Cocaine-addicted individuals say they find the drug much less enjoyable after years of use, but they have great difficulty quitting. A new brain imaging study led by researchers at the Icahn School of Medicine at Mount Sinai reveals why this might be so, as well as why a common psychological therapy may not work in addicted cocaine users.

Their study, published September 5 in the journal Addiction Biology, finds that chronic users have a “global impairment” in the ventromedial prefrontal cortex (VMPFC), an area of the brain that is linked to impulse and self-control, and is responsible for the kind of learning that assigns value to objects and behaviors.

The Mount Sinai study investigated a specific type of learning called extinction – the process by which a new, affectively neutral, association replaces an old, affectively arousing association – to identify the neurobiological mechanism that underlies the persistence of drug seeking in addiction despite negative consequences and a reduction in the drug’s rewarding affects.

To investigate these questions, the research team collected functional magnetic resonance imaging (fMRI) data on a three-phase classical conditioning paradigm in individuals with a history of chronic cocaine use and healthy control individuals without the drug habit. They found that in drug-addicted individuals, there was a VMPFC-mediated impairment in forming and maintaining new associations for stimuli that were previously, although no longer, predictive of both drug and non-drug related outcomes.

“Our study data suggests that it will be hard for longtime cocaine users to unlearn what once was a positive experience if this ‘unlearning’ or new learning relies on this brain region to be effective,” says the study’s lead investigator, Anna Konova, PhD, who worked on the study while at the Icahn School of Medicine, but who is now a postdoctoral fellow at the Center for Neural Science at New York University.

Extinction forms the basis for exposure therapy, which is often used to treat anxiety disorders like phobias.

“There is a strong impetus for extinction-based therapy in addiction, but our findings highlight potential limitations of these existing therapies in their reliance on the VMPFC to achieve therapeutic benefits,” said the study’s senior investigator, Rita Z. Goldstein, PhD, who directs Mount Sinai’s Neuropsychoimaging of Addiction and Related Conditions research group. Dr. Goldstein is an international expert in the use of functional neuroimaging methods to examine the neurobiological basis of impaired cognitive and emotional functioning in human drug addiction and other disorders of self-control. Dr. Konova was a graduate student in Dr. Goldstein’s lab.

“The idea behind extinction learning as a therapeutic intervention is that a user can learn to substitute a relaxing thought—such as taking a nature stroll—for the thought of procuring cocaine when walking by their neighborhood park where they might have previously purchased or consumed the drug. By relying on these new associations, an addicted individual may be able to control their habit,” said Dr. Konova.

Fear-based extinction learning is now widely used to treat anxiety, such as in phobias and post-traumatic stress disorder (PTSD). In this technique, a person is exposed to the thing that makes them afraid until the fear response to that thing (which is no longer associated with any real harm) is reduced and eventually extinguished, perhaps by forming a new, neutral or positive, association with their originally feared object or situation.

While previous experiments have suggested VMPFC impairment in addicted individuals who have long used stimulants such as cocaine - a consistent finding is that the gray matter (a marker of neuronal morphological integrity) is altered in that brain area in these individuals - this is the first experiment to examine if these chang