Prefrontal cortical volume reduction associated with frontal cortex function deficit in 6-week abstinent crack-cocaine dependent men

Abstract

Background: This study examined regional cortical volumes in 6-week abstinent men dependent on crack-cocaine only (Cr) or on both crack-cocaine and alcohol (CrA). Our goal was to test the a priori hypothesis of prefrontal cortical volume reduction, along with associated impairments in frontal mediated functions, and to look for differences between the Cr and CrA groups. Methods: Structural magnetic resonance imaging (MRI) of the brain and neuropsychological assessment were performed on 17 6-week abstinent Cr subjects, 29 six-week abstinent CrA subjects, and 20 normal controls. Cortical volume was quantified in the prefrontal, parietal, temporal and occipital regions. Results: Cr and CrA subjects showed comparable reductions in prefrontal gray matter volume compared to controls; this reduction was negatively associated with performance impairments in the executive function domain. Conclusions: Dependence on Cr (with or without concomitant alcohol dependence) was associated with reduced prefrontal cortical volume. Cr dependence with concomitant alcohol dependence was not associated with greater prefrontal volume reductions than Cr dependence alone. The existence of these findings at 6-week abstinence indicates that they are not a result of acute cocaine or alcohol exposure. The association of reduced prefrontal cortical volume with cognitive impairments in frontal cortex mediated abilities suggests that this reduced cerebral volume has functional consequences.

Introduction

There are very few studies of structural brain changes secondary to dependence on crack-cocaine (Cr), especially after a period of sustained abstinence. There is also little literature to date that examines the comorbid effects of chronic cocaine and alcohol abuse, even though a majority of cocaine abusers also abuse alcohol (Grant and Harford, 1990), and many individuals who present for substance abuse services exhibit both alcohol and cocaine dependence (Brown et al., 1994).

Preferential prefrontal gray matter atrophy associated with alcohol abuse was first suggested by Courville (1955), and continues as one of the strongest and most frequent findings in investigations of the cerebral effects of alcohol dependence (Harper and Kril, 1990, Pfefferbaum et al., 1995, Pfefferbaum et al., 1998). The advent of MRI has led to many imaging studies that document frontal lobe volume deficits in alcoholics and polysubstance dependent individuals (including individuals dependent on cocaine) (Bartzokis et al., 2000, Danos et al., 1988, Liu et al., 1998, O'Neill et al., 2001, Pascual-Leone et al., 1991, Pezawas et al., 1998, Pfefferbaum et al., 1998). Frontal lobe mediated functional impairments have also been documented in chronic alcoholism (reviewed by Fein et al. (1990) and by Oscar-Berman (2000)). The frontal (including fronto-limbic) system functions affected include emotional reactivity, behavioral inhibition, problem solving, abstraction, working memory, planning, and susceptibility to interference. Frontal-cerebellar circuits are also disrupted which affect problem solving, contextual memory, and execution and learning of procedures (Sullivan et al., 2000).

Our neuropsychological studies of subjects 6-weeks abstinent from Cr dependence or from both crack and alcohol (CrA) dependence found the greatest deficits in the executive function domain, which is mediated by the frontal cortex (Di Sclafani et al., in press). In earlier electrophysiological studies, we found that abstinent Cr and CrA dependent individuals had a delayed latency of the frontal cortex mediated orienting response to novel stimuli (the P3A component) (Biggins et al., 1997). Various other investigators have used PET and SPECT functional imaging to show deficits in cerebral blood flow in the prefrontal cortex of cocaine abusers (Tumeh et al., 1990, Volkow et al., 1988, Weber et al., 1993).

The use of Cr has been associated with a high incidence of cocaine-related stroke. Daras et al. (1994) reported on 55 cases of neurovascular events (25 ischemic and 30 hemorrhagic) related to cocaine use. They suggest that a sudden cocaine-associated rise in systemic arterial pressure may cause hemorrhages, frequently in association with an underlying aneurysm or arterial venous malformation. Vasospasm, arteritis, myocardial infarction with cardiac arrhythmias and increased platelet aggregation may provoke infarcts. Konzen et al. (1995) presented three case descriptions documenting brain infarcts in cocaine users that appear to result from vasospasm of large arteries and secondary intravascular thrombosis. Bartzokis et al. (1999) hypothesized that the incidence of white matter signal hyperintensities (possibly symptomatic of cerebral ischemia in cocaine abusers) observed on T2-weighted MRI would be increased in asymptomatic crack cocaine dependent individuals. They compared 61 Cr dependent participants (age 25–66 years) with 57 normal controls of comparable age. The cocaine-dependent sample had four times the incidence of hyperintense lesions as controls. The incidence of lesions increased with age in the cocaine dependent sample, and this increase was not related to the number of years cocaine was used. The authors concluded that Cr dependent participants had a significantly increased age-related risk of white matter damage.

In the present study, we examined volumes of regional cortical tissue and white matter signal hyperintensities in 6-week abstinent Cr and CrA subjects compared to normal controls. We expected both the Cr and CrA samples to demonstrate prefrontal cortical volume deficits, with consequent frontal mediated functional impairments. We also expected the substance dependent samples to show an increased volume of white matter signal hyperintensities compared to normal controls. We hypothesized that the sample dependent on both cocaine and alcohol would show both greater structural and greater functional effects than the sample dependent on cocaine alone.