The neurophysiology of attention-deficit/hyperactivity disorder

Abstract

Recent reviews of the neurobiology of Attention-Deficit/Hyperactivity Disorder (AD/HD) have concluded that there is no single pathophysiological profile underlying this disorder. Certainly, dysfunctions in the frontal/subcortical pathways that control attention and motor behavior are implicated. However, no diagnostic criteria or behavioral/neuroimaging techniques allow a clear discrimination among subtypes within this disorder, especially when problems with learning are also considered. Two major Quantitative EEG (QEEG) subtypes have been found to characterize AD/HD. Here we review the major findings in the neurophysiology of AD/HD, focusing on QEEG, and briefly present our previous findings using a source localization technique called Variable Resolution Electromagnetic Tomography (VARETA). These two techniques represent a possible objective method to identify specific patterns corresponding to EEG-defined subtypes of AD/HD. We then propose a model representing the distribution of the neural generators in these two major AD/HD subtypes, localized within basal ganglia and right anterior cortical regions, and hippocampal, para-hippocampal and temporal cortical regions, respectively. A comprehensive review of neurochemical, genetic, neuroimaging, pharmacological and neuropsychological evidence in support of this model is then presented. These results indicate the value of the neurophysiological model of AD/HD and support the involvement of different neuroanatomical systems, particularly the dopaminergic pathways.

Introduction

Attention-Deficit/Hyperactivity Disorder (AD/HD), with or without hyperactivity, still remains one of the most controversial issues in child psychiatry, especially in the endeavor to clarify the relationship between this disorder and Learning Disability (LD). The controversy begins with the operational definition of this pathology and, in general, with the terminology for classification and evaluation of children with behavioral and cognitive problems. Over time, the label for defining children who have in common some degree of inattentiveness, distractibility, impulsivity, hyperactivity, aggressiveness and learning problems has been changed repeatedly until the current definition, which distinguishes those who are predominantly inattentive (AD/HDin), or predominantly hyperactive–impulsive (AD/HDhyp), from a combined type (AD/HDcom), as a part of the same syndrome, but distinct from LD (American Psychiatric Association, 1987, American Psychiatric Association., 1994).

No current diagnostic criteria or technique allows a clear discrimination among and within these two neuropsychiatric entities, and there is considerable comorbidity between these two classes of disorders. Small sample sizes and restricted patient sampling procedures make it difficult to generalize research findings about possible pathophysiological substrates that might serve to define this population of children. Further, both are associated with an increased incidence of other psychiatric problems, such as anxiety, conduct, oppositional defiant, obsessive–compulsive or mood disorders (Biederman et al., 1991, Cantwell and Baker, 1991, Semrud-Clikeman et al., 1992, Bird et al., 1993, Pliszka, 2000). Finally, the broad nature of interventional strategies required for these disorders suggests that a heterogeneous population of children may be subsumed under the denominations of AD/HDin, AD/HDcom and LD (Semrud-Clikeman et al., 1992, Mann et al., 1992, Barkley, 1997a, Weinberg and Brumback, 1992). Due to the difficulty of classification, epidemiological data are widely different from study to study. The prevalence of AD/HD has been estimated around 5–10% among school-aged children (Rostain, 1991, Schachar, 1991, Taylor et al., 1991, Cantwell, 2004, Scahill and Schwab-Stone, 2000, Brown et al., 2001) and the prevalence of LD around 5% (Lyon, 1996). A review of epidemiological studies using standardized diagnostic criteria suggests that 3–6% of the school-aged population (elementary through high school) may suffer from AD/HD, although the percentage of US youth being treated for AD/HD is at the lower end of this prevalence range (Goldman et al., 1998).

For the above-stated reasons, it would be of great importance to find a biological marker that could help physicians in making a differential diagnosis and selecting a treatment for children with learning and attention problems. A National Institute of Mental Health Committee has identified Quantitative Electroencephalography (QEEG) as a possible objective method to identify functional measures of child and adolescent psychopathology (Jensen et al., 1993). Compared with other methods of functional neuroimaging (PET, SPECT, fMRI), QEEG is easier to perform, less expensive, non-invasive and safer (Kuperman et al., 1990). In addition to QEEG, a new source localization method called Variable Resolution Electromagnetic Tomography (VARETA; Valdes-Sosa et al., 1996, Bosch-Bayard et al., 2001) provides a virtual MRI representation of the EEG generators within the brain. Such localization might yield further insight into the underlying pathophysiology of AD/HD.

In this paper, we summarize the major findings of neurobiological studies on AD/HD, highlighting convergent points of view about pathophysiological substrates. Consistent with these investigations, we describe our results using the VARETA method in an exploratory fashion in the two main EEG-defined subtypes of AD/HD children obtained with a QEEG analysis. We also examine the clinical role of these techniques in the evaluation of AD/HD brain dysfunction. According to our findings, we propose a neurophysiological model for AD/HD that substantially involves the dopaminergic pathways.