CNS Drugs

, Volume 23, Supplement 1, pp 33–41 | Cite as

Toward a New Understanding of Attention-Deficit Hyperactivity Disorder Pathophysiology

An Important Role for Prefrontal Cortex Dysfunction
  • Amy F. T. Arnsten
Review Article


Recent advances in neurobiology have aided our understanding of attention-deficit hyperactivity disorder (ADHD). The higher-order association cortices in the temporal and parietal lobes and prefrontal cortex (PFC) interconnect to mediate aspects of attention. The parietal association cortices are important for orienting attentional resources in time/space, while the temporal association cortices analyse visual features critical for identifying objects/ places. These posterior cortices are engaged by the salience of a stimulus (its physical characteristics such as movement and colour). Conversely, the PFC is critical for regulating attention based on relevance (i.e. its meaning). The PFC is important for screening distractions, sustaining attention and shifting/ dividing attention in a task-appropriate manner. The PFC is critical for regulating behaviour/emotion, especially for inhibiting inappropriate emotions, impulses and habits. The PFC is needed for allocating/planning to achieve goals and organizing behaviour/thought. These regulatory abilities are often referred to as executive functions. In humans, the right hemisphere of the PFC is important for regulating distractions, inappropriate behaviour and emotional responses. Imaging studies of patients with ADHD indicate that these regions are underactive with weakened connections to other parts of the brain.

The PFC regulates attention and behaviour through networks of interconnected pyramidal cells. These networks excite each other to store goals/ rules to guide actions and are highly dependent on their neurochemical environment, as small changes in the catecholamines noradrenaline (NA) or dopamine (DA) can have marked effects on PFC function. NA and DA are released in the PFC according to our arousal state; too little (during fatigue or boredom) or too much (during stress) impairs PFC function. Optimal amounts are released when we are alert/interested. The beneficial effects of NA occur at postsynaptic α2A-receptors on the dendritic spines of PFC pyramidal cells. Stimulation of these receptors initiates a series of chemical events inside the cell. These chemical signals lead to the closing of special ion channels, thus strengthening the connectivity of network inputs to the cell. Conversely, the beneficial effects of moderate amounts of DA occur at D1 receptors, which act by weakening irrelevant inputs to the cells on another set of spines. Genetic linkage studies of ADHD suggest that these catecholamine pathways may be altered in some families with ADHD, e.g. alterations in the enzyme that synthesizes NA (DA β-hydroxylase) are associated with weakened PFC abilities.

Pharmacological studies in animals indicate catecholamine actions in the PFC are highly relevant to ADHD. Blocking NA α2A-receptors in the PFC with yohimbine produces a profile similar to ADHD: locomotor hyper-activity, impulsivity and poor working memory. Conversely, drugs that enhance α2-receptor stimulation improve PFC function. Guanfacine directly stimulates postsynaptic α2A-receptors in the PFC and improves functioning, while methylphenidate and atomoxetine increase endogenous NA and DA levels and indirectly improve PFC function via α2A- and D1 receptor actions. Methylphenidate and atomoxetine have more potent actions in the PFC than in subcortical structures, which may explain why proper administration of stimulant medications does not lead to abuse. Further understanding of the neurobiology of attention and impulse control will allow us to better tailor treatments for specific patient needs.


Methylphenidate Atomoxetine Stimulant Medication Guanfacine Association Cortex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Amy Arnsten, PhD has a licence agreement with Shire Pharmaceuticals for the development of guanfacine for the treatment of ADHD and related disorders.


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Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Amy F. T. Arnsten
    • 1
  1. 1.Department of NeurobiologyYale University School of MedicineNew HavenUSA

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