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

Abstract

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.

FIGURE 1

Catecholamines have an inverted U influence on prefrontal cortex (PFC) function, whereby either too little or too much norepinephrine (NE) or dopamine (DA) impairs PFC cognitive abilities. Since the PFC is essential for attention regulation, optimal catecholamine actions in PFC are needed for focused, organized attention. Poor concentration and distractibility are common symptoms of weakened PFC function.

FIGURE 2

A working model of how catecholamines may gate inputs onto prefrontal cortex (PFC) neurons. Electrophysiological and anatomical data suggest that norepinephrine (NE) acts at α2A-adrenoceptors on dendritic spines to enhance connectivity with inputs from other neurons with shared characteristics, and thus increase the “signal” of that neuron. For example, a neuron spatial tuned for 90° needs to connect with other 90° neurons in order to generate network firing to represent this spatial location in the absence of environmental stimulation. α2A-Adrenoceptors increase this connectivity with other members of the network by inhibiting cAMP production in the dendritic spine, thus closing nearby hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, increasing membrane resistance and strengthening inputs onto the spine. In contrast, D1 receptors on separate spines appear to gate out inputs from neurons with dissimilar properties (e.g., 45°), thus decreasing “noise.” This appears to be accomplished, at least in part, by increasing the production of cAMP within the spine, opening HCN channels, and shunting inputs onto that spine. This may occur in a dynamic fashion, to narrow or broaden the tuning of the neuron according to task demands.