What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: the critical role of early developmental events on prefrontal function

Abstract

The present review surveys a broad range of findings on the functions of the rodent prefrontal cortex (PFC) in the context of the known pathophysiology of attention-deficit/hyperactivity disorder (ADHD). An overview of clinical findings concludes that dysfunction of the right PFC plays a critical role in ADHD and that a number of early developmental factors conspire to increase the risk of the disorder. Rodent studies are described which go far in explaining how the core processes which are deficient in ADHD are mediated by the PFC and that the mesocortical dopamine (DA) system plays a central role in modulating these functions. These studies also demonstrate a surprising degree of cerebral lateralization of prefrontal function in the rat. Importantly, the PFC is highly vulnerable to a wide variety of early developmental insults, which parallel the known risk factors for ADHD. It is suggested that the regulation of physiological and behavioral arousal is a fundamental role of the PFC, upon which many "higher" prefrontal functions are dependent or at least influenced. These right hemispheric arousal systems, of which the mesocortical DA system is a component, are greatly affected by early adverse events, both peri- and postnatally. Abnormal development, particularly of the right PFC and its DAergic afferents, is suggested to contribute directly to the core deficits of ADHD through dysregulation of the right frontostriatal system.