ADHD- and medication-related brain activation effects in concordantly affected parent–child dyads with ADHD Jeffery N. Epstein, 1 B.J. Casey, 2 Simon T. Tonev, 3 Matthew C. Davidson, 2 Allan L. Reiss, 4 Amy Garrett, 4 Stephen P. Hinshaw, 5 Laurence L. Greenhill, 6 Gary Glover, 4 Keith M. Shafritz, 7 Alan Vitolo, 5 Lisa A. Kotler, 6 Matthew A. Jarrett, 3 and Julie Spicer 2 1 Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2 Sackler Institute, Weill Medical College of Cornell University, New York, USA; 3 Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; 4 Department of Psychiatry, Stanford University Medical Center, Palo Alto, CA, USA; 5 Department of Psychology, University of California, Berkeley, CA, USA; 6 Division of Child Psychiatry, Columbia University Medical Center/New York State Psychiatric Institute, New York, USA; 7 Department of Psychology, Hofstra University, Hempstead, NY, USA Background: Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological abnormalities and response to stimulant medica- tion. Method: A group of concordantly diagnosed ADHD parent–child dyads was compared to a matched sample of normal parent–child dyads. In addition, ADHD dyads were administered double- blind methylphenidate and placebo in a counterbalanced fashion over two consecutive days of testing. Frontostriatal function was measured using functional magnetic resonance imaging (fMRI) during performance of a go/no-go task. Results: Youths and adults with ADHD showed attenuated activity in fronto-striatal regions. In addition, adults with ADHD appeared to activate non-fronto-striatal regions more than normals. A stimulant medication trial showed that among youths, stimulant medication increased activation in fronto-striatal and cerebellar regions. In adults with ADHD, increases in activa- tion were observed in the striatum and cerebellum, but not in prefrontal regions. Conclusions: This study extends findings of fronto-striatal dysfunction to adults with ADHD and highlights the importance of frontostriatal and frontocerebellar circuitry in this disorder, providing evidence of an endophenotype for examining the genetics of ADHD. Keywords: ADHD, adolescence, adulthood, brain imaging, devel- opment, fMRI, methylphenidate, neuropsychology, children, parents. Abbreviations: MTA: Multimodal Treatment Study of ADHD; LNCG: local normative comparison group; CAADID: Conners Adult ADHD Diagnostic Interview for DSM-IV. Attention-deficit/hyperactivity disorder (ADHD) is a common developmental disorder of childhood with a prevalence rate of approximately 5–8% in the US (American Psychiatric Association, 1994; Centers for Disease Control, 2005). ADHD and related impair- ments frequently persist into adolescence and adulthood (Biederman, Mick, & Faraone, 2000; Rasmussen & Gillberg, 2000; Weiss & Hechtman, 1993). Beyond the defining behavioral character- istics of ADHD (i.e., inattention, impulsivity, and hyperactivity), a large neuropsychological literature has documented several areas of cognitive impair- ment. Most notably, deficits in response inhibition (i.e., suppression of a prepotent response in favor of an appropriate response; Nigg, 2001) have been reported for children, adolescents, and adults with ADHD using a variety of neuropsychological tasks (Hervey, Epstein, & Curry, 2004; Willcutt, Doyle, Nigg, Faraone, & Pennington, 2005). Deficits in response inhibition are hypothesized to result from some form of abnormality in the fronto- striatal circuitry in the brains of ADHD patients. Evidence for this hypothesis comes from several sources. First, imaging studies with normal particip- ants clearly demonstrate the role of the prefrontal cortices in tasks involving response inhibition (Casey et al., 1997b; Konishi et al., 1999; Konishi, Nakaj- ima, Uchida, Sekihara, & Miyashita, 1998; Menon, Adleman, White, Glover, & Reiss, 2001; Rubia et al., 2001; Tamm, Menon, & Reiss, 2002). Second, patients with frontal lobe lesions have response inhibition deficits similar to those seen in patients with ADHD (Stuss, Murphy, Binns, & Alexander, 2003). Third, several studies have shown corre- lations between behavioral performance on response inhibition tasks and MRI-based measures of Conflict of interest statement: No conflicts declared. Journal of Child Psychology and Psychiatry 48:9 (2007), pp 899–913 doi:10.1111/j.1469-7610.2007.01761.x Ó 2007 The Authors Journal compilation Ó 2007 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA