On Dead Salmon, Drugs, and “Lighting Up” the Brain

Are fMRIs truly useful in addiction medicine?

What would it take to make neuroimaging a truly valuable tool for addiction medicine? Pictures of brain regions “lighting up” have always been exciting, as the early phase of neuroimaging predictably inspired rapture. Phase 2 arrived when a group of U.S. postdocs created the infamous dead salmon fMRI scan, showing that an exciting and colorful picture of false positives was entirely possible. As Neuroskeptic put it to the Globe and Mail, “Scientific journals prefer to publish results that are positive and ‘sexy,’ just like other media.”

That is nice to hear, since it takes the full blast of the heat lamp off journalists and directs it at those scientists with a habit of overamping MRI studies, even when the sample in the studies is exceedingly small. Plenty of blame to go around. Moreover, both scientists and journalists must contend with the fact that the bulk of the scientific world’s research resides behind steep pay walls—steep enough that even prestigious universities have been wailing lately about the cost of just getting one’s hands on the research reports, let along doing the research. “Media literacy in science journalism is really stunted by the fact that we don’t have access to primary sources,” said a spokesperson for the Electronic Frontier Foundation.

So much blame going around, in fact, that enthusiasm for President Obama’s recently announced brain initiative seems particularly muted among one group universally expected to rally around the project—neuroscientists themselves. Having helped to create the hype, some brain scientists are now suggesting that the only appropriate attitude is healthy skepticism about where the money will be used, and whose pockets will be picked to come up with the $100 million in kickoff funds.  Rather than jumping in unison when Obama said the program would allow us to “better understand how we think and how we learn and how we remember,” skeptical neuroscientists note that “Manhattan Project”-style programs are out of fashioned in today’s distributed, system-wide landscape of experiment. “Without specific goals, hypotheses, or endpoints,” said an Emory University neuroscientist in the Globe and Mail article, “the research effort becomes a fishing expedition.”

Myself, I like to fish. But not if the pond’s too small. In a recent post at National Geographic’s blog, “Not Exactly Rocket Science,” Ed Yong quoted a neuroscientist at the University of Bristol: “If you have lots of people running studies that are too small to get a clear answer, that’s more wasteful in the long-term.”

Exactly so, and one might think that a large, coordinated, possibly international initiative at studying the architecture and function of the human brain might serve as a powerful antidote to a micro-universe of tiny studies and insignificant findings.

But forget the big and little pictures for a moment. Let’s focus on what’s in it for addiction studies. What would have to happen—how would fMRIs, PETs and EEGs have to be used in order to advance our understanding of drug and alcohol abuse?

In a recent editorial —“What neuroimaging has and has not yet added to our understanding of addiction”—Martina Reske of the Institute of Neuroscience and Medicine in Julich, Germany, argues that we must take “three critical steps to implement neuroimaging as a new basis for diagnostics and treatment of substance use disorders: first, we need to merge diverse imaging findings into one comprehensive brain imaging perspective of addiction. Next, we need to identify prediction algorithms for individual substance users.” And finally, Reske writes in Addiction, “The ultimate goal has to be the development of treatment regimens based on neuroimaging results.” The interested lay public may be forgiven for assuming that all three of these conditions were already being met.

Specifically, Reske argues for “multi-modal approaches to overcome technological shortcomings. Simultaneous EEG-fMRI, for instance, combines high temporal and spatial resolution of exactly the same mental process, and hybrid MR-PET imaging allows for functional/structural and molecular characterizations.” What might stand in the way of such solutions, you ask? Reske answers that it is likely to be “the existing researchers’ hesitation, unwillingness or inability to consolidate findings from different imaging modalities.” In this case, she suggests, it is the scientists themselves, perhaps overly protective of individual turfs and research fiefdoms, who are hemming and hawing about large-scale collaborative efforts.

To reach a level of clinical relevance for addiction, neuroimaging must be used to delineate and identify “occasional versus habitual versus compulsive use or intoxication versus abstinence versus relapse.” These are not things that existing neuroimagery can do for us, but Reske believes one promising avenue will be the identification of subjects with an abnormally high risk for relapse, something neither patients nor therapists are very good at predicting. (This immediately brings neuroimaging up against a ripe field of ethical questions having to do with the identification and disclosure of high-risk subjects.)

What other payoffs might there be? Reske can think of a few: “First, linkage of neuroimaging and pharmacological studies will prove useful for predicting response to medication. Secondly, knowledge of the biological differences between responders and non-responders to available treatments might facilitate identification of the best-suited therapy for that particular individual. Thirdly, understanding which brain regions show alterations in functioning should spur the development of specific medications, cognitive-behavioral or neuroimaging-based trainings that target optimal activation levels in these regions.”

Neuroimaging is not yet specific or sensitive enough, and its practitioners not yet practiced enough, to accomplish these tasks except in a tantalizingly patchwork fashion. Neuroimaging-based predictions of addiction liability and damage and relapse make up an infant science, ripe for both growth and abuse. Obviously, it will take the gold standard of longitudinal studies involving enormous samples of participants, who would ideally be followed and scanned for decades. But such studies are, as Reske reminds us, “methodologically challenging, expensive and not promising in terms of short-term publication of results.” It sounds like the kind of Big Project that might fit under the umbrella of, say, a major, well-funded, multi-year brain research initiative endorsed by the President of the United States….

Photo Credit: https://docs.uabgrid.uab.edu/

Brain Scans and Addiction Research: The Early Years

X-ray specs for drug effects.

The science of addiction and the technology of brain scans have both developed exponentially in the past two decades. The search for specific neurobiological markers for addiction was made possible by positron emission tomography, better known as the PET scan. Known more casually as the PET/CT scanner, the device was named the Invention of the Year in 2000 by Time Magazine. (The CT scan, for computerized tomography, uses an X-ray machine and a contrast die to measure absorption rates in different brain areas.)

The idea of a PET scan is simple: Doctors inject test subjects with radioactively tagged glucose, which passes the blood-brain barrier with ease. The more electrochemically active portions of the brain burn extra glucose for energy. So, by noting precisely where the tagged glucose has gone, and converting that information into a digital two-dimensional array, a PET scan serves as a neurobiological map of brain activity in response to specific stimuli. Functionally, PET scans are admittedly imperfect pictures of the brain, showing general areas that “light up” during the performance of a task, or in response to a drug. Technically, a PET scanner is detecting gamma rays given off when particles from the radioactive tracer collide with electrons in the brain. A variation on this approach is the SPECT scan (single photon emission tomography).

The neuroimaging techniques that followed, like nuclear magnetic resonance imaging, or MRI, provided an additional level of analysis. MRI machines look similar to PET scanners, but are essentially large magnetic field generators. They were originally known as NMRIs, for nuclear magnetic resonance imagers, but the “nuclear” part seems to have disappeared over the years. MRI scans don’t involve radioactive tracers—they track blood flow, often by means of a contrast agent. Hydrogen, a major component of water and blood, gives off identifiable energy signatures when surrounded by giant magnets. If an area of the brain is showing increased activity, it means that somewhere in that area, some brain cells are demanding more oxygen.  A rush of blood to that area supplies it, an MRI scan detects it, and a computer plots it.

 With PET and MRI scans, scientists could study the brain as a set of molecules in motion. They could create a three-dimensional picture of the brain, with the sagittal, transaxial and coronal planes all visible at once—almost a brain hologram. Addiction scientists could watch tiny areas of the brain light up with activity under the influence of specific mood-altering chemicals. Two areas of the brain were of particular interest. One was the nucleus accumbens, which was involved in the regulation of dopamine and serotonin synthesis. The other was the locus ceruleus—a tiny area of the brain saturated with cells involved in the production and release of the neurotransmitter norepinephrine.

Alcohol, cocaine, the opiates, and other drugs made the nucleus accumbens and associated regions bloom with activity on the MRI and PET scans. These early snapshots of your brain on drugs specifically showed that psychoactive drugs of abuse, the ones that altered mood and emotion, did so at the very sites in the brain known to be involved in regulating emotional states and primary drives. Without scans, scientists would not have been able to confirm the workings of the brain’s reward system in specific anatomical detail.

 As a rule, the same areas of the brain tended to light up no matter what addictive drug was under study. Whether it was a molecule of stimulation, or a molecule of sedation, sooner or later it went surging through the diffuse aggregation of mid-brain structures involved with emotion, memory, mood, sleep, and a host of specific behaviors ranging from appetite to risk-taking.

That the subjects also showed similar brain activity when they quit doing drugs was of equal interest in the beginning. Early work by Dr. Kenneth Blum at the University of Texas Health Science Center and others demonstrated that certain characteristic forms of brain activity took place in the locus ceruleus whenever abstinent addicts experienced strong cravings. The locus ceruleus helps control levels of the original “fight or flight” chemical, norepinephrine, and when an addict in withdrawal panics, the locus ceruleus lights up. Other studies of the nucleus accumbens showed abnormal firing rates in scanned addicts who were deep into an episode of craving. Drug hunger in abstinent addicts, it appeared, was not all in the head, or strictly psychological. Cravings have a biological basis, and brain scans helped to clinch the case.

Graphics credit: http://learn.genetics.utah.edu

This Is Your Brain on Drugs

High-tech imaging reveals the chemistry of addiction

Drug intoxication produces characteristic waveform signatures in the mammalian brain. The search for specific biological markers in the brain was made possible by positron emission tomography, better known as the PET scan. The idea is simple: Doctors inject test subjects with radioactively tagged glucose, which passes the blood-brain barrier with ease. The more electrochemically active portions of the brain burn extra glucose for energy. By noting precisely where the tagged glucose has gone, and converting that information into a digital two-dimensional array, a PET scan serves as a neurobiological map of brain activity in response to specific stimuli. Functionally, PET scans are pictures of the brain, showing specific areas that “light up” during the performance of a task, or in response to a drug.

Neuroimaging techniques like nuclear magnetic resonance imaging, or MRI, provide another level of detail. With MRIs, scientists could study the brain as a living work in progress. They could create a three-dimensional picture of the brain, with the sagittal, transaxial and coronal planes all visible at once—almost a brain hologram. For the first time, addiction scientists could watch areas of the brain light up with activity under the influence of specific mood-altering chemicals.

Two areas were of particular interest. One was the nucleus accumbens, which was involved in the regulation of dopamine and serotonin synthesis. The other was the locus ceruleus—a tiny area of the brain saturated with cells involved in the production and release of the neurotransmitter norepinephrine. Norepinephrine is another important neurotransmitter in the story. It is also known as noradrenaline, and is essentially identical to adrenaline (the latter also called, confusingly, epinephrine). For practical purposes, the four terms are essentially synonymous.

Alcohol, cocaine, the opiates, and other drugs made these two areas of the brain bloom with activity on the MRI and PET scans. These snapshots of your brain on drugs specifically showed that psychoactive drugs of abuse, the ones that altered mood and emotion, did so at the very sites in the brain known to be involved in regulating emotional states. As a general rule, the same areas of the brain tended to light up no matter what addictive drug was under study. Whether it was a molecule of rapture, or a molecule of sorrow, sooner or later it went surging through the brain’s limbic system--a diffuse aggregation of mid-brain structures involved with emotion, memory, mood, sleep, and a host of specific behaviors ranging from appetite to risk-taking.

That the subjects also showed characteristic brain activity when they quit doing drugs was of equal interest. Dr. Kenneth Blum and his coworkers at the University of Texas Health Science Center demonstrated that certain waveforms occur in the locus ceruleus when abstinent addicts experience cravings. The locus ceruleus helps control levels of the original “fight or flight” chemical, norepinephrine, and when an addict in withdrawal panics, the locus ceruleus lights up like the Fourth of July.

Other studies of the nucleus accumbens showed abnormal firing rates in scanned addicts who were deep into an episode of craving. Drug hunger in abstinent addicts, it appeared, was not all in the head, or strictly psychological. Cravings have a biological basis.