Striatal Disruption in Attention Deficit-Hyperactivity Disorder (ADHD)

B.J. Casey, Ph.D.

Weill Medical College of Cornell University

Funded in January, 1997: $ for 3 years
LAY SUMMARY . BIOGRAPHY . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

INVESTIGATOR BIOGRAPHIES

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B.J. Casey, Ph.D.

Associate Professor
Weill Medical College of Cornell

HYPOTHESIS

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Hypothesis:
To determine whether disruption in the normal development of the basal ganglia, as observed in children born prematurely with intraventricular hemorrhage, results in deficits in response inhibition characteristic of the symptomatology observed in ADHD.

Goals:
1. To more directly test, using functional MRI, the hypothesis that the prefrontal cortex and basal ganglia, specifically the caudate nuclei, subserve the processes of response inhibition affected in ADHD.

2. To determine whether disruption in the normal development of the basal ganglia, as observed in children born prematurely with intraventricular hemorrhage (caudate bleeds), results in deficits in response inhibition characteristic of the symptomatology observed in ADHD.

3. To constrain the model of how and when damage to frontostriatal regions leads to ADHD to facilitate the development of early identification and treatment strategies.

Methods:
The researchers collect behavioral measures with a computerized battery of three response inhibition tasks developed in their laboratory and biological measures with both structural and functional magnetic resonance imaging (MRI). Behavioral performance, MRI-based brain volume, and brain activity are then compared across groups of children with and without striatal disruption associated with perinatal insults and in children with and without ADHD.

Follow-on Funding:
John Merck Scholarship  PI  04/01/97-03/31/01  Merck Fund

Frontostriatal Development and Cognitive Control  PI  05/01/01-04/30/06  NIMH (R01 MH63255)

Functional Neuroanatomical Deficits in ADHD Families  PI  05/01/02-04/30/05  NIMH (R01 MH64166)

 

FINDINGS

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Our behavioral, clinical and neuroimaging data from our children with histories of intraventricular hemorrhage (IVH) are consistent with our hypothesis of disruption in behavioral inhibition at the level of the basal ganglia.  First, these children perform poorly on tasks that require them to suppress attention toward a salient stimulus or a compelling response.  Second, these children are at greater risk of developing disorders with known inhibitory deficits (e.g., ADHD and Tic Disorders). Third, MRI-based morphometry measures show decreased volume of the basal ganglia, specifically the caudate nucleus, in children with IVH compared to age-matched controls.  Fourth, fMRI results showed little to no activity in the caudate nucleus in children with IVH of grade II or higher  while activity was reliably observed in prefrontal cortex ( a region assumed to play a role in behavioral inhibition), but was not correlated with behavioral performance.  In sum, disruption of the basal ganglia thalamocortical circuits at the level of the basal ganglia appears sufficient to disrupt inhibitory control.

 

SELECTED PUBLICATIONS

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Epstein, J. N., Casey, B. J., Tonev, S. T., Davidson, M., Reiss, A., Garrett, A., Hinshaw, S.P., Greenhill, L.L., Glover, G., Shafritz, KM, Vitolo, A., Kotler, L.A., Jarrett, M.A., Spicer, J. ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD. J Child Psychol Psychiatry. 2007 Sep;48(9):899-913.

Epstein J. N., Casey B. J., Tonev S. T., Davidson M., Reiss A., Garrett A., Hinshaw S.P., Greenhill L.L., Glover G., Vitolo A., Kotler L.A., Jarrett M.A., and Spicer J. Assessment and prevention of head motion during imaging of patients with attention deficit-hyperactivity disorder. Psychiatry Res. 2007 May 15;155(1):75-82.

Casey B.J., Nigg J.T., and Durston S.T.  New potential leads in the biology and treatment of ADHD.  Curr Opin Neurol. 2007 Apr;20(2):119-24.

Durston S., Mulder M., Casey B.J., Ziermans T., and van Engeland H.  Activation in ventral prefrontal cortex is sensitive to genetic vulnerability for ADHD. Biol Psychiatry. 2006 Nov 15;60(10):1062-70.

Casey B.J. and Durston S. From behavior to cognition to the brain and back: what have we learned from functional imaging studies of attention deficit hyperactivity disorder? Am J Psychiatry. 2006 Jun;163(6):957-60.

Nigg J.T. and Casey B.J. An integrative theory of attention deficit-hyperactivity disorder based on the cognitive and affective neurosciences. Dev Psychopathol. 2005 Summer;17(3):785-806.

Durston S., Fossella J.A., Casey B.J., Hulshoff Pol H.E., Galvan A., Schnack H.G., Steenhuis M.P., Minderaa R.B., Buitelaar J.K., Kahn R.S., and van Engeland H. Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit-hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry. 2005 Jul;10(7):678-85.

Durston S., Tottenham N.T., Thomas K.M., Davidson M.C., Eigsti I.M., Yang Y., Ulug A.M., and Casey B.J.  Differential patterns of striatal activation in children with and without ADHD. Biol Psychiatry. 2003 May 15;53(10):871-8.

Casey B.J., Tottenham N., and Fossella J.  Clinical, imaging, lesion, and genetic approaches toward a model of cognitive control. Dev Psychobiol. 2002 Apr;40(3):237-54.

Casey B.J., Giedd J.N., and Thomas K.M. Structural and functional brain development and its relation to cognitive development.  Biol Psychol. 2000 Oct;54(1-3):241-57.