Increased cerebral perfusion in adult attention deficit hyperactivity disorder is normalised by stimulant treatment: A non-invasive MRI pilot study
Introduction
Attention deficit hyperactivity disorder (ADHD) is a developmental psychiatric disorder thought to affect approximately 4% of school-age children, of whom 30%–65% continue to exhibit symptoms into adulthood (1994, Faraone and Biederman, 2006, Nutt and Fone, 2007). Over the long term those affected by ADHD tend to demonstrate reduced educational outcomes and an increased incidence of substance abuse, antisocial behaviour, anxiety, and depression (Kollins and McClernon, 2005, Upadhyaya and Rose, 2005, Spencer and Biederman, 2007). Currently ADHD is predominantly treated with stimulant medications such as methylphenidate or amphetamine, which primarily release and prevent the reuptake of catecholamines (dopamine and noradrenaline), increasing the activity of these neurotransmitter systems (Seeman and Madras, 1998, Arnsten, 2006). Since these stimulant medications have been demonstrated to bring about a transitory reduction in ADHD symptoms, the dopaminergic and noradrenergic pathways have been the focus of much of the existing work exploring the neurobiology of ADHD.
Neuroimaging studies have provided further support for the notion that the major catecholaminergic pathways are abnormal in ADHD (for review see Castellanos and Tannock, 2002, Durston, 2003, Bush and Valera, 2005). Specifically, widespread reductions in frontal grey matter and basal ganglia volumes have been repeatedly demonstrated in children and adolescents with ADHD, as have reductions in cerebellar, and corpus callosal volumes (Castellanos and Giedd, 1994, Castellanos and Giedd, 1996, Castellanos and Giedd, 2001, Castellanos and Lee, 2002, Giedd and Castellanos, 1994, Aylward and Reiss, 1996, Baumgardner and Singer, 1996, Filipek and SemrudClikeman, 1997, Overmeyer and Bullmore, 2001, Castellanos and Tannock, 2002, Hesslinger and van Elst, 2002), although there has been some inconsistency with respect to the laterality of the volume changes observed.
Evidence for functional cerebral deficits in ADHD first emerged from SPECT studies conducted by Lou and colleagues between 1984 and 1990 (Lou and Henriksen, 1984, Lou and Henriksen, 1989). While these early studies suffered from several methodological constraints (Castellanos, 2002), they consistently demonstrated decreased perfusion in the striatum relative to age-matched controls. Further SPECT studies in children and adolescents with ADHD additionally demonstrated abnormal perfusion in frontal, temporal, and cerebellar regions (Amen et al., 1993, Gustafsson and Thernlund, 2000, Kim and Lee, 2002).
Functional abnormalities have also emerged from task-based Positron Emission Tomography (PET) and Blood Oxygen Level Dependent (BOLD) functional MRI studies (Vaidya and Austin, 1998, Bush and Frazier, 1999, Rubia and Overmeyer, 1999, Schweitzer and Faber, 2000, Durston, 2003), which have been crucial in defining the neural correlates of task-related cognitive deficits in ADHD. BOLD fMRI methods offer increased spatial and temporal resolution relative to emission tomography methods, but standard BOLD fMRI techniques are unable to provide information with regard to the baseline perfusion, known to be abnormal from the early PET and SPECT literature. The BOLD signal also depends in a complicated way on several instrumental and biological factors (Buxton et al., 2004), the latter of which includes the relaxation time T2* and the interaction between regional perfusion and the metabolic rate of oxygen consumption. Since T2* and regional perfusion are known to be altered in ADHD (Teicher and Anderson, 2000, Anderson and Polcari, 2002), and since these factors are not quantifiable with a typical BOLD fMRI experiment, the baseline BOLD fMRI signal cannot be easily compared between subjects or groups. The earlier SPECT and PET studies have been able to identify areas of abnormal perfusion and metabolism, but many of these nuclear medicine studies have been limited by the lack of a suitable control group, largely because of the ethical considerations associated with exposing healthy volunteers to ionising radiation. In addition, all but one of these previous neuroimaging studies have focused on children and adolescents with ADHD, and the one previous study in adults with ADHD only examined the effects of medication, without including a control group (Schweitzer et al., 2003). Given the large changes in brain structure and function associated with brain development and the known changes in clinical ADHD phenomenology with age (Blakemore and Choudhury, 2006, Rubia and Smith, 2006, Shaw and Greenstein, 2006, Toga and Thompson, 2006), a compelling argument exists for extending functional neuroimaging investigations of ADHD to a range of age groups. The primary purpose of this pilot study was to investigate differences in regional cerebral perfusion between adults with ADHD and controls with continuous arterial spin labelling (CASL) perfusion MRI. A secondary purpose was to assess the perfusion response to treatment with stimulant medication. Although methylphenidate decreased striatal blood flow in the only previous study in adults with ADHD, (Schweitzer et al., 2003) in consideration of the more extensive literature in children with ADHD, we hypothesised that perfusion would be lower in frontal and, particularly, striatal brain regions relative to controls and that stimulant treatment would act to normalise perfusion in these regions.
Section snippets
Participants
Nine right-handed male patients with ADHD (mean age 30 years, range 20–48) were recruited from the Maudsley adult ADHD clinic (Van Der Linden et al., 2000). All patients fulfilled DSM-IV criteria for ADHD as assessed by interview with the patient and a relative or close friend, and also fulfilled criteria as a child based on retrospective analysis of school and parental reports. All patients were clinically responsive to stimulant treatment and had been treated for a minimum of one month prior
Results
The results of the group comparison between the unmedicated ADHD patients and the controls are shown in Fig. 1 and Table 1. At a cluster-wise significance level of p < 0.005 (corrected), the ADHD patients demonstrate significantly higher perfusion in the left caudate and regions of frontal and parietal grey and white matter.
The results of the comparison between the ADHD group on and off treatment are shown in Fig. 2 and Table 1. Perfusion decreased with medication in clusters centred in the left
Discussion
Although the neurobiological basis of ADHD has not yet been established, structural and functional neuroimaging studies in children and adolescents have shown widespread differences in frontal, striatal, and cerebellar regions (Schweitzer and Faber, 2000, Teicher and Anderson, 2000, Hesslinger and van Elst, 2002, Durston, 2003). These areas are known to be involved in impulsivity and motor regulation as well as the control and regulation of attention processes, and the frontal and striatal
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