Progress over the past 50 years in our understanding of the neurobiology of attention deficit disorder with hyperactivity is reviewed by child psychiatrists at the National Institute of Mental Health, Bethesda, MD. Since Bradley first described the paradoxical calming effect of the stimulant benzedrine on hyperactive children (Amer J Psychiat 1937:94:577), more than 20 neuropharmacological agents have been used for the study and treatment of children with attention deficit disorder with hyperactivity (ADDH). Biochemical, pharmacological, and anatomical hypotheses are analyzed and may be summarized as follows: (1) stimulants are the treatment of choice and all beneficial drugs have effects on catecholamine metabolism; (2) alteration in noradrenergic function appears necessary for clinical efficacy; (3) a role for norepinephrine but not serotonin metabolism in the pathophysiology is likely; (4) support for a frontal lobe anatomical location of CNS dysfunction for ADDH seems more conclusive than hypothalmic dysfunction; (5) different sites of dysfunction in the cortical-striatal “circuit” might account for the varying symptoms of the ADDH syndrome. 
COMMENT: The possible importance of brain injury or other neuropathological lesions in the pathogenesis of hyperkinetic behavior is often discounted in favor of environmental factors, and the authors emphasis on the neuroanatomical hypothesis and especially frontal lobe dysfunction in ADDH is refreshing. Some of the earlier experimental neuroanatomical studies of hyperkinesia have been concerned with the effects of ablation or destruction of different cortical and subcortical structures on locomotor activity. Bilateral removal of the prefrontal and frontal areas in the monkey and smaller animals causes the greatest total increase in activity (Kennard MA et al. J Neurophysiol 1941:4:512. Millichap JG et al. Excerpta Medica 1974:130-139). We found an increase in locomotor activity of mice with prefrontal cortical lesions and those animals with the highest level of post-operative activity responded to methylphenidate with a reduction in locomotor activity. We suggested that animals with prefrontal cortical lesions should make valuable experimental models for testing new drugs. The beneficial effect of methylphenidate on hyperactivity in our patients was related to the level of motor activity before treatment and the degree of neurologic abnormality. ADDH patients with the greatest number of neurologic signs were most active and were most likely to benefit from stimulant therapy . A neuroanatomical basis for ADDH in some children might be substantiated by the MRI.