. In research funded during the initial grant period we addressed this barrier by taking advantage of the relationship (in developmental timing and anatomic proximity) between motor control and both cognitive and emotional control to pursue the physiology of inhibitory mechanisms in ADHD. We developed, refined, and compared techniques to easily and precisely evaluate developing motor function and physiology in 8-12 year old children with ADHD. Using Transcranial Magnetic Stimulation (TMS) in motor cortex, we found that Short Interval Cortical Inhibition (SICI), which is mediated by GABAergic interneurons and modulated by dopaminergic/ reward input, is reduced in children with ADHD. Importantly, this SICI reduction correlates with ADHD behavioral symptom severity as well as measures of motor impairment. We also generated novel preliminary findings linking motor cortex GABA, measured with magnetic resonance spectroscopy (MRS), to ADHD and SICI. The broad aim of this application is to 1) develop this ADHD SICI biomarker from resting M1 by extending from baseline (resting) cortical function (rSICI) to informative behavioral (response inhibition) and motivational (reward delay aversion) domains using innovative f(functional)SICI paradigms, 2) clarify the DAergic and GABAergic basis for SICI using pharmacologic challenge and magnetic resonance spectroscopy (MRS) techniques.
AIM 1 To quantify fSICI during response inhibition as a biomarker of ADHD.
AIM 2 To quantify fSICI during immediate and delayed reward presentation as a biomarker of ADHD.
AIM 3 To quantify effects of DA on rSICI and fSICI.
AIM 4 To determine whether motor cortex GABA levels 1) differ in ADHD vs. TD and 2) correlate with rSICI and fSICI in Aims 1 and 2. Achieving these aims will lay groundwork for future use of SICI as a pragmatic and biologically meaningful quantitative measure that can be applied to investigations of ADHD treatment, genetics, and risk factors for serious long term outcomes.

Public Health Relevance

Children with Attention Deficit Hyperactivity Disorder (ADHD) experience high rates of academic underachievement, substance abuse, and criminal behavior. Core ADHD impairments in attention, impulse control, and appropriate responses to rewards are difficult to study precisely, which has hindered the development of highly effective treatments. In the first period of this grant, we identified that a quantitative measure in the bran, Transcranial Magnetic Stimulation - evoked Short Interval Cortical Inhibition (SICI), is significantly correlated with ADHD behaviors in 8-12 year old children. The purpose of this study is to measure SICI during impulse control and immediate and delayed reward responses, and to study underlying brain chemical signaling in ways that will direct us to more effective childhood ADHD treatments that prevent adult complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH078160-08
Application #
8672670
Study Section
Special Emphasis Panel (ZRG1-BDCN-W (02))
Program Officer
Garvey, Marjorie A
Project Start
2006-09-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$408,143
Indirect Cost
$138,369
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
155342439
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Ament, Katarina; Mejia, Amanda; Buhlman, Rebecca et al. (2015) Evidence for specificity of motor impairments in catching and balance in children with autism. J Autism Dev Disord 45:742-51
Shou, Haochang; Eloyan, Ani; Nebel, Mary Beth et al. (2014) Shrinkage prediction of seed-voxel brain connectivity using resting state fMRI. Neuroimage 102 Pt 2:938-44
Nebel, Mary Beth; Joel, Suresh E; Muschelli, John et al. (2014) Disruption of functional organization within the primary motor cortex in children with autism. Hum Brain Mapp 35:567-80
Puts, Nicolaas A J; Wodka, Ericka L; Tommerdahl, Mark et al. (2014) Impaired tactile processing in children with autism spectrum disorder. J Neurophysiol 111:1803-11
Puts, Nicolaas A; Wodka, Ericka L; Tommerdahl, Mark et al. (2014) Reply to Dickinson and Milne. J Neurophysiol 112:1600-1
dos Santos Siqueira, Anderson; Biazoli Junior, Claudinei Eduardo; Comfort, William Edgar et al. (2014) Abnormal functional resting-state networks in ADHD: graph theory and pattern recognition analysis of fMRI data. Biomed Res Int 2014:380531
Elton, Amanda; Alcauter, Sarael; Gao, Wei (2014) Network connectivity abnormality profile supports a categorical-dimensional hybrid model of ADHD. Hum Brain Mapp 35:4531-43
Muschelli, John; Nebel, Mary Beth; Caffo, Brian S et al. (2014) Reduction of motion-related artifacts in resting state fMRI using aCompCor. Neuroimage 96:22-35
Puts, Nicolaas A J; Edden, Richard A E; Wodka, Ericka L et al. (2013) A vibrotactile behavioral battery for investigating somatosensory processing in children and adults. J Neurosci Methods 218:39-47
Barber, Anita D; Caffo, Brian S; Pekar, James J et al. (2013) Developmental changes in within- and between-network connectivity between late childhood and adulthood. Neuropsychologia 51:156-67

Showing the most recent 10 out of 23 publications