Understanding the Neurobiological Basis of ADHD

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Although the exact origin of ADHD is not known, ADHD is a neurobehavioral disorder thought to be associated with structural and chemical alterations in the prefrontal cortex, the front-most portion of the brain responsible for many higher-order mental functions—including those that regulate attention and behavior.1 Multiple research studies conducted in both humans and animals support various theories regarding the prefrontal cortex and the neurobiological basis of ADHD, as described in this section. Some of this research also is summarized in this videovideo.

Brain Structure Within the Prefrontal Cortex

The 3 Subregions of the Prefrontal Cortex Related to the 3 Core Symptoms of ADHD2

Current understanding of the neurobiology of ADHD may point to a link between structural differences in the prefrontal cortex and the 3 core symptoms of ADHD.

More specifically, studies suggest that deficits or dysregulation in 3 different subregions of the prefrontal cortex may together result in the spectrum of ADHD symptoms (see Figure).3,4

  • The dorsolateral prefrontal cortex regulates attention—Impairment may lead to symptoms of inattention and distraction.3,5-6
  • The right inferior prefrontal cortex regulates behavior—Impairment may lead to symptoms of impulsivity and hyperactivity.3,7
  • The ventromedial prefrontal cortex regulates emotional responses.3

Impaired Neural Networks Involving the Prefrontal Cortex

Research suggests that impaired neural networks involving the prefrontal cortex may be associated with the symptoms that manifest in patients with ADHD.

The prefrontal cortex networks thought to be impaired in ADHD include:

  • Attention networks—Impaired activation within the prefrontal cortex and other brain regions associated with attention networks has been demonstrated through functional neuroimaging studies in patients with ADHD.8-11
  • Inhibitory control networks—Dysregulation of the prefrontal cortex and other brain centers associated with inhibitory control networks has been identified in patients with ADHD.12-13

Aberrations in Neurotransmitter Release May Affect Prefrontal Cortex Function

Neurotransmitter Transmission Within the Prefrontal Cortex8,14

In addition to deficits in the prefrontal cortex and its related networks, research conducted in animals suggests that inappropriate neurotransmitter levels may also impair prefrontal cortex function.15-16

Networks connecting the prefrontal cortex with other parts of the brain are highly dependent on their neurochemical environment. Two neurotransmitters, norepinephrine and dopamine, play a critical and essential role in prefrontal cortex function (see Figure).16

  • Norepinephrine enhances prefrontal cortex function by increasing appropriate signals—Norepinephrine stimulates postsynaptic receptors to strengthen appropriate network connections and allow networks to continuously fire for long periods.
  • Dopamine enhances prefrontal cortex function by decreasing inappropriate noise—Dopamine stimulates postsynaptic receptors that act to suppress cellular inputs that are irrelevant to current demands.

Just small changes in norepinephrine and dopamine levels can exert marked effects on prefrontal cortex function. Insufficient norepinephrine and dopamine levels, which impair prefrontal cortex function, have been associated with symptoms of ADHD. Optimal amounts of both norepinephrine and dopamine levels are released when we are alert or interested.15-18


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  11. Vance A, Silk TJ, Casey M, et al. Right parietal dysfunction in children with attention deficit hyperactivity disorder, combined type: a functional MRI study. Mol Psychiatry. 2007;12(9):826-832.
  12. Epstein JN, Casey BJ, Tonev ST, et al. ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD. J Child Psychol Psychiatry. 2007;48(9):899-913.
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  14. Dendy CAZ, Durheim M, Ellison AT. CHADD Educator’s Manual on Attention-Deficit/Hyperactivity Disorder AD/HD. An In-Depth Look From an Educational Perspective. Lynchburg, VA: Progress Printing; 2006.
  15. Levy F. Dopamine vs noradrenaline: inverted-U effects and ADHD theories. Aust NZ J Psychiatry. 2009;43(2):101-108.
  16. Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 2009;23(suppl 1):33-41.
  17. Arnsten AF. Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry. 2006;67(suppl 8):7-12.
  18. Arnsten AFT, Castellanos FX. Neurobiology of attention regulation and its disorders. In: Martin A, Scahill L, Charney D, Leckman J, eds. Pediatric Psychopharmacology: Principles and Practice. New York, NY: Oxford University Press. 2003:99-109.