That electric feeling

Advances in genetics and imaging offer hope for understanding ADHD

Bill Snyder
Published: November, 2003

ADHD hasn't stopped 14-year-old J.T. King from succeeding in school or competing in chess tournaments.  He says the medication he takes—a lont-acting form of methylphenidate—helps him stay calm and "think harder."
Photo illustration by Dean Dixon
Before he started taking Ritalin four years ago, J.T. King just couldn’t sit still. “I feel like I have electricity running through me,” he told his parents when he was in the second grade. “I feel like if I stuck my hands out, … lightning bolts would come out of my fingers.”

J.T. is still bothered sometimes by that electric feeling. But today, thanks to the medication, his parents’ perseverance and his own determination, the gregarious seventh grader is succeeding in school, competing in chess tournaments and mastering every video game he tries. “He’s awesome,” marvels his mother, Jere King.

This 14-year-old computer whiz from Franklin, Tenn., has attention deficit hyperactivity disorder (ADHD), the most commonly diagnosed behavioral problem in children. There is recurring debate about whether ADHD is over-diagnosed, or whether some hyperactive youngsters aren’t getting the treatment they need.

What confounds any discussion about the diagnosis and treatment of ADHD is its complexity. ADHD is actually a constellation of symptoms – the hallmarks of which are a persistent pattern of hyperactivity, impulsive behavior and difficulty paying attention. No single cause for these symptoms has yet been found and, to complicate matters even further, ADHD is often diagnosed in conjunction with learning disabilities and other behavior problems.

These mysteries are rapidly being unraveled, thanks to recent advances in genetics, brain imaging and the ability to manipulate the genetic make-up of laboratory mice. “Advancements in technology have changed the whole field completely,” asserts Richard Shelton, M.D., professor of Psychiatry and Pharmacology at Vanderbilt University Medical Center, and an expert on the treatment of depression, bipolar disorder and ADHD. “I’m asking questions now that I couldn’t possibly have asked even five years ago.”

To understand ADHD, as well as other disorders of brain functioning, we must first journey deep into the nervous system – down to the cellular level. There we’ll find the molecules that make it possible for electrical signals to jump the gaps between individual nerve cells, called synapses, and transmit information at lightning speed throughout the body.

Sweeping the synapse
The dopamine transporter, pictured here as a vacuum -like tube, sweeps dopamine back into the nerve cell after its job is done (top panel).  Drugs like Ritalin are thought to block the dopamine transporter, thereby increasing the supply of dopamine in the synapse (bottom panel).
Illustrations by Dominic Doyle
The first molecules we’ll meet are the neurotransmitters, which actually jump the gap. They include dopamine, norepinephrine and serotonin. After leaving their nerve cell, they attach to and activate receptors on the next cell in line, much like a key fits into a lock. Millions of locks must be opened in this way to send messages down their “signaling pathways.” The ultimate goal may be to bend an arm or trigger the recollection of a childhood memory.

When these signals go awry, the body cannot function properly. Depression has been linked to a lack of serotonin. A loss of dopamine-producing cells in the brain causes Parkinson’s disease, the inability to control voluntary muscle movement. Altered levels of norepinephrine can trigger heart disorders, depression and attention deficits.

These three neurotransmitters have been implicated in a wide range of other brain disorders, from ADHD to schizophrenia, and they represent just a fraction of the molecules known to carry or modify messages along the convoluted avenues of nerves between our ears.

But it gets even more complicated. Dopamine has five known receptors (some of which also can be activated by norepinephrine), while serotonin has at least a dozen. On top of that, one of the dopamine receptors, D4, exists in several genetically distinct forms, or variants. Your dopamine messaging system may function differently, and you may respond differently to drugs that affect it, depending on which genetic variant you inherit.

A clean sweep

The next molecule we’ll meet on our journey is the transporter, an important regulator of neurotransmitter function. The transporter acts like a molecular vacuum cleaner, sweeping neurotransmitter back into the nerve cell after the message has jumped the gap, so it will be ready for the next signal.

When the transporter is blocked, neurotransmitter builds up in the synapse. This can be a good thing, if you’re trying to treat depression. By blocking the serotonin transporter, drugs like Prozac increase the supply of serotonin at the synapse, and help elevate mood.

"We're dealing with a syndrome with many, many complexities and variable presentations.  We need to be able to categorize subjects better.  And one way to do that would be if we could link their genetics with the risk for this disorder, and link more than their genetics, link specific biochemical pathways."
Randy Blakely, Ph.D., director of the Center for Molecular Neuroscience and Allan D. Bass Professor of Pharmacology at Vanderbilt.
Photo by Dean Dixon
Psychostimulants like cocaine, amphetamines and methylphenidate (Ritalin, etc.) are thought to act primarily on the dopamine transporter to increase the supply of dopamine in the synapse. In the average person, however, the results are less desirable: hyperactivity, impaired cognitive function and, potentially, addiction.

Children with ADHD have a paradoxical response to methylphenidate – they become less hyperactive, not more. They are better able to pay attention and are less impulsive, and they don’t become addicted to the drug. This suggests that there’s something different about their dopamine transporter, or about the complex interplay of molecules that carry dopamine messages through their brains.

And this is where the new science comes in.

ADHD appears to be highly heritable – meaning that it tends to run in families, especially when the disorder persists into adolescence and adulthood. Scientists believe that genetic mutations or variations may be involved, at least in some “subtypes” of ADHD.

The search for ADHD genes began with the observation that the drugs used to the treat the disorder act primarily on the dopamine system. To date, the strongest candidates are the genes for the D4 dopamine receptor and the dopamine transporter, for which variations, also called polymorphisms, have been found in studies of children with ADHD and their families.

Paying attention
To test the reaction time of a genetically engineered mouse that displays ADHD-like behaviors, Michael McDonald, Ph.D. and his colleagues at Vanderbilt University Medical Center shine brief flashes of light through one of three holes in the mouse's cage. 
By sticking his nose into the lighted hole, the mouse breaks an invisible infrared beam, triggering the release of a food pellet into the tray behind him.
Because the genetically engineered mice have difficulty paying attention compared to normal control mice, they have slower reaction times, fewer correct responses and, as a result, they are rewarded less often.
Illustrations by Dominic Doyle

The role of these genes in ADHD also is supported by studies of “knockout” mice, in which the genes have been altered so the proteins they encode do not function properly. Pioneering studies by Marc Caron, Ph.D., and his colleagues at Duke University, for example, have shown that disruption of the gene for the dopamine transporter in mice results in hyperactivity when they’re put in a novel environment.

The mice also “have a lot of problems in learning and memory tests,” says Caron, James B. Duke Professor of Cell Biology. When put in an eight-arm radial maze with a sweet breakfast cereal at the end of some of the arms, the knockout mice have a harder time finding the treat, compared to normal mice. “They keep going back to the same arm they’ve just been in,” he said. “They don’t learn.”

What was most surprising, however, was that when the knockout mice were given methylphenidate, they became less hyperactive and their cognitive skills improved. This finding challenged the conventional wisdom that the drug acts through the dopamine transporter to increase the brain’s supply of dopamine. Knockout mice didn’t have a functional transporter, and methylphenidate didn’t boost their dopamine levels. Yet the drug still calmed them.

The Prozac clue

Caron believes serotonin may be involved. In a 1999 study, he and his colleagues reported that the antidepressant Prozac, which blocks the serotonin transporter, reduced hyperactivity in mice with the “knocked out” dopamine transporter. So did L-tryptophan, the amino acid from which serotonin is synthesized. Both agents boost serotonin levels.

Mice are not humans, Caron cautions. In human studies, for example, Prozac has not been found to be effective in relieving symptoms of ADHD. But the mouse model suggests that ADHD is more than a dysfunction of the dopamine system. “My guess is that it’s probably 20, 30 or 50 genes that are involved in modulating pathways in the brain that could give you symptoms of ADHD,” he says. “It’s probably an imbalance between neurotransmitter systems.”

Randy Blakely, Ph.D., director of the Center for Molecular Neuroscience and Allan D. Bass Professor of Pharmacology at Vanderbilt, agrees that a lack of dopamine by itself cannot explain ADHD. There is evidence that norepinephrine is involved, he says.

For one thing, a new ADHD drug, Strattera, blocks the norepinephrine transporter, and seems to be particularly good at improving attention. Another clue, discovered recently at Vanderbilt, is the link between a mutation in the norepinephrine transporter and attentional problems in children and adults.

In the early 1990s, Blakely and his colleagues at Yale and Emory were the first to clone the genes that encode the norepinephrine and serotonin transporters. The identification of these genetic sequences, coupled with automated, high throughput screening techniques for evaluating them, has speeded the search for new drugs that may affect the function of the transporter proteins. These methods also are aiding the search for mutations in transporter genes, or variations in those genes that might be associated with a greater risk for disease.

Soon after coming to Vanderbilt in 1995, Blakely began collaborating with Dr. David Robertson, professor of Medicine, Pharmacology and Neurology, and an internationally known expert on heart rate and blood pressure regulation. They suspected that a mutation in the norepinephrine transporter might be responsible for orthostatic intolerance experienced by one of Robertson’s patients and her identical twin sister. The syndrome is characterized by a racing heart, nausea and dizziness when a person stands up.

Upon testing the women and their family, the researchers found a genetic mutation that effectively disabled the transporter in five family members, including the twins and their mother. All five had high blood levels of norepinephrine, and their heart rates jumped when they stood up, although only the twins had the full-blown syndrome.

The finding, reported three years ago in The New England Journal of Medicine, does not explain all cases of orthostatic intolerance, but this was the first neurotransmitter transporter mutation associated with specific symptoms of a disease, Blakely says.

The norepinephrine transporter in the heart comes from the same gene that makes the norepinephrine transporter in the brain. Since the mutation also would be expected to affect brain norepinephrine, the researchers recently evaluated members of the same family for attentional problems.

“The folks we were able to interview who have this particular (genetic) alteration had a consistent complaint that they had a hard time maintaining focused attention and concentration,” says Shelton, who has not yet published his findings in a scientific journal. “That certainly sounds very much like attention deficit disorder, and in fact if you go down through the symptoms, what they had was an alteration in attention without apparent hyperactivity.”

More than genetics

In another study, Blakely and Dr. Steve Couch, assistant professor of Pediatrics, are looking for genetic mutations that may affect the function of dopamine and norepinephrine transporters in children with ADHD and their family members.

“We’re dealing with a syndrome with many, many complexities and variable presentations,” Blakely explains. “We need to be able to categorize subjects better. And one way to do that would be if we could link their genetics with the risk for this disorder, and link more than their genetics, link specific biochemical pathways.”

Just as dopamine alone cannot explain ADHD, neither can genetics. Environment must play a role. Exposure to nicotine, cocaine and environmental pollutants in the womb has been implicated in the later development of ADHD, as have thyroid problems. Stress has been linked to various behavioral and attentional problems, and chronic sleep deprivation paradoxically produces hyperactivity in children.

In the late 1990s, Michael McDonald, Ph.D., and his colleagues at the National Institutes of Health became interested in a rare genetic condition called resistance to thyroid hormone (RTH) syndrome, which can cause mental retardation, short stature, deafness – and ADHD.

Most children with ADHD have normal thyroid function. But when the mutated version of the human gene that causes RTH is inserted into mice, the resulting “transgenic” animals exhibit the hallmark characteristics of ADHD – hyperactivity, impulsivity and difficulty paying attention.

“The hyperactivity dissipates when they get into adulthood, but the attentional deficits and impulsive behavior persist,” says McDonald, who has continued to study these “transgenic” mice since moving his lab to Vanderbilt in 1999. Males are more likely than females to exhibit these symptoms. In addition, methylphenidate dampens their hyperactivity, whereas the drug spurs more activity in normal control mice.

This mouse model, which displays many characteristics of the human condition, may be useful in testing new drugs to treat the disorder. It also may help explain how environmental factors – including exposure to hormones -- can contribute to the development of ADHD, says McDonald, who is assistant professor of Pharmacology and director of the Murine Neurobehavioral Laboratory.

As pups, the transgenic mice have a mild "thyroid resistance phenotype," characterized by high levels of thyroid stimulating hormone and high thyroid hormones, which also are seen in the human condition (RTH). This lasts for only three or four weeks, however. By the time the mice exhibit ADHD-like behaviors, their hormone levels are completely normal. "We think it's the elevated thyroid hormones (during development) that are causing the long-term brain and behavioral abnormalities," he says.

The tender brain

“The thyroid hormone is critically important for brain development, and regulates hundreds of genes,” McDonald continues. “What these mice show us is that it’s possible to have a transient thyroid abnormality during development, and later on to have many of the symptoms associated with ADHD.”

In McDonald’s studies, normal pups born to transgenic mothers have transient hyperactivity, suggesting that exposure to excess maternal thyroid hormones in the womb also can contribute to ADHD. “My suspicion is that transient thyroid abnormalities during development contribute to a lot more cases of ADHD than we’re currently aware of,” he says.

McDonald and his colleagues are using gene microarrays, plates containing thousands of different pieces of genetic sequences, to search for the expression of genes during different periods of development in the mouse that may be associated with the RTH mutation. Not long ago, it might have taken years to determine the impact of a single gene. Today, the Vanderbilt researchers can screen 23,000 genetic sequences simultaneously.

The thyroid connection to ADHD also raises questions about the role of pollutants. In particular, exposure to PCBs through breast milk or in the womb has been linked to problems with learning, memory and attention.

“A lot of these environmental chemicals like dioxins and PCBs impinge on the thyroid system,” McDonald explains. “These are ubiquitous toxins found in many of our foods. Children are very sensitive to that, much more than adults.”

Understanding ADHD will require “converging evidence” from a wide range of disciplines, including molecular genetics, behavioral neuroscience and clinical research, McDonald says.

What’s needed, adds Shelton, is a “molecular dissection” of ADHD – a way of matching an essential characteristic, such as hyperactivity, with a specific pathway, in this case, the dopamine system. This approach aims to rewrite the current classification system for ADHD, spur discovery of more specific and effective treatments, and resolve the debate over the over-diagnosis or under-diagnosis of the condition, he says.

J.T. King’s parents hope the answers come soon.

“I could pull my hair out sometimes with my son,’’ says J.T.’s mother, Jere King. “Then you have to stop and think, ‘OK. He didn’t mean it. It’s not intentional. Get a grip.’ ”

Constant reinforcement is essential. “You just have to always raise them up on the areas that they’re strong, praise them a lot to get their self confidence up, and in the areas that they’re not, you just have to be supportive and tell them they can do it,” she says.

Like most parents of children with a challenging condition, King often has wondered: “Why did this happen?” That question may not be answerable, although perhaps some day she’ll know how it happened. In the meantime, she’s determined to prevent ADHD from becoming for her son a disability – or an excuse.

“That’s not a crutch you can take through life with you,” she tells J.T. “That's something you have to recognize, accept and surmount.”

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