Fine-Tuning our Understanding of the ADHD Brain

The greater our understanding of an illness state, the better we are able to treat it.  As one of the core disorders in our practice, we constantly review and update our knowledge on ADHD. In the course of a recent review, I came across a wonderful compilation issue on ADHD in Biological Psychiatry (Biol Psychiatry June 15 2011, vol. 69).  The review issue covers a wide range of topics from psychostimulants as cognitive enhancers to the molecular genetics of ADHD.  The most relevant and clinically applicable article, however, was Amy Arnsten’s paper on “Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks” (Biol Psychiatry. 2011 June 15;69(12):e89-99).  She does a masterful job of presenting complex material in a clear and elegant manner.  Dr. Arnsten is able to capture the fluidity and dynamics of cortical functions associated with ADHD while still giving the reader anchor points that are useful in everyday clinical practice.

Dr. Arnsten’s article focuses on the effects of dopamine (DA) and norepinephrine (NE) on the dorsolateral prefrontal cortex (PFC).  This area of the brain has long been associated with executive function and working memory – the two primary problem areas associated with ADHD.  Executive functions are the neuropsychological capacities involved in planning, prioritizing and organizing tasks.  Working memory is the mind’s ability to keep and utilize information in short term storage, like the random access memory on a computer.  Though dopamine was held to be the primary neurotransmitter involved with ADHD, recent evidence has demonstrated that norepinephrine plays a significant role as well.  Working backwards from the evidence that medications used to treat ADHD such as methylphenidate and atomoxetine affect catecholamine (NE and DA) transmission in the PFC, Arnsten honed in on the specific receptors affected by these medications.  In her investigation, she found that the α2A receptor and D1 receptor had particular relevance to ADHD.

Recent studies found that norepinephrine strengthens PFC signaling through post- synaptic stimulation of α2A receptors on PFC neurons.   Conversely, dopamine acts at D1 receptors to decrease the signal to noise ratio by inhibiting stimulation from non-relevant external cues.  They also found that there is a “sweet spot” in the amount of norepinephrine and dopamine being released in the system, i.e. too much or too little markedly impairs PFC function. To break it down to a clinical level – medications such as methylphenidate or atomoxetine affect both norepinephrine and dopamine levels.  Appropriately increased levels of these neurochemicals then cause two actions to treat the symptoms of ADHD.  First, the norepinephrine ramps up signal strength for relevant stimuli through effects on α2A receptors, and second, the dopamine reduces the signal strength of non-relevant stimuli.

How do these ideas translate into the clinical realm?  Let’s imagine a person with ADHD working on a report on the computer.  Suddenly, an email pops up or the phone rings.  Untreated, his/her attention is immediately diverted to the new stimuli and a cascade of distractions ensues.  The report is left half -finished and the person doesn’t get back to it for hours.  Treated with methylphenidate, the non-relevant stimuli of an email pop up or phone call is now recognized but the dopamine working on the D1 receptor keeps that signal strength low, and the norepinephrine targeting the α2A receptor keeps the signal strength high for the report in front of him/her that needs to be finished.  This is referred to as “sculpting” or “spatial tuning” as the signal to noise ratio is kept appropriately calibrated to the task in front of the person that needs to be completed. This flow of dynamic signaling management is one of the hallmarks of executive function that can be so affected by ADHD.

Returning to the theme that greater understanding leads to better treatment, appreciation of the two component nature of attentional “sculpting” or “spatial tuning” enhances our ability to fine tune the treatment of our patient’s ADHD.   Clarifying whether our patient is having trouble with target signal emphasis and/or reducing distractor stimuli enables us to customize and more precisely adjust our medication interventions.  This insight is also useful for patients to better understand their specific challenges with this disorder.

We will continue to stay on top of advances like these in our practice areas of specialization so that we can better educate ourselves and you.