A Truer Measure of Addiction
By Jeannette Sabatini
Radiology Today
Vol. 20 No. 5 P. 18

Radiologists are making valuable contributions toward understanding this disease.

An individual can’t walk into a radiology center and get an image revealing whether they’ll develop an addiction, but radiologists are certainly making an impact in studies that are leading in that direction.

PET and MRI are proving especially beneficial, helping researchers to do the following:

• study the development and maintenance of addiction;
• understand the neurobiological, genetic, and behavioral mechanisms behind this epidemic;
• measure receptors and neurotransmitters in the brain that play a role;
• highlight molecular and cellular changes in specific brain regions thought to play a role in the transition to uncontrolled drug use;
• isolate areas of the brain relevant to substance use, craving, and risky decision making; and
• establish the influence of alcohol cues.

Findings from those studies will further the development of pharmacotherapies to address addiction mechanisms and determine who would benefit most from them.

A Game of Catch
Diana Martinez, MD, a professor of psychiatry at Columbia University Irving Medical Center in New York, has used PET to study addiction in all its forms. “When people ask me what kind of addiction I study, I answer that I really study all of them because, from my perspective, they all look the same, whether it is heroin, methamphetamine, tobacco, etc,” Martinez says.

Using PET, Martinez has been able to show the connection between malfunctioning neurotransmitters in the brain and the development of addiction. When describing how neurotransmitters work, she likens the process to a game of catch. “When nerves speak to each other, it’s like one neuron throwing a baseball, and the second neuron catching it. The second neuron recognizes it as a signal to do something,” Martinez says. “We can image both the baseball and the baseball mitt with PET.”

In her studies, the neurotransmitter dopamine served as the baseball being thrown into a neuron mitt. For some people, this game of catch between that baseball and the mitt is slower than usual, so those people have a lower level of dopamine. Since one of the signals dopamine modulates is the connection between a specific reward and behavior, that process is affected in people with low dopamine levels, she says. When something is rewarding, dopamine will signal to keep doing it; when the initial reward is no longer stimulating, dopamine will signal to switch to another approach.

“We think that with addiction, dopamine isn’t doing that,” Martinez says. “It is not telling the brain to switch between two competing rewards. The brain just keeps doing the same thing, even though it is no longer rewarding.”

Addictive substances, such as cocaine, alcohol, and methamphetamines, can temporarily boost that game to a normal level because they cause dopamine baseballs to be thrown. If a person has a low level of dopamine, he or she may not be able to stop and can eventually become addicted, Martinez explains.

To test this theory, Martinez used PET to determine the dopamine levels in the brains of a group of cocaine users who were offered a choice between two competing rewards: $5 and 6 mg of cocaine. According to Martinez, $5 would buy more than 6 mg of cocaine on the street. “Our goal was to see who was going to choose a larger but delayed reward over an immediate but lousy reward,” she says. “When we looked at the scans, the people with the lowest levels of dopamine were the ones who chose the cocaine, even though it was a terrible dose and even when we were giving out money. And the dopamine levels predicted that.

“People who, for some unknown reason, have a low or blunted level of dopamine may be more prone to become addicted to substances that bring that person’s level of dopamine up to a normal level, satisfying that person’s reward/response mechanism,” Martinez continues. “The trouble is, that satisfaction is temporary and, in the long run, unsatisfying.”

In further studies, Martinez added treatment to a similar scenario and gave cash to the cocaine users who participated in the study each time they were clean on routine check-ins. “We did the dopamine scans to see if they would predict who responded to the treatment and who didn’t, and the data showed that the people with the lowest levels of dopamine again didn’t respond to the treatment,” she says. “They came into the clinic two times maybe, and then they were gone.” Neither the cash nor the treatment could get them to switch from using cocaine.

“The PET images showed that addiction is associated with low levels of dopamine type 2 receptors and blunted dopamine release from neurons. These two biomarkers of addiction are also associated with a poor response to treatment,” Martinez explains.

Martinez wanted to continue her work to see whether people with low dopamine levels would switch their reward choices if they took medication that would raise their dopamine level. Unfortunately, she had to put off those studies when she started facing roadblocks to getting medicine that might work for such studies.

The biggest challenge to using PET for these studies related to the radiotracers involved, she says. “They have to be synthesized for each individual scan, and that requires a lot of infrastructure: a cyclotron and radioligand lab, personnel, a radiochemist, and assurances—radiotracers have to meet standards for human use. That also makes it expensive,” she notes.

“PET can be used to look at a lot of neurotransmitter systems, including dopamine, serotonin, norepinephrine, GABA [gamma-aminobutyric acid], and glutamate,” Martinez adds.

Turning Down the Intensity
At the Mayo Clinic in Rochester, Minnesota, John D. Port, MD, PhD, a professor of radiology and associate professor of psychiatry, is using MR spectroscopy (MRS) to measure levels of glutamate, which, like dopamine, plays a significant role in all aspects of thought and behavior, including those expressed by addiction. “Glutamate is used for a number of different functions in the brain, including building brain proteins, brain energy production, and what we’re most interested in—neurotransmission,” Port explains. ”It’s the most abundant excitatory neurotransmitter in the brain.”

With MRS, Port and his research team proved the link between glutamate levels in the brain and addiction as well as the impact of acamprosate treatment on suppressing glutamate in patients with alcohol dependence.

His study, “Elevated Glutamate Levels in the Left Dorsolateral Prefrontal Cortex Are Associated With Higher Cravings for Alcohol,” was published in 2016 in Alcoholism: Clinical and Experimental Research. For those studies, participants underwent proton MRS of the left dorsolateral prefrontal cortex (DLPFC) with 2D J-resolved averaged point resolved spectroscopy sequence. MRS data were processed with LCModel—a software tool for analysis and quantification of in vivo MR spectra—and cerebrospinal fluid (CSF)-corrected to generate metabolite concentrations.

Craving for alcohol and drinking patterns were quantified using the Penn Alcohol Craving Scale, a self-administered instrument for assessing craving that focuses on five factors: frequency of drinking, intensity of drinking, duration of thoughts about drinking, the ability to resist drinking, and the responder’s average rating of his or her craving over the course of a week. The study also utilized Time Line Follow-Back, a clinically proven drinking assessment method that requires those being assessed to estimate daily drinking over a specified time period, in this case 30 days.

Those studies, according to Port, proved a statistically significant positive correlation between glutamate levels and Penn Alcohol Craving Scale scores. That’s important because quantifying craving is essential for optimal management of alcohol use disorder, he explains.

Port went on to use MRS to evaluate the effect of acamprosate in treating alcohol-dependent individuals who had significantly elevated CSF-corrected glutamate in the midline anterior cingulate cortex (MACC) compared with controls. Acamprosate has an antidipsotropic effect that is mediated, in part, through glutamatergic neurotransmission, Port says. For patients who have significantly elevated CSF-corrected MACC glutamate levels, it normalized the hyperglutamatergic state; it also helped reduce craving intensity in early abstinence.

For the study, MRS was used to determine the glutamate levels in the MACC and to assess the effect of acamprosate treatment in a cohort of 13 subjects with alcohol dependence. The Penn Alcohol Craving Scale was used to assess craving intensity. After four weeks, those who underwent treatment showed a reduction in glutamate levels. Port and colleagues published those findings in the Journal of Clinical Psychopharmacology, also in 2016.

“MRS is beneficial because it allows us to measure neurotransmitter levels noninvasively,” Port says. “Yet, MRS requires that patients hold very still for the scans, and this can be difficult, especially if the patient has claustrophobia,” he adds. He says further research is needed to evaluate the use of these findings for clinical practice, including monitoring of craving intensity and individualized selection of treatment with antidipsotropic medications in subjects with alcohol dependence.

Understanding Craving
At the University of Colorado Anschutz Medical Center, Jody Tanabe, MD, a professor of radiology and psychiatry, is using functional MRI (fMRI) to study craving. “Our research involving neuromodulation of drug craving circuits is yielding interesting results,” Tanabe says.

Using fMRI, her team is investigating brain circuits thought to be involved in cigarette craving in smokers. They use transcranial magnetic stimulation to inhibit those regions. Their work will determine the influence of smoking cues on those structures to elucidate biological mechanisms that may contribute to smoking and cigarette craving.

fMRI has also helped Tanabe asses brain activity associated with behavioral characteristics that are relevant to substance use and may play a role in risky decision making. That research examined behavioral inhibition/behavioral approach association with orbitofrontal cortex and DLPFC activity during decision-making activities performed during fMRI. Behavioral approach scores were found to be higher in substance-dependent individuals than controls, and left orbitofrontal cortex activity during decision making was greater in substance-dependent individuals than controls, suggesting that the relationship between approach personality traits and risky behavior may involve the prefrontal cortex.

Tanabe’s studies also found sex differences in the brain structure of severe substance users. Sex-based gray matter changes in patients with stimulant dependence correlated with sex-based behavioral differences in behavioral approach and impulsivity, she says. Different psychological profiles in men and women with substance dependence were associated with specific neuroanatomic loci.

“Men and women differ in their patterns and trajectories of drug and alcohol addiction,” Tanabe explains. “We showed that differences in brain structure between healthy controls and drug users was modulated by sex: Differences in female users were much more substantial than differences in male users compared to their same-sex control counterpart.”

According to Tanabe, understanding sex differences in both the neuroimaging and clinical course of substance dependence could lead to improved sex-specific or individualized medical treatment and recovery plans.

“One of the most significant ways that radiology/brain imaging has proven useful is in understanding that there is a biological basis for addictions—that is, the uncontrolled compulsion to take and seek drugs despite known negative consequences,” Tanabe says. She moderated a session on addiction and imaging at RSNA 2018.

“Guided by animal models, brain imaging studies in humans have corroborated some findings of research. Animal work has shown that drugs lead to molecular and cellular changes that can have long-lasting effects and perpetuate drug-related behavior,” Tanabe says. “Bottom line: Addiction is a chronic, relapsing disease of the brain, and imaging supports this model.”

Despite some challenges, radiology is playing a large part in furthering studies on addiction. As far as radiologists are concerned, they will most likely gain a larger role in treating addiction when more studies are complete. Tanabe has a prediction of her own. She says, “If neuromodulation proves to be useful as an adjunctive treatment in substance use, then image-guided neuromodulation will lead to an expanded role for radiology and radiologists.”

— Jeannette Sabatini is a freelance writer based in Malvern, Pennsylvania.