We’re used to media splashes about so-called “holes” in the brain. But what neuroimaging really tells us about the effects of drug use is much subtler—and much more helpful.
We’ve come a long way since; the advent and exponential development of neuroimaging techniques allows us to visualize the mind’s hardware—and how it goes awry in addiction—in increasing detail and nuance. But the media bombardment of brightly-colored brain images can be overwhelming—and important points get lost. These slides are meant as a primer on some of the biggest stories to have emerged in addiction neuroimaging, and the insights they give. Of course, these examples are only a thin sliver of the available science—and scientists are still grappling with addiction’s overwhelming complexity. Without dismissing other relevant brain systems or equally important socio-cultural and environmental influences, our focus here is the striatum: a set of structures heavily involved in reward, motivation, habit formation—and the brain’s dopamine system.
One of the earliest addiction imaging experiments was also one of the gutsiest: in 1989 researchers set out to find what cocaine actually did in the brain, where it went, and what that meant. They tagged cocaine with a radioactive element, injected it into healthy volunteers, and used PET (positron emission tomography) to measure the location and time-course of radioactivity emitted. The result? Coke went straight to the striatum: the home of reward signaling and the formation of consequent behaviors. Here we see a horizontal brain slice over time (in minutes). The “hotter” colors represent more cocaine (the striatum is the two sickle-shaped hot-spots near the middle). The study also investigated time-course (right), showing the rapid cocaine uptake needed for a high—this paralleled the subjective effects reported by the volunteers, suggesting the two are related. The work demonstrated in humans that cocaine’s direct effects on the striatum and time-course modulate its subjective effects. The study was later repeated using methamphetamine instead (bottom row): the binding again primarily involved the striatum, but also extended to many other areas. The time-course, again paralleling subjective experience, was much longer-lasting than cocaine—explaining differences between the two stimulants in duration, subjective experience and long-term effects.
Sometimes it’s less obvious why people enjoy a drug. This recent study investigated psilocybin (magic mushrooms), a compound that binds to serotonin receptors and doesn’t have obviously rewarding dopamine effects. MRI (magnetic resonance imaging) was used to measure the magnetic properties of blood flowing into the brain, with the idea that active regions need more blood. Researchers injected volunteers with the drug and placebo, and measured changes in blood flow and oxygenation. To everyone’s surprise, MRI measures decreased with psilocybin, mainly in regions other than the striatum (yellow circle), including areas involved in association, consciousness and “constraining the experience of the world.” The scatterplot shows that the amount of decrease in MRI signal predicted the intensity of subjective effects. The study also found reduced communication between brain regions, suggesting that “decreased activity and connectivity” permits “an unconstrained style of cognition.” So some drugs without a direct striatum/dopamine effect can be found enjoyable, perhaps due more to the reward of changing perceptions—a uniquely human feature that seems hard to model in animals. In a separate study, the group also found that MRI measures related to memory vividness and subjective well-being at follow-up, suggesting a biological basis to the proposed use of psilocybin in psychotherapy.
One of the most consistent “hallmarks” of addiction is that levels of the D2 subtype of dopamine receptors (mostly found in the striatum) are lower in addicted than in non-addicted individuals. These images come from a number of PET studies which assessed D2 receptor levels, by injecting subjects with a radioactive compound that specifically binds to dopamine receptors and comparing levels between groups. The “cooler” colours indicate lower D2 levels in the addicted groups. This represents the possible identification of an addiction “biomarker”—an objective biological measure that can be investigated, monitored and perhaps manipulated for prevention or treatment. The real-world relevance of this is shown in the pink inset: in two studies (cocaine and meth), addicted subjects had their D2 levels measured, went through treatment, and were then contacted again to assess treatment success. Successful responders to treatment were found to have higher D2 levels than those who had relapsed, suggesting that D2 levels have some predictive value for success. Much remains to be filled-in in the dopamine receptor/treatment response black box. But this knowledge can help in the allocation of clinical attention and resources, or the identification of patients who may benefit from one type of treatment—like meds to increase dopamine transmission—over another.
The D2 dopamine receptor has also been used to investigate signs of recovery after abstinence. In this PET image, the “cooler-coloured” striatum of a one-month-abstinent meth user shows lowered binding of the radioactive compound, suggesting fewer receptors. But the striatum grows “bright” again after 14 months’ abstinence, suggesting increase in D2 receptor availability, or recovery of the receptors. This implies that brain cells don’t necessarily disappear permanently, but may temporarily adapt (perhaps retracting receptors in response to the dopamine bombardment from drug use)—or else that the remaining brain cells can compensate. Unfortunately, behavioral tests in the same study didn’t improve as much as D2 measures, and the finding has been difficult to replicate, which limits the study’s implications—but it does show the importance of timing in studies, and suggests that neurochemical changes aren’t necessarily permanent. (By the way, the black spots in the 14-month image are not holes in the brain, but a result of assigning colors to values, and setting the threshold at a certain level).
One problem with neuroimaging is that the pictures often don’t reveal much about functional relevance. How, if at all, do receptor levels translate to differences in experience, behaviour, thinking or feeling? This PET study measured the relationship between dopamine receptors and personality traits. The striatum blobs shown here don’t display radioactivity indicating D2 receptor levels, but rather the strength of the correlation between receptor levels and trait impulsivity (“hotter” colors mean a tighter relationship). In both meth-dependent and healthy subjects, the measures correlated inversely: those with the lowest D2 receptor availability were the most impulsive. This shows that dopamine receptor availability in the striatum can contribute to personality traits for the entire population—and addicted individuals, who tend to be on the low end of the D2 spectrum, are more likely to act impulsively than non-addicted individuals. It’s still frustratingly hard to determine what came first: drug use could cause a decrease in D2, or alternatively, low D2/high impulsivity could make people likelier to use drugs. Still, the study gives the “low D2 addiction biomarker” some behavioral meaning. It also explains some aspects of initiating or continued drug use, and raises clinical implications—as personality traits can be easily assessed and maybe used to evaluate dopamine-related intervention strategies.
Genetic factors contribute significantly to addiction, and imaging techniques can pick up and visualize genotype effects that less sensitive behavioural or self-report measures may not. This study investigated how genetic variation in the dopamine system affects smoking. Dopamine release in a certain part of the striatum is often considered the brain’s reward signal, and can be assessed in humans using PET. This requires measurement of a dopamine receptor-binding radioactive compound at two time-points; the difference between the points shows how much dopamine was released over time, knocking the compound off the receptor. The lower the second PET signal, the more dopamine was released. Subjects were scanned before and after a smoke break, then divided by genotype for three components of the dopamine system—each of which varies in function depending on genotype. Each row on the slide is a component: top, the dopamine transporter; middle, the D4 dopamine receptor; bottom, an enzyme that removes dopamine after release. For all three components, individuals with one genotype (left two panels) released more dopamine during the smoke break than those with another genotype (right two panels). So some people, due to their genetic makeup, find smoking more rewarding than others—and are likelier to continue or escalate use. Tiny biological differences can influence addiction processes, and a better understanding of them can aid prevention and intervention.
Behavioral or process addictions, like compulsive gambling, eating, or sex, have been getting lots of neuroimaging attention, partly due to their surface similarities with drug addiction, but their neurobiology remains largely unexplored. These results from several PET studies measuring D2 dopamine receptors in the striatum show that obese individuals who may be prone to compulsive overeating have low D2 levels—paralleling findings in compulsive drug users. This suggests biological commonalities between behavioural and drug addictions; it’s an exciting area currently gaining research momentum. Interestingly, in compulsive gambling—the only behavioural compulsion currently proposed for re-classification to addiction—low D2 receptor levels haven’t been found, although several studies have searched. This may mean that low D2 levels are sufficient, but not necessary, to drive addiction, and that other factors play a more important role here—or that the low D2 levels seen in drug addicts relate to the effects of drugs themselves, rather than addiction per se. This is a unique chance for scientists to learn about addiction without the potentially interfering effects of drugs, but clinically there are potential problems: drug addiction treatment options may have different effects when aimed at behavioural addictions. Of course, other biological parallels with drug addiction have been identified, and neuroimaging has played an important role in teasing apart the results.
Neuroimaging has enabled many advances in addiction science; it’s also added to the debate on personal culpability in addiction, by highlighting neurobiological factors that aren’t necessarily under our control. But the emotive influence of these images can also be used to more sinister effect, manipulating audiences into knee-jerk reactions. Sometimes this is done for the sake of eyeballs and obviously overwrought (right panel)—but other uses are more serious, including court evidence to support drug-related penalties. Even if an image comes from reputable scientific sources, it’s still subject to interpretation and presentation, which can easily be shifted to fit different needs. So we’re well advised to approach these images with questions. What is actually being shown? What do colors (or their absence) mean? What’s the behavioural significance, if any? And who is being shown? Is this a group of individuals, or one exemplar—and if the latter, is he or she representative of the population, or does the image pit the best in one group against the worst in another? How many times did they use the drug, how heavily, and how long were they abstinent? Could factors other than drug use account for the image? The answers may not be easy to come by. But posing these questions can help overcome gut responses, fostering a fuller, fairer understanding.
In the previous photo, even though the news article claimed to have “conclusively demonstrated severe and multiple disruptions,” the “black holes” don’t indicate dropout of actual brain tissue. They’re a result of threshold-setting: assigning “black vs. colour” at a particular signal value, with the choice of value entirely subjective. This is just one of the many caveats of neuroimaging. In human neuroimaging, for example, actual photographs are rare; more often, images are proxy signals for some biological event that have been digitized and computerized, reconstructed and transformed, and subjected to statistical testing and interpretation. Signals are small, assumptions are many, and at every point, a person intervenes in producing what will ultimately be displayed. The result can sometimes be utter junk—as demonstrated in a study that flashed pictures of human social interactions, and “found” associated brain activation…in a dead fish. Neuroimaging techniques, no matter how brilliant, are removed biological events, so can’t always be assumed to accurately reflect them. Addiction neuroimaging is a tricky area: the field is fraught with political static and agenda. Combine this with the computational limitations of neuroimaging, and emotionally charged headlines can ensue. Ultimately, though, a tool that can visualize the hardware of the mind is extremely valuable in any mental health field. It’s a privilege and a thrill to think of the possibilities ahead.