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Ann N Y Acad Sci. 2008;1129:236-45. doi: 10.1196/annals.1417.007.

Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function.

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Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA.


Neuropsychological and imaging studies indicate that attention deficit hyperactivity disorder (ADHD) is associated with alterations in prefrontal cortex (PFC) and its connections to striatum and cerebellum. Research in animals, in combination with observations of patients with cortical lesions, has shown that the PFC is critical for the regulation of behavior, attention, and affect using representational knowledge. The PFC is important for sustaining attention over a delay, inhibiting distraction, and dividing attention, while more posterior cortical areas are essential for perception and the allocation of attentional resources. The PFC in the right hemisphere is especially important for behavioral inhibition. Lesions to the PFC produce a profile of distractibility, forgetfulness, impulsivity, poor planning, and locomotor hyperactivity. The PFC is very sensitive to its neurochemical environment, and either too little (drowsiness) or too much (stress) catecholamine release in PFC weakens cognitive control of behavior and attention. Recent electrophysiological studies in animals suggest that norepinephrine enhances "signals" through postsynaptic alpha2A adrenoceptors in PFC, while dopamine decreases "noise" through modest levels of D1 receptor stimulation. alpha2A-Adrenoceptor stimulation strengthens the functional connectivity of PFC networks, while blockade of alpha2 receptors in the monkey PFC recreates the symptoms of ADHD, resulting in impaired working memory, increased impulsivity, and locomotor hyperactivity. Genetic alterations in catecholamine pathways may contribute to dysregulation of PFC circuits in this disorder. Medications may have many of their therapeutic effects by optimizing stimulation of alpha2A adrenoceptors and D1 receptors in the PFC, thus strengthening PFC regulation of behavior and attention.

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