New diagnostic tools may show us that there is more to ADHD than meets the eye.

Does the six-year-old girl staring dreamily out the window as the class moves on to a new activity have ADHD? What about the energetic little boy who cannot sit still or keep his hands to himself?

Most children have a few of the 18 symptoms of inattention, hyperactivity, and impulsivity used by the American Academy of Pediatrics to define ADHD (attention deficit hyperactivity disorder), a disorder of the central nervous system that causes an inability to inhibit responses (see box, “Diagnosis of ADHD” below). Few, however, fit the additional criteria for diagnosis listed in the Diagnostic and Statistical Manual of Mental Health Disorders, Fourth Edition (DSM-IV). To be diagnosed with ADHD, a child must exhibit six or more of either the nine inattention behaviors or the nine hyperactivity and impulsivity behaviors for at least six months and to a degree inconsistent with developmental level. The behaviors must also be problematic in at least two settings and should have begun by age seven.

Diagnosis of ADHD

The American Academy of Pediatrics currently recognizes three subtypes of ADHD: Inattentive type (ADHD/I), which meets at least six of nine inattention behaviors, Hyperactive-impulsive type (ADHD/HI), which meets at least six of nine hyperactive-impulsive behaviors, and Combined type (ADHD/C), which meets at least six of nine behaviors in each of the inattention and hyperactive-impulsive lists. Inattentive behaviors include those where the subject fails to give attention to details, makes careless mistakes, has difficulty sustaining attention in tasks or play, does not seem to listen when spoken to, does not follow through on instructions, has difficulty organizing tasks or activities, is reluctant to engage in tasks requiring sustained mental effort, loses things necessary for tasks or activities, is easily distracted by extraneous stimuli, and is forgetful in daily activities. Hyperactive behaviors include those where the subject fidgets and/or squirms, leaves seat when inappropriate, runs about or climbs when inappropriate, has difficulty playing quietly, is often “on the go” or “driven by motor”, and talks excessively. Impulsive behaviors include those where the subject blurts out answers, has difficulty awaiting turn, and interrupts or intrudes on others. Sources American Academy of Pediatrics Pediatrics 2000, 105, 1158–1170. American Academy of Pediatrics Pediatrics 2001, 108, 1033–1044.

Physicians, parents, and teachers often struggle to determine whether a child will grow out of these behaviors, needs more rigorous discipline, or actually has ADHD. Consequently, some children who do not have the disorder are treated for it, and others who do have it go untreated. Those left untreated, according to researcher Russell Barkley of the University of Massachusetts Medical School (Worcester), are often locked into a course of academic and social underachievement or failure.

According to one study of 21-year-old individuals diagnosed with ADHD as children, 30–50% will be retained in a grade, and 40% will not finish high school. In addition to academic underachievement, 37% will be involved in a teen pregnancy, and 16–20% will contract a sexually transmitted disease, as compared with 1% and 4%, respectively, for individuals without ADHD. Further, compared with people without ADHD, sufferers were 4 times more likely to be involved in automobile accidents and got 3.5 times more speeding tickets. Of even greater concern, 25–35% of people with ADHD will adopt serious, repetitive, antisocial behaviors, such as fighting and drug abuse. As adults, they can be expected to change jobs more often and to be seven times more likely to be fired from a job.

Until very recently, research scientists and the medical and mental health communities were in the dark about the causes of ADHD, which hampered the development of potential treatments and fueled public debate over whether the disorder exists at all. ADHD was attributed to excessive sugar in the diet, too much television, bad parenting, and even to the overactive imaginations of psychiatrists and pediatricians.

Fortunately for the 3–9% of children and 3–5% of adults in the United States estimated to be functionally impaired by ADHD, advances in medicine and technology are about to come to the rescue. Researchers and medical practitioners are assembling evidence that shows, unquestionably, that ADHD is a neurological disorder and are attempting to find more definitive methods of diagnosis.

ADHD Neurochemistry
Numerous studies have demonstrated that the neurotransmitter dopamine, which acts on neurons involved in emotion and movement, plays a key role in ADHD pathology. Dopamine neurons release dopamine into the synapse, where it is bound by receptors (DRD4) on the surface of neighboring target neurons. Binding of dopamine to DRD4 triggers a cascade of biochemical reactions inside the target cell and inhibits the target neuron’s response to other stimuli. A “dopamine pump”, controlled by dopamine transporter protein (DAT1) molecules on the surface of dopamine-producing neurons, maintains appropriate dopamine levels by scavenging and recycling unused dopamine. Normally, the balance between secretion, binding to target neurons, and recycling by DAT1 allows an individual to express appropriate responses to environmental and emotional stimuli.

In ADHD, this balance is not maintained, possibly because of variations in several genes that have been noted in individuals with ADHD. Some ADHD individuals have a variant of the DAT1 gene that, as Barkley explains, “makes that pump hyperactive and builds too many of them.” The overactive dopamine pumps “suck up the dopamine too fast”, says Barkley, potentially removing the controls from the neurons associated with emotion and movement. One might speculate that inhibiting DAT1 would keep the pumps from sucking up so much dopamine and restore balance to the system.

Interestingly, many of the stimulant medications most effective in ADHD (including Ritalin) target and inhibit DAT1. Further research on the various neurotransmitters associated with ADHD and the normal physiologic mechanisms that regulate their function could revolutionize clinical management of ADHD.

A Window into the Brain
Researchers at several institutions recently demonstrated that Altropane (E-2-carbomethoxy-3-(4-fluorophenyl)- N-1(1-iodoprop-1-en-3-yl)nortropane), a new brain-imaging drug from Boston Life Sciences, Inc., may allow physicians to peer into the brains of individuals with ADHD. A radiolabeled synthetic chemical that binds and inhibits DAT1, Altropane was originally developed as a probe for Parkinson’s disease, a movement disorder caused by death of dopamine-secreting neurons in the brain. A. J. Fischman and colleagues at Harvard Medical School and Massachusetts General Hospital (Boston) established Altropane as an excellent probe for radio imaging of DAT1 in the brains of nonhuman primates, people with Parkinson’s disease, and unaffected people. The researchers then postulated that ADHD symptoms might be caused by overexpression of DAT1 and tested Altropane on a small group of adult ADHD patients. Using single-photon-emission computed tomography (SPECT) with ¹²³I-Altropane, the researchers quantified DAT1 and concluded that ADHD patients had a 70% increase in age-corrected dopamine transporter density compared with controls.

A multisite follow-up study by Barkley and colleagues was recently completed and is the basis for ongoing trials aimed at the use of Altropane as a diagnostic test for ADHD. The new study, to be published later this year, confirmed earlier findings and also extended them to a younger, more carefully selected sample of ADHD adults. In addition, the degree of binding of Altropane indicated that increased DAT1 density was associated with increased severity of ADHD symptoms.

Clinicians, researchers, educators and, of course, ADHD patients, hope that this technology will lead to objective diagnostic tools with which to peek into the brains of children and adults with ADHD. Barkley speculates that as more genetic data become available, new subtypes of ADHD will emerge. Different “genotypes” of ADHD, he suspects, might imply different risks, responses to treatment, and life courses, eventually leading to treatments “tailored” to individual patients and maybe even to the design of new drugs that intervene only at the specific mechanism responsible for symptoms.

ADHD Alternatives
Several groups of children are likely to be misdiagnosed with ADHD, leaving other disabilities or extraordinary abilities unrecognized. Individuals with a central auditory processing disorder (CAPD) are often easily distracted, have difficulty starting and/or completing assignments, are easily flustered or confused in noisy environments, are sensitive to loud sounds, and demonstrate difficulty following verbal directions. These individuals usually have normal “hearing” but because of disorders of the central auditory nervous system, they cannot interpret or process speech when in a suboptimal listening environment.

Because of the overlap in behavioral characteristics indicative of CAPD and ADHD, Joan Burleigh and colleagues at the Center for Auditory Research at Colorado State University (Fort Collins) recently compared behavioral checklist data from three groups of individuals who had been tested for CAPD at the center. The researchers looked at

• aberrant auditory behaviors (e.g., easily distracted, easily flustered or confused, sensitive to loud noises);
• aberrant classroom behaviors (e.g., daydreaming, forgetfulness, restlessness, and incapacity to complete assignments);
• aberrant social/emotional behaviors (e.g., anxiety/tension, frustration, lack of confidence, attention seeking); and
• disinhibition behaviors (e.g., irritable, hyperactive, impulsive, disobedient, disruptive, uncooperative).

The first group (n = 41) had normal central auditory processing, the second group (n = 50) had been diagnosed with CAPD but had no indication of ADHD, and the third group (n = 57) had been diagnosed with ADHD and subsequently referred to the Center for CAPD for auditory processing testing.

Of the 24 criteria found to clearly distinguish between normal central auditory processing and CAPD, only the disinhibition behaviors were more frequently reported for ADHD/CAPD individuals than for those with CAPD alone. All aberrant auditory behaviors reported in CAPD/ADHD individuals and many of the aberrant classroom behaviors appeared just as frequently in the CAPD group that did not have ADHD. Interestingly, these are the behaviors most likely to indicate Inattentive-type ADHD, a subgroup that some ADHD researchers believe should not be included as a type of ADHD.

Another group of children that exhibit many behaviors characteristic of ADHD are exceptionally intelligent or “gifted” children, who are loosely defined as those with IQs higher than 120. These children often display exceptional intensity, emotionality, impatience, high energy, and inattentiveness. The behaviors may occur because the child is not sufficiently engaged in the classroom, in other words, bored. Alternatively, they may actually have “dual exceptionalities”—giftedness and ADHD.

Obviously, defining ADHD and its associated disorders remains a murky endeavor, but improvements in diagnosis and understanding will be forthcoming.

Further Reading

• Barkley, R. A. Attention-Deficit Hyperactivity Disorder. Sci. Am. Sept 1998; www.sciam.com/1998/0998issue/0998barkley.html.
• Burleigh, J.; McIntosh, K.; Thompson, M. Central Auditory Processing. In Sensory Integration: Theory and Practice, 2nd ed.; Bundy, A., Murray, E., Lane, S., Eds.; F. A. Davis Co.: Philadelphia, in press.
• Dougherty, D. D.; et al. Lancet 1999, 354, 91–96.
• Fischman, A. J.; et al. Synapse 1998, 29, 128–141.
• Lovecky, D. V. Gifted Children with ADHD; http://print.ditd.org/floater=71.html.