ADHD and the Prefrontal 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.Attention deficit/hyperactivity disorder (ADHD) is characterized by symptoms of inattention, poor impulse control, and increased motor activity. 1 In the last 20 years, advances in the fields of neuroscience and genetics have provided new insights into this common disorder. We have learned how genetic alterations can affect neural circuits and lead to the symptoms of ADHD, and how correcting these alterations can lead to rational treatments. Much of the research on ADHD has pointed to weaknesses in the prefrontal cortex (PFC), the most highly evolved of the association cortices. The PFC regulates attention and behavior through its widespread connections to sensory and motor cortices, and to subcortical structures such as the basal ganglia and cerebellum. Imaging studies have demonstrated that patients with ADHD have alterations in PFC circuits and demonstrate weaker PFC activation while trying to regulate attention and behavior. The PFC requires optimal levels of norepinephrine (NE) and dopamine Edited by Accardo and WFB Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: Potential relevance to attention deficit hyperactivity disorder

“…The current studies demonstrate that the selective DA reuptake inhibitor, AHN 2-005, improves PFC-dependent cognitive function as measured in this working memory task while lacking locomotor-activating or arousal-promoting actions. This behavioral profile is similar to all drugs currently approved for use in ADHD, including psychostimulants, SNRIs and α 2 -agonists (see Arnsten, 2009; Berridge and Devilbiss, 2011). Moreover, at a cognition-enhancing dose AHN 2-005 modestly elevated extracellular levels of DA and NE within the PFC (e.g.…”

“…This has been posited to reflect, in part, a prominent role of the NET in the clearance of DA within the PFC (Berridge and Devilbiss, 2011; Carboni et al, 2006; Yamamoto and Novotney, 1998). These and other observations indicate a pivotal role of PFC catecholamines in the cognition-enhancing/therapeutic actions of ADHD-related drugs (Arnsten, 2009; Arnsten and Dudley, 2005; Devilbiss and Berridge, 2008; Spencer et al, 2011). If NE and DA binding at the NE transporter (NET) in the PFC is competitive, elevations in extracellular DA are expected to result in an elevation in extracellular NE levels.…”

“…Pharmacological and lesion studies demonstrate that the delayed-response test of spatial working memory used in these studies is highly dependent on the PFC (Kesner et al, 1989; Spencer et al, 2011). Additionally, the pharmacological sensitivity of performance in this task closely aligns with the pharmacology of ADHD (Arnsten, 2009; Berridge et al, 2012; Gamo et al, 2010). This is in contrast with other animal-based tests of PFC-dependent function, including sustained attention and attentional set shifting, which display a pharmacological sensitivity distinct from both delayed alternation testing and ADHD.…”

“…To assess the potential use of AHN 2-005 in ADHD, we first examined the degree to which this compound improves PFC-dependent function of rats as measured in a delayed-response task of working memory. Importantly, the pharmacology of performance in this task aligns closely with the pharmacology of ADHD: all major classes of drugs used to treat ADHD (psychostimulants, SNRIs, α 2 -agonists) improve performance in this task (Arnsten, 2009; Berridge and Devilbiss, 2011). Thus this task is a useful preclinical screen for ADHD-related compounds.…”

Who says this is a modern disorder? The early history of attention deficit hyperactivity disorder

“…Such descriptions of what he termed "simple hyperexcitability" (Table 1) show greater resemblance to the current conceptualization of the hyperactive child than the observations of Sir George Still [62] . He believed that such conditions were due to an overactivity of the nerve cells in the cerebral cortex, as was demonstrated almost 100 years later [64][65][66] . In addition, Clouston [63] outlined a multimodal therapy that included a pharmacological intervention consisting of carefully dosed grains of potassium bromides to treat these children (Table 1).…”