Attention Deficit Hyperactivity Disorder (ADHD) is one of many labels for one of the most common and controversial conditions in child psychiatry. ADHD is conservatively estimated to occur in 3 - 7.5% of school age children, but some estimates range up to 17%. Thus 1 to 2 children per classroom are affected. The purpose of the accompanying article is to highlight the key studies that have led to our current understanding of ADHD, and to propose a new multidisciplinary approach that will guide our studies in the years to come. We believe that the field is ready to shift from descriptive approaches to one that attempts to define the underlying neuropsychiatric abnormalities by developing endophenotypes (inherited traits that predict the risk of developing a given disease, in the way that high cholesterol predicts an increased risk of heart disease) of ADHD.
The fruitless search for a single theory of ADHD
One of the major challenges facing physicians and researchers is that patients that have been diagnosed with ADHD may seem very different. For example, some may fidget and interrupt their classmates while others are quiet and daydream a lot. Or some may seem disorganized and forgetful, and others can't seem to wait for things to happen soon enough. These differences may in fact be very important, because they may indicate different causes, and also the need for different types of treatment.
Until now, physicians and scientists have focused on the commonalities amongst individuals with ADHD. This approach has been very useful, because it has led to the recognition of ADHD as a real medical/psychiatric condition and improved the accuracy and reliability of diagnosis. However, the unintended result has been that we have forgotten that the diagnosis of ADHD is still provisional, and only tells us about the symptoms, instead of informing us about the causes. For example, when a patient is diagnosed with a fever, all we really know is that the patient's temperature is elevated. The fever could have been caused by the flu, a serious bacterial illness such as meningitis, a chronic condition, like some forms of arthritis, or even some rare types of genetic fever syndromes. Current diagnostic approaches to ADHD all depend on the patient's history, and they tell us that individuals with ADHD have specific difficulties paying attention and regulating their behavior, but they do not tell us why. To progress further in our understanding, diagnosis, and treatment of patients with ADHD, we believe that we now need to focus on the differences among individuals with this diagnosis.
Causes of ADHD
Before 1980, the rules for determining psychiatric disorders were fairly vague and based on Freudian theories. In 1980 the American Psychiatric Association published the first set of symptom-based descriptive criteria, allowing scientists to diagnose psychiatric disorders more precisely and reliably. Those criteria were revised in 1987 and most recently in 1994 (published in the Diagnostic and Statistical Manual of Mental Disorders - 4th Edition (DSM-IV)). These criteria are acknowledged to be a work-in-progress, but they have helped scientists and physicians to better identify and diagnose ADHD. The increasing success of the Human Genome Project has made researchers enthusiastic to discover the genetic causes behind ADHD. However, causative factors include not only genetic variations or mutations, but also environmental factors and interactions between genes and environment. These factors are the initial causes of the multiple symptoms of ADHD, and our goal is to identify the various causes.
Genetic factors. A range of family, adoption, and twin studies have shown that most cases of ADHD are strongly influenced by genes. Recently, scientists have found some clues suggesting that genes linked to the neurotransmitters dopamine or norepinephrine are associated with ADHD.
Environmental factors. ADHD can also develop due to traumatic brain injury and juvenile stroke. Other environmental risk factors include severe early neglect and maternal smoking during pregnancy.
Hypothetical endophenotypes and behavior
ADHD, like all studied psychiatric disorders, is not caused by a single genetic mutation. In order to find the underlying causes of ADHD, we need to find the underlying mechanisms. Through this process, we hope to uncover the endophenotypes of ADHD. These are the measurable characteristics that might predict the risk of ADHD in the same way that serum cholesterol predicts the risk of heart disease. We believe that future studies will need to focus on such endophenotypes, and the ones we discuss below are: 1) hyperactivity; 2) inhibition; 3) the tendency to avoid delaying gratification; 4) variability in estimating time intervals; and 5) difficulties with very short-term memory.
1) Hyperactivity and dopamine
In experiments with animals, hyperactivity has been associated with both too much and too little dopamine, and human brain imaging studies also provide some evidence for a malfunctioning dopamine system in ADHD.
Unfortunately, determining dopamine levels in the brain can't be done without injecting small amounts of radioactivity, which means we can't do these studies with children. Studies are done with adults who have ADHD, but adult brains are not identical to the brains of children. So we now turn to other possible endophenotypes for ADHD which can be measured directly in children.
Inhibition - the ability to stop oneself - is one of the higher-order mental abilities, which also include the ability to disregard distractions, to monitor one's behavior, and to sort out the relevant information in problem-solving tasks. These abilities are collectively called "executive function," and there is much evidence that these abilities are impaired in many individuals who have ADHD.
Specifically, difficulty with inhibition (technically termed "response inhibition") has been proposed as the primary problem in ADHD, as is evidenced by the difference between the performances of children with and without ADHD on a test called a "stop task." In the stop task, children are asked to respond as quickly as they can to a "go" signal, unless they get a "stop" signal. Most studies find that ADHD patients need the "stop" warning to come much earlier if they're going to "put on the brakes." This explanation of ADHD predicts that most of the impulsive symptoms are the result of difficulties in stopping a planned action or thought.
3) Delay aversion
Another possible endophenotype is that of "delay aversion." Delay aversion refers to the tendency to choose immediate gratification over delayed gratification, even if the later reward is substantially larger than the one available immediately. This theory of ADHD predicts that most hyperactive and fidgety behaviors are the result of this intrinsic impatience. We know some of the key brain regions involved in these processes include the nucleus accumbens and perhaps the cerebellum from studies in experimental animals and plan to examine those regions in children and adolescents with ADHD.
4) Difficulties estimating time intervals
All brain functions require exquisitely coordinated operation of thousands or millions of neurons in a sort of grand neuronal symphony. Groups of neurons send and receive information to other groups in a highly coordinated manner that depends on temporal fidelity among other factors. Studies of the brain anatomy of patients with ADHD have shown that one of the most abnormal regions is the brain's cerebellum, which provides much of the temporal information for the rest of the brain. We know from recent studies that patients with ADHD of all ages have trouble estimating and reproducing correct time durations, from fractions of a second to a minute. Interestingly, these difficulties do not seem to improve with medication.
5) Very-short-term (Working) memory
Working memory is a system of processes and mechanisms that allows one to hold a piece of information "online" for a few seconds while other mental processes occur - a sort of mental scratch pad. Working memory controls attention and guides decision making and moment-by-moment behavior during an activity.
Current diagnostic guidelines divide ADHD into two clusters of symptoms: 1) hyperactive/impulsive and 2) inattentive. Since the inattentive cluster has been found to be more strongly associated with cognitive and academic impairments than the hyperactive/impulsive cluster, it is possible that only individuals with severe inattention (rather than ADHD per se) have working memory problems. Preliminary results from The Hospital for Sick Children in Toronto suggest that ADHD subgroups that differ in working memory ability also differ in cognitive response to stimulant medication (e.g., methylphenidate = Ritalin). This is an example of the kinds of comparisons and correlations we will be making in our research on this subject.
The current approach to psychiatric disorders has allowed us to improve the accuracy and reliability of diagnoses such as ADHD. This allows us to begin exploring the possible root causes of the various types of ADHD. We believe that by measuring patients' working memory, and/or their ability to reproduce or estimate temporal durations, and/or their ability to delay gratification, we will learn about some of the physiological components which can result in the symptoms we call ADHD. If we can confirm these scientific guesses, then we can start to distinguish the different types at a fundamental level, and eventually develop more effective treatments and true preventive strategies.
About the Authors
Rosemary Tannock, Ph.D., is a senior scientist in the Brain and Behavior Research Program of the Research Institute at The Hospital for Sick Children, and an Associate Professor of Child and Adolescent Psychiatry at the University of Toronto, Canada.
We thank Eleanor Ainslie for her assistance in preparing this summary.
References and Related Books
Neuroscience of Attention-Deficit/Hyperactivity Disorder: The Search for Endophenotypes. Nature Reviews Neuroscience, F. Xavier Castellanos and Rosemary Tannock, August 2002, Vol 3 No 8: HTML version
Developmental Trajectories of Brain Volume Abnormalities in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. F. Xavier Castellanos et al., JAMA, October 9, 2002, Vol. 288 No. 14
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