May 18, 2009

Imaging Addiction — PET and fMRI Are Tools for Better Understanding Drugs’ Effect on the Brain
By Dan Harvey
Radiology Today
Vol. 10 No. 10 P. 16

PET and functional MRI (fMRI) are helping researchers better understand drug addiction and may lead to new treatment strategies.

The National Institute on Drug Abuse (NIDA), which supports global research on drug abuse and addiction, has been at the vanguard of such research. The organization’s director, Nora D. Volkow, MD, helped pioneer use of brain imaging—PET in particular—to understand the toxic effects of drugs and their addictive properties.

“PET is a remarkable tool for investigating the effects of drugs, and its application sounded an alarm about the physiological dangers of drug usage, particularly cocaine,” says Volkow, whose imaging research revealed changes in the dopamine system that impact actions of the frontal brain regions involved with motivation, drive, and pleasure.

From a physiological perspective, PET provides a highly sensitive marker for brain function and, in turn, brain pathology, Volkow says. Those attributes translate into the following specific advantages:

• PET provides a powerful and sensitive tool for detecting drug toxicity.

• PET helps scientists understand exactly what happens in addicts’ brains.

• PET offers insight about the pharmacological properties that make certain drugs addictive.

“Essentially, PET shows what drugs do in the human brain that produces compulsive use and loss of control,” Volkow says.

Volkow first deployed PET for neuroimaging purposes in 1984 when she was an assistant professor at the University of Texas in Houston. She worked on the studies that showed, for the first time, that cocaine was not a safe drug and that its use could result in cerebrovascular accidents. “Initially, I wanted to detect general toxic effects in the brain and, in particular, cerebral blood flow in cocaine abusers,” she says, pointing out that PET enables imaging of the brain’s blood flow and glucose metabolism. Specifically, PET revealed disruption in brain perfusion, something not even suspected at the time. Later studies confirmed the observation.

In 1987, Volkow took a position with Brookhaven National Laboratory in Upton, N.Y., and ventured into more complex pharmacological issues, such as drug properties that lead to addiction and the loss of behavioral control. Based on her subsequent work, she suggested that cocaine’s effect resulted in part from the rapid rate in which it affects and then leaves the brain. The fast intake rate, she found, accounted for cocaine’s problematic reinforcing properties, while the fast departure encouraged the frequent compulsive use that is evident in habitual users.

Volkow also found that frequent usage activated brain circuitry related to behaviors that involve repetition, such as eating. Normally, these circuits become deactivated once the intended goal is accomplished; the human body’s homeostatic mechanisms provide the necessary feedback. However, as Volkow’s research demonstrated, chronic cocaine usage keeps the circuits activated, which fosters compulsive use. In the context of a repetitive behavior such as eating, without the proper functioning circuitry, you’d keep eating well beyond the level of satiety.

But certain questions remained, related to both drug usage and eating: Why can some people restrict their cocaine usage to the recreational level, and why doesn’t everyone overeat? The answer may lie in a pattern uncovered by Volkow’s research.

Volkow and colleagues perceived a consistently discernible pattern evident in the chronic use of drugs—not just cocaine, but heroin, alcohol, amphetamines, and others—that involved the diminished availability of dopamine D2 receptors. The reduction is associated with decreased activity in the prefrontal brain areas. The lower the D2 receptors in the striatum, the lower the activity in the orbitofrontal cortex (the brain region involved in the attribution of motivational value to a reinforcer) and in the cingulate gyrus (the brain region involved with inhibitory control and decision making). “These areas are critical in how we make decisions and motivate our behaviors,” Volkow explains.

Essentially, when the prefrontal cortex doesn’t function properly, the affected individual can’t control their desires or the resulting habits that these desires encourage. “We’ve observed this across a variety of addictions,” says Volkow. “Interestingly, we are also observing this in cases of pathological obesity.”

Labeling Drugs
Another advantage of PET is that researchers can label the drug of study—cocaine or methamphetamine—to directly investigate the impact on the human brain, especially related to dopamine, the internal bodily substance that functions as a “reward mechanism” and may be dysregulated in individuals susceptible to dependence.
Another area where PET shows promise is helping evaluate the extent to which new medications developed for positive purposes may present risk for abuse and subsequent addiction for susceptible individuals.

In a study in the March 18 issue of The Journal of the American Medical Association, Volkow and colleagues applied PET technology to a new medication with an abuse potential largely disregarded by most physicians. Modafinil, marketed under the trade name PROVIGIL, is an FDA-approved medication deemed nonaddictive that promotes wakefulness in people suffering from narcolepsy, sleep apnea, other sleep disorders, and fatigue. However, some view the drug as a booster for alertness and creativity, which makes it attractive beyond its approved use.

Led by Volkow and colleague Joanna Fowler, PhD, researchers explored the ramifications of usage, and their research suggests that modafinil could be addictive. Their pilot study involved 10 healthy men who either ingested modafinil in 200- or 400-mg dosages or a placebo. Subjects then submitted to two sets of PET brain scans. This imaging revealed that modafinil blocks dopamine receptors. “We observed that PROVIGIL, by blocking the receptors, increases dopamine in the brain, similar to what happens with stimulant drugs such as methylphenidate,” says Volkow.

In essence, the research suggests that modafinil may have detrimental effects for people who are vulnerable to addiction. “Drugs have different effects on different people, and clinicians need to be aware of that,” says Volkow.

Lingering Reservations
Some people in the field remain unconvinced that such neuroimaging provides any value, sometimes suggesting that it’s expensive “pseudoscience.”
“The expense of imaging technology and studies is an ever-present criticism,” says James Eliassen, PhD, a research assistant professor at the University of Cincinnati who has used MRI technology in neuroimaging research related to drug usage. “But ‘pseudoscience’ is a denigrating label that has afflicted neuroimaging for years.”

Some still think of this field as nothing more than a high-tech version of phrenology. “As researchers move forward, we need to be careful not to perpetuate that perception,” he adds.

Others, such as Stanton Peele, PhD, a social/clinical psychologist and a former advisor for the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, fourth edition section on substance abuse, believe that neuroimaging represents a reductive—and thus, “wrong-headed”—approach. “We think that these powerful imaging techniques will solve the problem of addiction, but the technology doesn’t reveal anything substantial because it can’t differentiate between habitual use and addictive use,” he says.

Peele believes it would be more effective to focus closely on the users, the consequences of their usage, and its impact on their lives. “The attempt to measure addiction by objective means is part of a moralistic approach, and the NIDA is really a moralistic agency—even though it pretends to be a scientific organization—and its job is not to differentiate addictive drug use from nonaddictive drug use,” he says.

Volkow and others disagree with Peele’s characterization. She says that in the NIDA’s perspective, drug use isn’t a fully conscious act for which users should be punished for their transgressions. Instead, usage stems from a neurological pathology and involves biochemical and physiological abnormalities, in which users are punished by their transgressions—an important distinction.

“NIDA has moved beyond the concept of addiction as criminal activity. Research has moved drug addiction into the realm of medical disorder,” says Volkow. “This approach, we hope, will bring about quicker and more long-lasting recovery.”

That shift represents a significant transition in medicine. “What medical imaging has helped foster in this area has been transformative and positive,” Volkow says.

Ongoing Research
While specific treatments have yet to be developed, other research provides additional information. Scientists at the Ludwig Maximilians University of Munich in Germany recently reported in The Journal of Nuclear Medicine a direct link between hereditary personality traits involving reward dependency and the human brain’s endorphin system. In the paper, “Opioid Receptor PET Reveals the Psychobiologic Correlates of Reward Processing,” the researchers presented evidence that lends credence to the idea that brain chemistry mainlines into individual traits.

In the study, the researchers sought to identify biochemical correlates of personality traits in healthy humans. They focused on the role of the brain’s opioidergic (endorphine) system, which provides a connection between someone’s level of reward expectancy and the brain’s ability to transmit naturally occurring opiates.

Researcher Mathias Schreckenberger, MD, a professor of nuclear medicine at Germany’s Johannes Gutenberg University of Mainz, explains that some people’s personality dimensions remain stable throughout their lives; however, others are at high risk for addiction. As such, Schreckenberger and colleagues sought the correlative between personality traits and addictive behavior, with the hope of finding a biological basis for personality traits.

The study included 23 men with no history of substance abuse. They were given fluoroethyl-diprenorphine, a radiolabeled chemical that binds readily to the brain’s natural opioidergic receptors, says Schreckenberger.

Following administration, the subjects underwent PET scans, which were compared with the subjects’ Cloninger’s questionnaire answers. This questionnaire evaluates personality based on four categories: novelty seeking, harm avoidance, reward dependence, and persistence. The comparison showed that binding to opiate receptors in the ventral striatum—a so-called reward system region of the brain—correlates closely to an individual’s degree of reward dependence.

Subjects tending toward a higher approval need also showed the highest opiate uptake. “Going in, we didn’t know what personality dimensions would correlate to which parts of the brain and which opioidergic system,” says Schreckenberger. “So the findings were very exciting. Essentially, reward dependence positively correlated to core structures of the reward system.”

The correlation was confined to the ventral striatum, a key reward system area, as well as a strong factor in addictive-behavior development. Simply stated, people with a high reward dependence exhibit a high concentration of available opiate receptors in that brain region, while people with lower dependence have less receptors.

In terms of genetics, the reward system is ancient, Schreckenberger says, and it generates a positive response to human behavior that requires reward for survival activities, such as eating and sex. “We think we found the biological basis of addiction by determining the regulation of the reward system,” says Schreckenberger.

Understanding Substance Abuse
He says the findings provide a greater understanding of the functional relationship among personality, neurobiology, and addictive behavior. The bottom line is that, like Volkow’s research, the study may lead to a better understanding of substance abuse and its treatment. As a result of their work, the German researchers believe that PET will become the preferred imaging technique for therapy related to addictive behavior. It’s the only method, they point out, that reveals specific local changes in neurotransmitter systems involved with addiction, such as opiate, dopamine, and serotonin receptors. They also believe that PET could help predict positive responses to treatment, specifically involving medications that block substances such as morphine, heroin, or alcohol from binding to opiate receptors.

But PET isn’t the only imaging modality that is advancing the understanding of drug usage, addiction, and the implications. At the University of Cincinnati, Eliassen has developed a research program that applies MRI technology to the neural origins of addiction. The program’s objectives include the following:

• using fMRI to identify brain regions that participate in reinforcement learning and then to understand how these regions are affected by addiction; and

• developing MRI biomarkers of structural, functional, and biochemical changes in the brain during addiction and to use these markers to assess treatment success.

Concerning the first objective, Eliassen points out that drugs of abuse directly and forcefully activate the midbrain dopaminergic system, which typically participates in reinforcement learning regarding ordinary rewards such as food.

“As drug addiction has been characterized as a learning disorder, addicted individuals learn to engage in compulsive, drug-seeking behaviors because these behaviors predict the reward of intoxication,” Eliassen says.

Brain Differences
The difference between typical and addicted reward behavior, he adds, is represented by the example of a hungry animal that will eat until it is sated. From there, it moves on to satisfy other needs. Conversely, an addict’s desire for intoxication supplants the needs and desires related to a healthy and productive lifestyle. Eliassen explains that negative consequences of addiction, such as a deteriorating lifestyle, should overwhelm the desire for intoxication. But that’s not the case with addicts, and it relates to how their brains perceive rewards and punishment and how reinforcement comes into play.

Using fMRI, Eliassen and colleagues are investigating a revised associative learning model of addiction. This model suggests that separate brain areas represent reward and punishment. Eliassen speculates that associative learning models could be successfully revised to account for addiction by the unequal action of drugs of abuse on the brain’s reward and punishment systems. “We like fMRI because it allows you to look at blood flow changes in the brain that can be related to particular behavorial or cognitive events,” he says.

As for the program’s second objective, Eliassen and colleagues are identifying brain biomarkers through structural, spectroscopic, and functional MRI. Identification of biomarkers, he says, could provide researchers tools to assess the severity of substance dependence or measure treatment success. Eliassen is specifically looking at methylenedioxy-methamphetamine (MDMA), better known as Ecstasy.

He and his team are trying to determine whether MDMA changes the structure, function, and biochemistry of the human brain. “I received an NIH [National Institute of Health] Career Development Award, and I am using the funding to look at the effects of MDMA, which is perceived by users as a relatively benign, recreational drug,” he says. “However, researchers have indicated that it has toxic effects on the nerve cells that supply seratonin to the brain. Studies with animal models indicate that it damages those cells. Further, the damage is perhaps permanent.”

But Eliassen notes that evidence in human studies is less convincing. “Thus, we’re using fMRI in a study where we are recruiting MDMA users to examine the effects on their brain functions. So far, we’ve gathered some evidence that appears to show increases in frontal lobe activities that suggest users need to put more effort in cognitive tasks we’re asking them to perform. But, right now, everything we’re doing is unpublished,” he says.

Volkow says that along with PET, MRI in its various forms will provide powerful tools to develop new algorithms. “Functional MRI, especially, will be useful for investigating drug use,” she says. “It can be used to perform biofeedback, with the fMRI signals serving as biomarkers. With fMRI available in the clinical setting, one day we may be able to use it to develop biomarkers that can help tailor treatments and help predict treatment outcomes in addicted patients.”

— Dan Harvey is a freelance writer based in Wilmington, Del., and a frequent contributor to Radiology Today.