The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex

Abstract

Attention deficit/hyperactivity disorder (ADHD) is characterized by symptoms of inattention, impulsivity, and locomotor hyperactivity. Recent advances in neurobiology, imaging, and genetics have led to a greater understanding of the etiology and treatment of ADHD. Studies have found that ADHD is associated with weaker function and structure of prefrontal cortex (PFC) circuits, especially in the right hemisphere. The prefrontal association cortex plays a crucial role in regulating attention, behavior, and emotion, with the right hemisphere specialized for behavioral inhibition. The PFC is highly dependent on the correct neurochemical environment for proper function: noradrenergic stimulation of postsynaptic alpha-2A adrenoceptors and dopaminergic stimulation of D1 receptors is necessary for optimal prefrontal function. ADHD is associated with genetic changes that weaken catecholamine signaling and, in some patients, with slowed PFC maturation. Effective pharmacologic treatments for ADHD all enhance catecholamine signaling in the PFC and strengthen its regulation of attention and behavior. Recent animal studies show that therapeutic doses of stimulant medications preferentially increase norepinephrine and, to a lesser extent, dopamine, in the PFC. These doses reduce locomotor activity and improve PFC regulation of attention and behavior through enhanced catecholamine stimulation of alpha-2A and D1 receptors. These findings in animals are consistent with improved PFC function in normal human subjects and, more prominently, in patients with ADHD. Thus, a highly cohesive story is emerging regarding the etiology and treatment of ADHD.

Figure 1

The PFC regulates “top-down” attention, allocating and directing attentional resources based on stimulus relevance. Top-down attention includes stimulus gating, reducing distractibility and sustaining attention on relevant information. These operations are thought to arise from PFC projections back to the sensory cortices. In contrast, the posterior sensory cortices mediate “bottom-up” attention, processing sensory characteristics based on stimulus salience. Most patients with ADHD have difficulties with top-down attention regulation.

Figure 2

The PFC regulates behavior and inhibits inappropriate impulses. In humans, the right inferior PFC is specialized for behavioral inhibition. Projections from this area to the premotor and motor cortices, the basal ganglia (striatum and subthalamic nucleus), and the cerebellum (by way of the pontine nuclei) are likely involved in the inhibition of inappropriate movements and impulses. In monkeys, blockade of alpha-2A receptors in the PFC induces a pattern of impulsive responding and locomotor hyperactivity.,

Figure 3

The PFC guides attention, behavior, and emotion through networks of pyramidal cells. These pyramidal cells engage in recurrent excitation to represent stimuli (e.g., the spatial positions 90° or 270°, as shown here) or to represent goals or rules. The networks interconnect through synapses on dendritic spines that contain NE alpha-2A receptors or DA D1 receptors. Network connectivity is powerfully modulated by the catecholamines: NE alpha-2A receptor stimulation strengthens network inputs from cells with shared network properties by reducing the production of cAMP, thus closing HCN channels and enhancing synaptic inputs to the spine (increasing “signals”). Conversely, optimal levels of DA D1 receptor stimulation weaken irrelevant inputs to the neuron by increasing the production of cAMP, opening HCN channels near the synapse, and shunting incoming information (decreasing “noise”). Thus, for the network representing 90°, alpha-2A receptor stimulation increases the strength of connections from other 90° neurons, and D1 receptor stimulation weakens the connections from neurons with dissimilar characteristics (e.g., 270°). Adapted with permission from Arnsten AF 2007.

Figure 4

The regulatory functions of the PFC are highly dependent on its neurochemical state. The catecholamines NE and DA are released based on our state of arousal. Either too little or too much catecholamine release is detrimental to PFC function: there is an inverted U dose-response relationship. Inadequate catecholamine release is associated with fatigue and ADHD, and excessive catecholamine release occurs during uncontrollable stress or very high doses of stimulant medications. NE has its highest affinity for alpha-2A receptors and has lower affinity for alpha-1 and beta-1 receptors. Thus, different receptors are engaged based on the amount of NE released in the PFC. Therapeutic doses of stimulants, atomoxetine, or guanfacine likely normalize catecholamine transmission in patients with inadequate DA or NE levels, or both, thus bringing PFC function to more optimal levels at the top of the inverted U.