A brain imaging study carried out at Massachusetts General Hospital (MGH) reveals abnormalities in the cortex – the outer surface of the brain – of cocaine addicts that appear to correlate with dysfunction in areas responsible for attention and for reward-based decision-making. While some of these abnormalities may reflect an inborn vulnerability to drug use, others appear to be the result of long-term cocaine exposure. The report appears in the October 9 issue of Neuron.

“These data point to a mixture of both drug effects and predisposition underlying the structural alterations we observed,” says Hans Breiter, MD, principal investigator of the Phenotype Genotype Project in Addiction and Mood Disorder in the MGH Departments of Radiology and Psychiatry. “They also suggest that a key feature of addiction – reduction in the range of activities in which addicts participate – has a neural signature in the form of reduced cortical thickness in frontal regions of the brain.”

It is known that addicts make judgments and decisions differently than non-addicted people do.

But it is not well understood how these differences relate to structural alterations in the brain – particularly changes in the cortex, the highly folded outer layer that helps plan, execute, and control behavior. Magnetic resonance imaging studies were taken of 20 cocaine addicts and 20 carefully matched control participants to investigate variations in cortical thickness. While the cortical thickness of some brain regions can vary widely among healthy individuals of similar age and background, the total brain volume is usually consistent.

In comparison to their healthy counterparts, cocaine addicts were found to have significantly less overall cortical volume, particularly in areas regulating reward function and involved with decision-making. The marked cortical thinness of areas involved in reward regulation and attention was not compensated by increases in other areas. In addition, although the cortex of some frontal regions is typically thicker in the right hemisphere than the left, this relationship was reversed for the addicts. Throughout the brain, cocaine addicts had much less variation in cortical thickness than did controls.

The participants also took part in several behavioral tests. One test of reward and motivation involves people pressing keyboard keys to control how long they viewed pictures of average and attractive faces. Addicts had much less variation than control participants did in their key pressing to view these faces and overall expressed a lower level of preference to all of the faces, including beautiful female faces toward which most healthy controls have strong positive responses. Those results correlated closely with the reduced cortical thickness in the reward regulation areas of addicts. In tests of the ability to pay careful attention to challenging tasks, the addicts also performed less well than control participants, which also correlated with thinner cortex in another region known to be important for attention.

The decreased variability of cortical thickness and assymetry between hemispheres seen in the addicts was not associated with how long they had been using drugs, Breiter notes, and is likely to reflect an inborn predisposition to drug use. Right- and left-side differences in the brain are important for many behaviors, and when they are altered, there is usually a genetic cause. In contrast, another brain region involved with the regulation of reward – the cingulate – had cortical thickness measures that were related to the length of cocaine exposure but not to how long participants used nicotine or alcohol, implying that cocaine itself caused that difference.

Together, these observations provide evidence that addiction-associated cortical thickness abnormalities may reflect both drug use and a pre-existing inclination to abuse drugs. “The severity of these cortical alterations point to the potential importance of prevention efforts to keep susceptible individuals from beginning to use cocaine,” Breiter says. “Next we need to see if these findings are limited to cocaine users by testing larger groups of participants with different addictions and with commonly accompanying diagnoses like depression.”

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Major support for this study came from the Office of National Drug Control Policy, with additional support from the National Institute on Drug Abuse, the MGH Department of Radiology, the National Center for Research Resources and the Mental Illness and Neuroscience Discovery Institute. The study is part of a long-term Phenotype Genotype Project on Addiction and Mood Disorder, directed by Breiter. Along with lead author Nikos Makris, MD, MGH Department of Psychiatry; the study’s co-authors are Greg Gasic, PhD, David Kennedy, PhD, Myong Joo Lee, Byong Woo Kim, and Claudia Baxter, Martinos Center for Biomedical Imaging; Steven Hodge and Jonathan Kaiser, MGH Neurology; and Anne Blood, PhD, Eden Evins, MD, Larry Seidman, PhD, Dan Iosifescu, MD, Sang Lee, Roy Perlis, MD, Jordan Smoller, MD, and Maruizio Fava, MD, MGH Psychiatry.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

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