Elsevier

NeuroImage

Volume 19, Issue 3, July 2003, Pages 1085-1094
NeuroImage

Regular article
Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task

https://doi.org/10.1016/S1053-8119(03)00113-7Get rights and content

Abstract

Cocaine abusers demonstrate faulty decision-making as manifested by their inability to discontinue self-destructive drug-seeking behaviors. The orbitofrontal cortex (OFC) plays an important role in decision-making. In this preliminary study we tested whether 25-day-abstinent cocaine abusers show alterations in normalized cerebral blood flow (rCBF) in the OFC using PET with 15O during the Iowa Gambling Task (a decision-making task). This task measures the ability to weigh short-term rewards against long-term losses. A control task matched the sensorimotor aspects of the task but did not require decision-making. Cocaine abusers (N = 13) showed greater activation during performance of the Iowa Gambling Task in the right OFC and less activation in the right dorsolateral prefrontal cortex (DLPFC) and left medial prefrontal cortex (MPFC) compared to a control group (N = 13). Better Iowa Gambling Task performance was associated with greater activation in the right OFC in both groups. Also, the amount of cocaine used (grams/week) prior to the 25 days of enforced abstinence was negatively correlated with activation in the left OFC. Greater activation in the OFC in cocaine abusers compared to a control group may reflect differences in the anticipation of reward while less activation in the DLPFC and MPFC may reflect differences in planning and working memory. These findings suggest that cocaine abusers show persistent functional abnormalities in prefrontal neural networks involved in decision-making and these effects are related to cocaine abuse. Compromised decision-making could contribute to the development of addiction and undermine attempts at abstinence.

Introduction

A survey in 2000 estimated that there were 1.2 million cocaine users in the United States 265,000 of whom were crack users (National Household Survey on Drug Abuse, 1999). The accumulated evidence suggests that repeated self-administration of cocaine despite its potential physical, psychological, and social consequences, is attributable to damage to specific neural networks involved in decision-making and performance monitoring Volkow and Fowler 2000, Volkow and Fowler 2000unpublished observations). This model might explain why cocaine abusers continue to use cocaine despite their inability to relive the powerful pleasurable experiences of their first drug administration (Fischman et al., 1985). Taken together, these observations suggest that cocaine abusers might have difficulty making advantageous decisions. Therefore, it is important to identify and clarify the neural substrates that underlie decision-making. This may elucidate mechanisms contributing to continued high-risk behaviors in cocaine abusers. Better understanding of these mechanisms would then lead to improved prevention and intervention strategies. The orbitofrontal cortex (OFC) is a crucial component of a neural network that subserves positive reinforcement in primates (Rolls and Baylis, 1994). In humans, the OFC has reciprocal connections with many brain regions that mediate the rewarding effects of cocaine as well as decision-making and compulsive behaviors Rolls 2000, Volkow and Fowler 2000. Damage to the OFC produces personality changes that include irresponsibility and persistence in self-destructive behaviors.

Evidence suggesting a change in the role of the OFC as a function of addiction comes from neuroimaging studies using positron emission tomography (PET). These studies have consistently revealed increased activation in the OFC, the anterior cingulate, the right insular region, and the amygdala in response to cocaine-related cues Bonson et al 2002, Childress et al 1999, Wang et al 1999, Grant et al 1996. Other studies have also shown that cocaine abuse is related to a disruption in the striato-thalamo-orbitofrontal circuit Volkow et al 1993, Volkow and Fowler 2000, Goldstein et al 2001. Specifically, higher relative OFC metabolism was correlated with worse conflict monitoring (lower score on the Stroop) in nonaddicted individuals and with better conflict monitoring (higher score) in addicted individuals (Goldstein et al., 2001). These data suggest that addicted individuals are more dependent on the OFC in order to perform as well as controls (Goldstein et al., 2001). One limitation of this study was that the Stroop task was not administered during the PET - FDG scan acquisition. In addition to PET studies, investigations of brain morphology show smaller gray matter volumes in regions such as the ventromedial orbitofrontal, anterior cingulate, anteroventral insular, superior temporal cortices (Franklin et al., 2002), and the prefrontal cortex as a whole in cocaine abusers in comparison to controls (Lui et al., 1998).

In addition to the OFC, we reasoned that the dorsolateral prefrontal cortex (DLPFC) might also be dysfunctional in the cocaine abuser. The DLPFC plays a role in maintaining attentional demands of a task including planning, controlling performance (MacDonald et al., 2000), and learning and memory (de Zubicaray et al., 2001). For example, we found that cocaine abusers showed significantly less activation than controls in the right DLPFC during performance on the Stroop task compared to controls (Bolla et al., personal observations). Activation in the DLPFC showed a negative correlation with the amount of cocaine used prior to admission to the study. That is, the more cocaine used per week, the less the activation. Further understanding of functional alterations in the OFC and DLPFC in cocaine abusers may elucidate mechanisms of addiction and poor decision-making.

Neuropsychological testing has shown a variety of performance deficits in cocaine abusers including impairments in decision-making and judgment, when compared to controls Strickland et al 1993, Ardila et al 1991; Bolla et al 1999, Bolla et al 2000. The Iowa Gambling Task was developed to test decision-making in everyday life in patients with lesions of the ventromedial prefrontal cortex (VMPFC) (Bechara et al., 1994). Specifically, the task tests a person’s ability to choose between high gains with a risk for even higher losses, and low gains with a risk for smaller losses. Patients with lesions in the VMPFC consistently performed more poorly on this task than controls Bechara et al 2000a, Bechara et al 1999, Bechara et al 1997, Bechara et al 1994. Substance abusers also show performance deficits on this task Bartzokis et al 2000, Grant et al 2000. Performance on the Iowa Gambling Task appears to be mediated by a neural network composed of the OFC, the amygdala, somatosensory/insular cortices, and the peripheral nervous system Bechara et al 1999, Bechara et al 1997, Ernst et al 2002.

The primary aim of this study was to determine if 25-day-abstinent cocaine abusers demonstrated differences in brain activation (normalized rCBF) compared to non-drug users during performance on the Iowa Gambling Task compared to a control task. We hypothesized that the cocaine abusers would show abnormalities in relative rCBF primarily in the OFC and DLPFC while performing the task compared to a group of control participants. Based on our previous PET work and neuropsychological data, we also hypothesized that grams per week of cocaine used prior to the 25 days of enforced abstinence that preceded the study would be negatively correlated with activation in the OFC and DLPFC of cocaine abusers during performance of the Iowa Gambling Task Bolla et al 1999, Bolla et al 2000. The characterization of persistent neurobehavioral deficits during the initial phase of abstinence from drug use is important because such deficits could impair the individual’s ability to discontinue self-destructive addictive behavior.

Section snippets

Participants

The institutional review boards of the National Institute on Drug Abuse - Intramural Research Program (NIDA-IRP), the Johns Hopkins Medical Institutions Joint Committee on Clinical Investigation, and the Johns Hopkins Bayview Medical Institutional Review Boards approved this protocol. All participants gave written informed consent and were compensated for their time. Control subjects and cocaine abusers were recruited using newspaper advertisements. Participant selection was based on drug use

Demographics and drug use (Table 1)

The control group (n = 13) was matched to the cocaine group (n = 13) on Shipley IQ score and sex. No group differences were found in years of education, Shipley IQ, maternal education, or Hollingshead Index of socioeconomic status. The cocaine group was older (36 years versus 30 years). Also, there were more cigarette smokers in the cocaine group than the control group (11/13 versus 7/13). Smoking was the main route of cocaine administration for all the cocaine users (84% smoked exclusively).

Discussion

Consistent with our hypothesis, we found functional abnormalities in brain activity in cocaine abusers. Specifically, abstinent cocaine abusers show greater activation during the Iowa Gambling Task in the right OFC and less activation in the right DLPFC when compared to controls. Less activation in the left MPFC was also observed in the cocaine group. In addition, the amount of cocaine used (grams/week) prior to the 25 days of abstinence was negatively correlated with activation in the left

Acknowledgements

This work was supported by NIH Grants DA 11426 (KB) and the JHBMC-GCRC (MO1 RR02719) and the DHHS/NIH/NIDA Intramural Research Program. We thank all the nurses and staff at NIDA-IRP, the Brain Imaging Center, and the Bayview GCRC who contributed to this project. We especially thank Debra Hill, B.A., for computer and database support and Steve Grant, Ph.D., for his intellectual contributions to this work.

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