Evaluation of the Dopamine Hypothesis of ADHD with PET Brain Imaging

Evaluation of the Dopamine Hypothesis of ADHD with PET Brain Imaging

James Swanson, Tim Wigal, Scott Kollins, Jeff Newcorn, Gene-Jack Wang, Frank Telang, Jacob Hooker, Jean Logan, Wei Zhu, Yeming Ma, Chris Wong, Kith Pradhan, Johanna Fowler, and Nora Volkow

The Dopamine (DA) Hypothesis of ADHD suggests that abnormalities in the synaptic mechanisms of DA transmission may be disrupted.   A DA Deficit was proposed long ago (Wender, 1971; Levy, 1990), and modern advances in anatomical brain imaging (Castellanos, 1997) and molecular biology (Swanson et al, 1998) focused this theory on abnormalities in DA receptors and DA transporters (DAT).  Relatively recently, single photon emission computed tomography (SPECT) and positron emission tomography (PET) brain imaging studies have evaluated the DA Deficit Hypothesis.  In a SPECT brain imaging study, Dougherty et al (1999a) reported that in a small group of adults with ADHD and a history of treatment with stimulant medication have an over expression of DAT in the caudate nucleus of the brain, and they proposed the hypothesis that increased DAT density would act to accelerate removal of DA from the synaptic cleft and thus contribute to a DA deficit.  Krause et al (2000) suggested that treatment with methylphenidate normalized the deficit by reducing the abnormally high DAT density in the brain.  This plausible theory was challenged by some studies (e.g., van Dyck et a, 2002) and supported by others (e.g., Spencer et al, 2007), but it gained widespread acceptance and a consensus emerged that high DAT density was an important factor in the etiology and treatment of ADHD (e.g., see Russell, 2009).  For the past decade, a collaborative group has conducted PET studies at Brookhaven National Laboratory (BNL) to test the DA deficit hypothesis.  An initial study (Volkow et al, 2007) with stimulant-naïve ADHD adults and age-matched controls did not confirm the hypothesis of increased DAT density in the caudate and suggest the opposite (i.e., decreased rather than increased DAT density).  The next study (Volkow et al, 2009) expanded the sample and focused on brain regions associated with reward and motivation (nucleus accumbens) as well as cognition and attention (caudate nucleus), and found decreased DAT density in both of these brain regions, providing some evidence that ADHD may be characterized as a “motivation deficit disorder” as well as an “attention deficit disorder”.   The most recent study (Wang et al, 2009) found that long-term treatment with therapeutic doses of methylphenidate increased DAT density.  This program of research led us to revise the DA Deficit theory of ADHD based on plasticity of the DA system of the brain.  We suggest that (a) in the natural course of ADHD, decreased DA release may create a chronic DA deficit in the brain and a compensatory decrease in DAT density, (b) treatment with methylphenidate that potently blocks DAT may overcorrect this deficit temporarily by increasing DA to high levels in multiple brain regions associated with cognition and motivation, (c) a compensatory brain response may operate to increased DAT density and to reduce the correction of the underlying DA deficit, and (d) homeostatic properties of the brain DA systems may contribute to the long-term waning of the cognitive and behavioral effects of stimulant medication that has been reported in Multimodal Treatment study of ADHD (MTA) that has been suggested in long-term follow-up of treatment initiated in childhood and maintained in some cases into adolescence (Swanson et al, 2007; Molina et al, 2007) and adulthood Molina et al (2009).