Going Deep: Surgery For Addiction?

Controversial DBS technique shows early promise for Parkinson’s, Tourette’s.

Bielefeld, Germany—

The third in an irregular series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again. The conference, held at the Center for Interdisciplinary Research (ZiF) at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.  Part One is here.  Part Two is here.

All addictive drugs increase the production of dopamine in the nucleus accumbens, as do other highly pleasurable activities. Part of the medial forebrain bundle (MFB), which mediates punishment and reward, the nucleus accumbens is the ultimate target for the dopamine released by the ingestion of cocaine, for example. The nucleus accumbens is a very old and evolutionarily well-preserved structure in the brain. If you remove large slices of the nucleus accumbens, or knock it out entirely, animals no longer want addictive drugs.

This is essentially the same pathway that regulates our food and water-seeking behavior. By directly or indirectly influencing the molecules of pleasure, alcohol and other drugs trigger key neurochemical events that are central to our feelings of both reward and disappointment. In this sense, the reward pathway is a route to both pleasure and pain. Studies of the nucleus accumbens have demonstrated abnormal firing rates in scanned addicts who were deep into episodes of craving. The craving for a reward denied causes dopamine levels in the nucleus accumbens to crash dramatically, as they do when users go off drugs.

During his presentation in Bielefeld, “Stimulating the Addictive Brain,” Dr. Jens Kuhn of the University Hospital of Cologne walked the audience through an explanation of one of the most controversial addiction treatment options of all, known as deep brain stimulation. For those unfamiliar with DBS, this surgical procedure uses implanted brain electrodes and a subdermal set of wires connected to a small power source to directly stimulate a designated area of the brain via electric current.  Deep brain stimulation (DBS) is becoming an established treatment option for some movement disorders, in particular Parkinson’s disease. It is also being investigated for obsessive–compulsive disorder, major depression, and Tourette’s syndrome.

Kuhn and his researchers, the first German group to investigate deep brain stimulation beginning in 2002, started by investigating Tourette’s and OCD. But soon, Kuhn said, it became clear that “valid animal studies show significant induced improvement in cocaine, morphine and alcohol addiction behavior following DBS of the nucleus accumbens…. the few patients who underwent DBS surgery for addiction remained abstinent or had a major reduction of relapses.” 

Carrie Wade and others at the Scripps Research Institute and Aix-Marseille University in France  electrically stimulated the subthalamic nucleus and got addicted rats to take less heroin and become less motivated for the task of bar pressing to receive the drug. Earlier work had demonstrated a similar effect in rats’ motivation for cocaine use. “This research takes a non-drug therapy that is already approved for human use and demonstrates that it may be an option for treating heroin abuse,” Wade said in a prepared statement.

Dr. Kuhn told the audience that DBS is a “focused neuromodulation procedure to enrich electrical activity” applied to certain brain regions and requiring only “minimally invasive” surgery. In the case of DBS surgery for addiction, which Dr. Kuhn has performed in clinical settings, the target is the nucleus accumbens, which Kuhn called “the key player in the so-called limbic reward loop.”

The problem is that these investigations, while positive in many cases, are small and scattered thus far, and do not represent a systematic investigation of the procedure by the field of neuroscience at large. Not yet, anyway. And maybe not ever. There are very few published studies on human addicts, Kuhn said, “but luckily, the ethical implications of DBS are being more and more discussed.”

Unfortunately, as Kuhn pointed out, “neurosurgical interventions in psychiatric patients raise ethical considerations not only based on the disreputable experiences of the era of psychosurgery.” But that’s a good starting point. The procedure, despite one’s best efforts, conjures up images of “psychosurgery”—prefrontal lobotomies, or early electroconvulsive shock therapy (ECT). It doesn’t help that the likeliest mechanism of action that explains DBS is that high frequency stimulation causes functional lesions at the specific brain sites. From almost every angle, it seems ham-handed and crude—until you see some videos of results, like this one of a Tourette’s patient: Video

Kuhn acknowledged that a number of medical professional believe DBS is a poor choice for addiction, and its use “is premature due to expenses, possible risks and the assumed poor scientific rationale of the method in this field.”  In a letter to the journal Addiction, Adrian Carter and Wayne Hall of the University of Queensland, Australia, noted that some of the positive reports come from China, where scientists have experimented with ablation of portions of the nucleus accumbens and other brain areas. And it seems to work. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain isn’t likely to catch on, except as a seminar topic for medical ethicists. Carter and Hall call the evidence base for the safety and efficacy of DBS in addiction “weak,” and argue that “the addition of an expensive neurosurgical treatment that costs of the order of $50,000 will worsen this situation by utilizing scare health resources to treat a very small number of patients with the income to pay for it.”

In a history of “stereotactic lesions” as a treatment for movement disorders, researchers at The George Washington University School of Medicine and Health Sciences reviewed efforts to expand the use of DBS to include specific psychiatric disorders like depression and obsessive-compulsive disorders. Writing in the Journal of Neurosurgery in 2010, they concluded that “addiction and schizophrenia showed the least improvement from surgery. Therefore, pursuing the treatment of these disorders with DBS using the targets in these studies may be ineffective.”

The Neurotech Business Report recently documented that St. Jude Medical, a manufacturer of surgical devices, has shut down its clinical trial of DBS for depression (h/t Vaughan Bell). The company’s website said “The BROADEN (BROdmann Area 25 DEep brain Neuromodulation) Study” has been closed and is no longer enrolling participants. The article suggests that “the complexity of specifying the precise brain circuits involved with major depression” may have been the reason for halting the trial.

Known risks associated with deep brain stimulation placement include: dizziness, infection, loss of balance, and speech or vision problems. In addition, the devices, wires and leads that make up the system, which are all implanted in the brain or under the skin, can break or fail in various ways. DBS can also alter glucose metabolism and food intake in lab rats. Altogether, there are few case reports, and the mechanism of action remains essentially uncharacterized. In the case of addiction, this is one treatment that does not seem ready for prime time. It would be premature to move DBS beyond the clinical trial stage in humans without additional data.

Photo Credit: http://biomed.brown.edu

Drug Craving, or How to Be Your Own Worst Enemy

Plus the disease model, warts and all.

Bielefeld, Germany—

The second in an irregular series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again. The conference, held at the Center for Interdisciplinary Research (ZiF) at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.  Part One is here.

Marc Lewis, a developmental neuroscientist who is currently professor of human development and applied psychology at Radboud University in The Netherlands, and who spent five days discussing addiction with the Dalai Lama and a small group of scientists, scholars, and addiction specialists in Dharamsala, India, last year, was a late but welcome addition to the speaker list at the conference.

Author of Memoirs of an Addicted Brain, and a self-confessed “drug addict turned neuroscientist,” Dr. Lewis always brings a thought-provoking dual perspective to his work on addiction. (See my review of his book here.) He also blogs here.

In Bielefeld, Dr. Lewis offered up a wide-ranging view of what addiction is and is not, linking neuroscience, psychology, and Buddhism in the process. 

Craving is “the one condition all addicts agree is their worst enemy,” Lewis said. “This is one place where science and subjectivity have to come together. Scientists need to focus on this, because addicts are completely unanimous about it. This is the enemy. It’s not physical withdrawal symptoms, it’s not relief. It is craving.”

Buddhism teaches that “craving is the fundamental engine of personality development,” Lewis said. “It’s what keeps us going around and around.” But if you don’t much like the notion of the wheel of reincarnation, Lewis suggested, then you can contemplate “the cyclical nature of how we repeat patterns in life that lead to suffering.”

“Craving is such an unpleasant state, that after a while, you end up doing it, you get the drugs. I did opiates, and I would spend hours and hours trying to sit on my hands, trying to watch something on TV, trying to go for a walk, and finally, there’s this thing that keeps rising in the background, and it doesn’t go away. It was a constantly growing tension, an anxiety and discomfort, that came from very deep down. You spend most of your energy trying to hold this thing at bay, and according to the ego depletion literature, you can’t do that for very long. These cognitive control centers just give up. They are limited resources.”

Craving is not a steady state. It grows. “Neuroscience helps us understanding why craving is so nasty.” Enter “delay discounting,” a term from behavioral economics used by several speakers during the conference. Delay discounting is the proposition that the perceived value of something rises steeply as the reward gets closer in time. A variation of this idea is seen in the classic marshmallow test for children: One marshmallow now, or two if you wait until later?

“Craving traps you in delay discounting,” said Lewis. “Immediate reward is worth more than imagined future happiness. The job of dopamine in the striatum is to increase the attractiveness or value of one goal, and to reduce the attractiveness and value of all the other goals. This is a brain that is well designed for addiction. You get tons of dopamine rising up in anticipation of reward. So you’re really stuck in the immediate. At which point you’ve effectively lost contact with the rest of your life. In the narrative of who you are, you can’t even include next week, or the next morning.”

Nonetheless, Lewis finds serious problems with the standard disease model of addiction, as championed by NIDA’s Nora Volkow and other in the NIH, however brain-based he may be. As a developmental neuroscientist, Lewis is predisposed to viewing the brain as a locus of change by definition. “The disease model uses brain change as a foundational premise. But brains change with development, anyway. And in fact, brains are designed to change.”

Any proper model of addiction, he insisted, has to correspond with what we know about brain change. “But it also has to correspond with addicts’ experiences. I was a drug addict from about age 25 to 30. I was in really bad shape. And now I talk with a lot of drug addicts, and one of the things that I keep hearing is that scientists and clinicians don’t really know what they’re doing—they don’t know where to go with it. They know that addiction is really nasty, but they don’t know what it’s like, unless they’ve been there.”

Lewis offered a view of addiction that shifts the semantic focus from disease to development. The drug is not the culprit. By reconceptualizing addiction as a developmental disorder, he suggested, we can move the debate forward into the world, where the action is:

Addiction results from accelerated learning, the acquisition of thought patterns that rapidly self-perpetuate because of the brain’s tendency to become sensitized to highly attractive rewards. This is a developmental process, accelerated by a neurochemical feedback loop that is particular to strong attractions. Like other developmental outcomes, addiction isn’t easy to reverse, because it’s based on synaptic restructuring. Like other developmental outcomes, it arises from neural plasticity, and uses it up at the same time.

And the mechanisms responsible are the same ones responsible for many things that involve desire, learning, reward seeking, and compulsive behavior—including the so-called behavioral addictions like overeating and compulsive sex. However, “the severe consequences of addiction don’t make it a disease, any more than the consequences of violence make violence a disease.”

In an email exchange after the conference, I followed up with Dr. Lewis on some of these matters, and he sent me the following additional thoughts on the “diseasing” of addiction:

Proponents of the disease model argue that addiction changes the brain. And they're right: it does. But the brain changes anyway, at every level, from gene expression, to cell density, to the size and shape of the cortex itself. Of course, neuroscientists who subscribe to the disease model must know that brains change over development. Their take on pathological brain change would have to be very specific in order to be convincing. For example, they would have to show that the kind (or extent or location) of brain change characteristic of addiction is nothing like that observed in normal learning and development. But this they cannot do. The kind of brain changes seen in addiction also show up when people take up rock collecting, fall in love, learn how to cook, or become obsessed with their appearance. The brain contains only a few major traffic routes for learning and goal seeking. And, like the main streets of a busy city, they are often under construction.  Brain disease may be a useful metaphor for how addiction seems, but it's not a valid explanation for how it actually works.

What is This Thing Called Neuroplasticity?

And how does it impact addiction and recovery?

Bielefeld, Germany—

The first in an irregular series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again. The conference, held at the Center for Interdisciplinary Research (ZiF) at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.

One of the stated missions of the conference at Bielefeld’s Center for Interdisciplinary Research was to confront the leaky battleship called the disease model of addiction. Is it the name that needs changing, or the entire concept? Is addiction “hardwired,” or do things like learning and memory and choice and environmental circumstance play commanding roles that have been lost in the excitement over the latest fMRI scan?

What exactly is this neuroplasticity the conference was investigating? From a technical point of view, it refers to the brain’s ability to form new neural connections in response to illness, injury, or new environmental situations, just to name three. Nerve cells engage in a bit of conjuring known as “axonal sprouting,” which can include rerouting new connections around damaged axons. Alternatively, connections are pruned or reduced. Neuroplasticity is not an unmitigated blessing. Consider intrusive tinnitus, a loud and continuous ringing or hissing in the ears, which is thought to be the result of the rewiring of brain cells involved in the processing of sound, rather than the sole result of injury to cochlear hair cells.

The fact that the brain is malleable is not a new idea, to be sure. Psychologist Vaughn Bell, writing at Mind Hacks, has listed a number of scientific papers, from as early as 1896, which discuss the possibility of neural regeneration. But there is a problem with neuroplasticity, writes Bell, and it is that “there is no accepted scientific definition for the term, and, in its broad sense, it means nothing more than ‘something in the brain has changed.’” Bell quotes the introduction to the science text, Toward a Theory of Neuroplasticity: “While many scientists use the word neuroplasticity as an umbrella term, it means different things to different researchers in different subfields… In brief, a mutually agreed upon framework does not appear to exist.”

So the conference was dealing with two very slippery semantic concepts when it linked neuroplasticity and addiction. There were discussions of the epistemology of addiction, and at least one reference to Foucault, and plenty of arguments about dopamine, to keep things properly interdisciplinary. “Talking about ‘neuroscience,’” said Robert Malenka of Stanford University’s Institute for Neuro-Innovation and Translational Neurosciences, “is like talking about ‘art.’”

What do we really know about synaptic restructuring, or “brains in the wild,” as anthropologist Daniel Lende of the University of South Florida characterized it during his presentation? Lende, who called for using both neurobiology and ethnography in investigative research, said that more empirical work was needed if we are to better understand addiction “outside of clinical and laboratory settings.” Indeed, the prevailing conference notion was to open this discussion outwards, to include plasticity in all its ramifications—neural, medical psychological, sociological, and legal—including, as well, the ethical issues surrounding addiction.

Among the addiction treatment modalities discussed in conference presentations were optogenetics, deep brain stimulation, psychedelic drugs, moderation, and cognitive therapies modeled after systems used to treat various obsessive-compulsive disorders. Some treatment approaches, such as optogenetics and deep brain stimulation, “have the potential to challenge previous notions of permanence and changeability, with enormous implications for legal strategies, treatment, stigmatization, and addicts’ conceptions of themselves,” in the words of Clark and Nagel.

Interestingly, there was little discussion of anti-craving medications, like naltrexone for alcohol and methadone for heroin. Nor was the standard “Minnesota Model” of 12 Step treatment much in evidence during the presentations oriented toward treatment. The emphasis was on future treatments, which was understandable, given that almost no one is satisfied with treatment as it is now generally offered. (There was also a running discussion of the extent to which America’s botched health care system and associated insurance companies have screwed up the addiction treatment landscape for everybody.)

It sometimes seems as if the more we study addiction, the farther it slips from our grasp, receding as we advance. Certainly health workers of every stripe, in every field from cancer to infectious diseases to mental health disorders, have despaired about their understanding of the terrain of the disorder they were studying. But even the term addiction is now officially under fire. The DSM5 has banished the word from its pages, for starters.

Developmental psychologist Reinout Wiers of the University of Amsterdam used a common metaphor, the rider on an unruly horse, to stand in for the bewildering clash of top-down and bottom-up neural processes that underlie addictive behaviors. The impulsive horse and the reflective rider must come to terms, without entering into a mutually destructive spiral of negative behavior patterns. Not an easy task.