White matter hyperintensities in subjects with cocaine and opiate dependence and healthy comparison subjects

White matter hyperintensities in subjects with cocaine and opiate dependence and healthy comparison subjects

Psychiatry Research: Neuroimaging 131 (2004) 135 – 145 www.elsevier.com/locate/psychresns White matter hyperintensities in subjects with cocaine and ...

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Psychiatry Research: Neuroimaging 131 (2004) 135 – 145 www.elsevier.com/locate/psychresns

White matter hyperintensities in subjects with cocaine and opiate dependence and healthy comparison subjects In Kyoon Lyoo a,*, Chris C. Streeter b, Kyung Heup Ahn a, Ho Kyu Lee c, Mark H. Pollack d, Marisa M. Silveri a, Leanne Nassar a, Jonathan M. Levin a, Ofra Sarid-Segal b, Domenic A. Ciraulo b, Perry F. Renshaw a, Marc J. Kaufman a a

McLean Hospital Brain Imaging Center and Department of Psychiatry, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA b Boston University Medical Center, Boston University School of Medicine and VA Boston Healthcare System, Boston, MA, USA c Department of Radiology, Ulsan University College of Medicine, Seoul, South Korea d Massachusetts General Hospital and Habit Management Institute, Inc., Boston, MA, USA Received 25 March 2003; received in revised form 3 January 2004; accepted 1 April 2004

Abstract The prevalence, severity, and location of white matter signal hyperintensities (WMH) on brain magnetic resonance images were compared in patients with cocaine or opiate dependence and healthy subjects. Patients with cocaine (n = 32) and opiate dependence (n = 32), whose diagnoses were confirmed with the Structured Clinical Interview for DSM-IV, and age- and sex-matched healthy subjects (n = 32) were scanned using a 1.5 T whole body GE magnetic resonance scanner. Axial proton-density and T2-weighted images were obtained as well as fluid-attenuated inversion recovery axial images. The severity of WMH was assessed separately for deep (and insular) and periventricular WMH, using a modified composite version of the rating scales of Fazekas and Coffey. The cocaine-dependent group had greater severity of WMH than the opiate-dependent group, which in turn had greater severity of WMH than the healthy comparison group (odds ratios = 2.54 and 2.90, respectively). The cocaine-dependent group had greater lesion severity of deep and insular WMH than the opiate-dependent group and the healthy comparison group (odds ratio>3.25 for deep WMH; odds ratio>4.38 for insular WMH). For periventricular WMH, there were no significant differences between the three groups. The frontal lobes were the predominant locations of WMH in both substance-dependent groups. The greater prevalence and severity of WMH in cocaine-dependent subjects than in opiate-dependent subjects may reflect the fact that cocaine induces more ischemia via vasoconstriction than opiates. Also, there was a trend for lower WMH severity in substancedependent women relative to the healthy comparison group, possibly due to estrogen’s protective effect against cerebrovascular accidents. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Cocaine-related disorders; Opiate-related disorders; White matter hyperintensities; Brain magnetic resonance imaging

* Corresponding author. Tel.: +1-617-855-3337; fax: +1-617-855-2770. E-mail address: [email protected] (I.K. Lyoo). 0925-4927/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2004.04.001

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1. Introduction White matter signal hyperintensities (WMH) are patchy or diffuse white matter changes seen on T2weighted magnetic resonance images (MRI) (Awad et al., 1986) with corresponding neuropathologies that include dilated perivascular spaces, perivascular demyelination, astrocytic gliosis and arteriosclerosis (Awad et al., 1986; Kirkpatrick and Hayman, 1987; Grafton et al., 1991). Cerebral ischemia (Ginsberg et al., 1976), cerebral edema (Nag, 1984), and disturbed cerebrospinal fluid circulation (Bradley et al., 1991) have been suggested as pathological mechanisms for WMH. WMH may be located either in subcortical areas (deep WMH) or around the ventricles (periventricular WMH). While deep WMH are regarded as localized demyelinated areas caused by vascular mechanisms such as change of vascular permeability and arteriosclerosis, reports of ischemic pathophysiology leading to periventricular WMH have been less consistent (Isaka et al., 1994; Adachi et al., 1997; Ince and Fernando, 2002). WMH increase with age (Brant-Zawadzki et al., 1985; Yetkin et al., 1993). In addition, cardiovascular risk factors such as arteriosclerosis, hypertension and diabetes mellitus are known risk factors for WMH (Awad et al., 1986; Johnson et al., 1987; Coffey et al., 1988; Fazekas et al., 1988). The prevalence and significance of WMH on brain MRI have been studied in subjects with a number of psychiatric disorders, including major depression (Coffey et al., 1988; Krishnan et al., 1988; Lyoo et al., 2002), bipolar disorder (Dupont et al., 1990), schizophrenia (Keshavan et al., 1996), obsessive – compulsive disorder (Garber et al., 1989), panic disorder (Fontaine et al., 1990), and dementia (Gupta et al., 1988). However, there have been only a few WMH studies in subjects with substance abuse (Volkow et al., 1988; Bartzokis et al., 1999a, 2000). Volkow et al. (1988) observed demyelinating lesions on brain MRI in four out of seven drug abusers. Bartzokis et al. (1999a, 2000) have reported an increased prevalence of WMH, especially in cerebral white matter and insular cortex, in cocaine-dependent men. Based on prior reports of brain perfusion defects and ischemic lesions in cocaine and opiate abusers (Strassmann et al., 1969; Volkow et al., 1992; Strick-

land et al., 1993; Daras et al., 1994; Fessler et al., 1997; Andersen and Skullerud, 1999; Neiman et al., 2000), we hypothesized that subjects with cocaine and opiate dependence would have an increased prevalence of deep, but not periventricular, WMH relative to healthy comparison subjects. In addition, given the reports that cocaine is associated with more frequent ischemic strokes than opiates (Neiman et al., 2000) and that opiates induce nitric oxide-mediated vasodilatation (Benyo and Wahl, 1996), we hypothesized that the severity of WMH would be greater in cocaine-dependent than in opiate-dependent subjects. Estrogen has been reported to have a protective effect against cerebrovascular accidents (Paganini-Hill et al., 1988; Finucane et al., 1993) and possibly WMH (Schmidt et al., 1996). More perfusion abnormalities are seen in cocaine-dependent men than women (Levin et al., 1994) and cocaine-induced cerebral vasoconstriction is greater in men than women (Kaufman et al., 2001). Consequently, we also hypothesized that women with substance dependence would have a lesser degree of WMH relative to men with substance dependence. In the present study, we assessed the severity and prevalence of WMH on brain MR in age- and sexmatched cocaine-dependent (n = 32, 23 males, nine females), opiate-dependent (n = 32), and healthy comparison (n = 32) subjects.

2. Methods 2.1. Subjects Thirty-two cocaine-dependent subjects recruited from a NIDA-sponsored treatment trial at the Boston Medical Center, Boston, MA, and 32 opiate-dependent patients who underwent a methadone maintenance treatment program or methadone plus cognitive-behavioral treatment in the Habit Management Institute, Boston, MA, were recruited. All subjects were between 18 and 60 years of age and met DSM-IV criteria for cocaine dependence or opiate dependence, as diagnosed by trained psychiatrists using the Structured Clinical Interview for DSM-IV (SCID-IV). Exclusion criteria included psychiatric, neurologic and medical disorders requiring immediate treatment;

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additional current substance abuse/dependence diagnosis except nicotine and alcohol abuse/dependence; and contraindications to scanning (metallic implants, pacemaker, pregnancy or claustrophobia). Subjects with neurological illness that might affect scan results were also excluded. Subjects were tested for the presence of drug metabolites in their urine. Comorbid drug use is a common confound and it is not possible to find substantial numbers of pure cocaine or opiate abusers. We hoped that enrolling a large number of subjects would in part compensate for different drug use profiles by individual subjects and provide meaningful data indicating relative severities of WMH in opiate dependence vs. cocaine dependence. Thirty-two age- and sex-matched healthy comparison subjects were also recruited through advertisements at McLean Hospital and were free of any current or past history of DSM-IV axis I diagnoses, as determined by the SCID-IV. Written informed consent was obtained from all participants. All aspects of the clinical research protocol were reviewed and approved by respective Institutional Review Boards. 2.2. Magnetic resonance imaging and rating of white matter hyperintensities Brain MRI was performed using a 1.5-T whole body imaging system (Horizon Echo-Speed, General Electric Medical Systems, Milwaukee, WI). Axial protondensity and T2-weighted images (TE = 30/80 ms, TR = 3000 ms, 256  192 matrix; field of view = 24 cm, flip angle = 45j, NEX = 0.5, 3-mm-thick slices, no skip) were obtained as well as fluid-attenuated inversion recovery (FLAIR) axial images (TE = 133 ms, TR = 9002 ms, TI = 2200 ms, 256  192 matrix; field of view = 22 cm, 5-mm-thick slices, 2-mm skip) (Hajnal et al., 1992; Kato et al., 2000). An experienced neuroradiologist (H.K.L.), who had no knowledge of the reason for referral or the clinical diagnosis, reviewed T2 and FLAIR images on all 96 MRI scans. These readings were used to determine the prevalence, severity, and location of WMH. The severity of WMH was assessed separately for deep and periventricular WMH (Kertesz et al., 1988; Coffey et al., 1990). Insular WMH, which were included in the deep WMH ratings, were also coded

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separately considering prior reports of increased WMH in the insular region (Bartzokis et al., 1999b). Foci of hyperintensity in the deep white matter were rated as follows according to the Fazekas classification (Fazekas et al., 1987): grade 0 = absence; grade 1 = punctuate foci; grade 2 = beginning confluence of foci; grade 3 = large confluent area. Subjects with grade 1 WMH by the Fazekas classification were subclassified as follows according to the modified version of the Coffey classification (Coffey et al., 1990): grade 1– 1=(number of 1 or 2 and each with a diameter < 5 mm); grade 1– 2=(number < 10 and the largest lesion having a diameter between 5 and 10 mm); grades 1 –3=(number of 10 or more or at least one lesion with a diameter >10 mm). No Fazekas grade 3 deep white matter lesions were observed on brain MR images for our study subjects. Foci of hyperintensity in periventricular white matter were also rated according to the Fazekas classification as follows: grade 0 = absence; grade 1 = ‘cap’ or pencil-thin lining, grade 2 = smooth ‘halo’; grade 3 = irregular periventricular WMH extending into the deep white matter. There were no grade 3 periventricular lesions observed on brain MR images for our study subjects. Locations for WMH regions were noted as follows: frontal, temporal, parietal, occipital, insular regions for deep WMH; subcortical gray matters; frontal and non-frontal for periventricular for periventricular WMH. Sidedness of WMH was also noted. The same reader reviewed 20 randomly selected cases on two occasions separated by an interval of 2 weeks. The kappa values for intrarater reliability were 0.85 and 0.81 with regard to the presence or absence of grade 1 or severe deep and periventricular WMH, respectively; 0.73 and 0.75 for the severity ratings of deep and periventricular WMH, respectively (Landis and Koch, 1977; Fleiss, 1981). Interrater reliability, established with another radiologist (W.K.M.), was 0.81 with regard to the presence or absence of grade 1 deep or periventricular WMH, and 0.71 and 0.67 for the severity ratings of deep and periventricular WMH, respectively. 2.3. Statistical analysis Group differences in demographic variables that involved continuous data were computed by one-way

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Table 1 Demographic and clinical characteristics in subjects with cocaine or opiate dependence and healthy comparison subjects Demographic variablesa

Cocaine group (n = 32)

Opiate group (n = 32)

Comparison group (n = 32)

Age (years) Sex (male/female) Handedness (right/left) Weight (pounds) Years of abuse Comorbid abuseb [1 year Alcohol Aocaine Opiate Marijuana

43.4 (7.4) 23/9 (72%/28%) 29/3 (91%/9%) 172.3 (30.2) 15.5 F 8.3 *4 *6

42.2 (7.4) 23/9 (72%/28%) 27/3*1 (90%/10%) 176.8 (30.5) 21.4 F 10.1 *5 *7

40.5 (8.0) 23/9 (72%/28%) 29/2*2 (94%/6%) 167.5*3 (27.9) –

19 (32) 7 24

13 11 (32) 9

– – – –

No significant differences between groups in age, sex, handedness and weight. Sample sizes for calculating numbers for the table were not complete in the following instances: *1n = 30; *2n = 31; *3n = 31; *4n = 31; *5n = 29; *6n = 31; *7n = 29. ‘ – ’: Not applicable. a Results are reported as means (S.D.) or as numbers (%). b Did not meet criteria for dependence.

analysis of variance. Group differences involving categorical data were assessed using Fisher’s exact tests for 2 by k table. Considering that there are ordinal categories for WMH, ordinal multinomial logistic regression analysis was chosen as the primary statistical analysis method to compare severity differences in WMH between groups. Odds ratios were calculated for significant differences. Statistical significance was defined at the 0.05 level, two-tailed. Stata 6.0 for Windows was used for all computations (Stata, 1999).

3. Results Table 1 presents the demographic and clinical characteristics of each diagnostic group. There were no significant differences in age, sex, handedness and weight among the three groups. Out of 32 cocaine-dependent subjects, two subjects had hypertension and one subject had diabetes mellitus. Out of 32 opiate-dependent subjects, one subject had hypertension and three subjects had diabetes mellitus. All 32 healthy comparison subjects were without either a current or a history of major medical illness at the time of scanning. Consequently, there were no significant differences in the prevalence of medical comorbidities between groups.

For the cocaine-dependent group, 11 subjects had current alcohol abuse/dependence and nine subjects had past history of alcohol abuse/dependence. For opiate-dependent subjects, subjects with a diagnosis of alcohol dependence were not permitted. Social drinking was not an exclusion criterion for the study groups. The cocaine-dependent and opiate-dependent groups had greater severity of all WMH (deep and periventricular WMH combined) than the healthy comparison group (ordinal logistic regression: coefficient = 2.00, z = 3.88, P < 0.001, odds ratio = 7.35; ordinal logistic regression: coefficient = 1.06, z = 2.19, P = 0.028, odds ratio = 2.90, respectively) (Fig. 1). The cocaine-dependent group had greater severity of all WMH than the opiate-dependent group (ordinal logistic regression: coefficient = 0.93, z = 1.97, P = 0.049, odds ratio = 2.54). For deep WMH, the cocaine-dependent group had greater lesion severity than the opiate-dependent and healthy comparison groups (ordinal logistic regression: coefficient = 1.17, z = 2.39, P = 0.017, odds ratio = 3.25; ordinal logistic regression: coefficient = 2.24, z = 3.89, P < 0.001, odds ratio = 9.45, respectively) (Fig. 1). The difference in lesion severity between the opiate-dependent and comparison groups did not reach statistical significance (ordinal logistic regression: coefficient = 1.06, z = 1.89, P = 0.059). For insular WMH,

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Fig. 1. Prevalence of T2 white matter hyperintensities in subjects with cocaine or opiate dependence and healthy comparison subjects. Each group had 32 subjects (male/female = 23/9). Deep white matter hyperintensity (WMH) includes insular WMH. Ordinal logistic regression analyses: Severity of WMH: cocaine>opiate>comparison; Severity of deep WMH: cocaine>opiate z comparison; Severity of periventricular WMH: no significant difference; Severity of insular WMH: cocaine>opiate, comparison; Severity of deep WMH in cocaine-dependent subjects: (male z female). Abbreviations: – . WMH, white matter hyperintensities. – . ‘>’ Difference by P < 0.05: ‘ z ’ probable difference by P < 0.10.

the cocaine-dependent group had greater lesion severity than the opiate-dependent or comparison groups (ordinal logistic regression: coefficient = 1.54, z = 2.16, P = 0.031, odds ratio = 4.67; ordinal logistic regression: coefficient = 1.47, z = 2.07, P = 0.039, odds ratio = 4.38, respectively). There were no significant differences between opiate-dependent and comparison groups for the insular WMH (ordinal logistic regression: coefficient = 0.06, z = 0.086, P = 0.940). For periventricular WMH, there were no significant differences

between the cocaine-dependent, opiate-dependent and comparison groups (ordinal logistic regression: coefficient < 1.01, z < 1.74, P z 0.08). Locations of deep WMH were as follows, frontal lobes (n = 16, n = 14 and n = 4 for the cocaine-dependent, opiate-dependent and healthy comparison groups, respectively), parietal lobes (n = 2, n = 1, and n = 1 for cocaine, opiate and comparison groups, respectively), temporal lobes (n = 1 for the cocainedependent group), and basal ganglia (n = 3, n = 1, and

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n = 1 for the cocaine-dependent, opiate-dependent, and comparison groups, respectively). Lesions were right lateralized (n = 4 and n = 3 for the opiate-dependent and comparison groups, respectively), left lateralized (n = 6, n = 3 and n = 1 for the cocainedependent, opiate-dependent and comparison groups, respectively), and bilateral (n = 13, n = 8, and n = 2 for the cocaine-dependent, opiate-dependent, and comparison groups, respectively). Numbers for locations and sidedness are not mutually exclusive. Periventricular WMH are all in frontal areas and bilateral. Age was included in all statistical models. Age was a significant predictor for the presence of all WMH (ordinal logistic regression: coefficient = 0.08, z = 2.72, P = 0.007, odds ratio = 1.08), controlling for sex and diagnosis. Although the sex difference in the prevalence of WMH did not reach statistical significance, this information is reported here for completeness. Female substance-dependent (both cocaine and opiates) subjects (n = 18) had a tendency to have less severe WMH compared with male substance-dependent (both cocaine and opiates) subjects (n = 46) for deep WMH (ordinal logistic regression: coefficient = 1.06, z = 1.89, P = 0.059). This trend is mainly due to the sex difference in deep WMH in cocaine-dependent subjects (ordinal logistic regression: coefficient = 1.51, z = 1.88, P = 0.060).

4. Discussion The prevalence and severity of WMH in opiatedependent subjects were greater than in age- and sexmatched healthy comparison subjects, as hypothesized. In contrast to prior reports of ischemic lesions in the basal ganglia (Vila and Chamorro, 1997; Andersen and Skullerud, 1999), T2-weighted hyperintensities were not frequently found in these regions in opiate-dependent subjects. Our study subjects may be on a less severe spectrum of opiate dependence, mainly due to stricter exclusion criteria, whereas subjects with lesions in globus pallidus in prior studies had neurological symptoms (Zuckerman et al., 1996; Vila and Chamorro, 1997). Also, as hypothesized, the prevalence and severity of WMH in cocaine-dependent subjects were greater

than in age- and sex-matched healthy comparison subjects. Considering that these differences were mainly caused by deep WMH rather than periventricular WMH, vascular mechanisms for these changes are suggested. This finding is in line with a previous report of Bartzokis et al. (1999b), who measured WMH using a 0 to 3 point rating scale for cerebral white matter, insular subcortex white matter, and subcortical gray matter in male subjects with cocaine dependence. Ratings of grade 3 were used as a cut-off point for a probable pathological process. While this method is effective in identifying more definitive WMH lesions, our method of using all ratings in a statistical model may provide increased sensitivity, especially early in the disease course or in psychiatric disorders without extensive WMH lesions (Lyoo et al., 2002). As hypothesized, the prevalence and severity of WMH were greater in cocaine-dependent subjects than in opiate-dependent subjects. A few possible factors may explain this difference. First, cocaine induces ischemia more frequently and severely than opiates (Neiman et al., 2000). Second, the different mechanisms of ischemia between two drugs may underlie this difference in severity. While cocaine has direct vasoconstrictive effects (He et al., 1994; Kaufman et al., 1998), opiates can cause both vasodilatation and vasoconstriction (Benyo and Wahl, 1996; Neiman et al., 2000). Third, cocaine and opiates have different influences on dopamine and opiate receptors and associated secondary messenger systems in vessel wall and surrounding tissues (Benyo and Wahl, 1996; Schlaepfer et al., 1997). In addition, opiates can activate nitric oxide, which may confer vascular protective effects (Faraci and Brian, 1994; Benyo and Wahl, 1996). Pathophysiological mechanisms of WMH may differ by location. Vascular or ischemic causes have been well established for deep WMH and less so for periventricular WMH (Isaka et al., 1994; Adachi et al., 1997; Ince and Fernando, 2002). The present finding of a significant difference in deep WMH, but not periventricular WMH, is in line with our hypothesis of increased WMH via vascular mechanisms in cocaine- and opiate-dependent subjects (Neiman et al., 2000). Deep WMH were predominantly located in frontal regions in subjects with cocaine and opiate depen-

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dence. The frontal lobes were also the main locations for WMH in other psychiatric disorders (Lyoo et al., 2002). Increased WMH in frontal regions in cocainedependent subjects are consistent with prior functional neuroimaging studies demonstrating decreased cerebral blood flow in frontal lobe areas (Volkow et al., 1992; Strickland et al., 1993; Volkow et al., 1993) and cognitive deficits in attention and concept formation (Berry et al., 1993; Rosselli and Ardila, 1996). The frontal lobe region also was the predominant location for WMH in opiate-dependent subjects. This is consistent with reports of decreased frontal lobe perfusion (Rose et al., 1996; Gerra et al., 1998) and cognitive dysfunction, which are suggestive of deficits in cortico-striatal circuitry (Ornstein et al., 2000). The insular region has been reported to play an important role in obsessive – compulsive behavior or craving (Breiter et al., 1996; Rauch et al., 1997; Wang et al., 1999). There is also a recent report of gray matter density decrease in insular cortex in cocainedependent subjects (Franklin et al., 2002). Our finding that the cocaine group had a greater prevalence of WMH in the insular region compared with opiate or comparison groups is congruent with these reports. One possible explanation for increased insular WMH would be that insular regions are known to be vulnerable to vasoconstrictive conditions since these regions are supplied by branches of the middle cerebral artery without anastomoses (Bartzokis et al., 1999b). Given that there are significant between-group differences in the severity of deep WMH, i.e. cocaine-dependent > opiate-dependent > healthy comparison groups, these findings suggest that pathophysiology of WMH in opiate-dependent subjects may be less dependent on vascular factors as in most psychiatric disorders (Coffey et al., 1988; Gupta et al., 1988; Krishnan et al., 1988; Garber et al., 1989; Dupont et al., 1990; Fontaine et al., 1990; Keshavan et al., 1996; Lyoo et al., 2002) where no distinct cerebrovascular pathophysiology has been reported. Although statistically not significant, there was a trend for lower WMH severity for women ( P = 0.059) relative to the comparison group, with this marginal difference being mainly due to sex differences in deep WMH ( P = 0.060) (Fig. 1). This potentially demonstrates that estrogen’s protective effect against cerebrovascular accidents (Paganini-Hill et al., 1988;

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Finucane et al., 1993) may work even in the presence of cocaine or opiate abuse. This potential sex effect is consistent with the report that women with estrogen replacement therapy have a lower rate and extent of WMH that are inversely correlated with the duration of estrogen treatment (Schmidt et al., 1996) and the report that cocainedependent women have fewer perfusion abnormalities, than cocaine-dependent men and were indistinguishable from control women. (Levin et al., 1994). Our findings that age was positively correlated with WMH in cocaine- or opiate-dependent subjects are in line with previous reports that age is a risk factor for WMH (Brant-Zawadzki et al., 1985; Yetkin et al., 1993). It is interesting, however, that this trend was not found in healthy comparison subjects, possibly reflecting the fact that our healthy comparison subjects, with a relatively young mean age (40.5 years), do not have significant age-related increases in WMH in the absence of cocaine or opiate abuse. To the best of our knowledge, this is the first report that systematically measured the rates and severity of deep, insular, and periventricular WMH in age- and sex-matched subjects with cocaine and opiate dependence relative to findings in healthy comparison subjects. In addition, a more detailed WMH rating, instead of a cut-off value, was adopted in our study to detect more subtle and cumulative effects. This is important since most individuals with psychiatric disorders have WMH far less frequently and less severely than do those with neurological disorders (Coffey et al., 1988; Lyoo et al., 2002) and because the current study population is relatively young. The present results confirmed that cocaine abuse is a more powerful risk factor for WMH than opiate abuse, as was hypothesized. Limitations include the comorbidity of alcohol abuse in cocaine-dependent and opiate-dependent subjects, especially as alcohol consumption may lead to chemical or anatomical white matter lesions (Sullivan et al., 1996; Schweinsburg et al., 2001) as well as that of opiate and cocaine abuse in the cocaine- and opiate-dependent group, respectively. Since this study was designed and powered to detect differences in prevalence and severity of WMH between cocaine, opiate and healthy comparison groups, statistical power was too low to reach definitive conclusions with respect to sex effects.

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Smoking is nearly ubiquitous in cocaine and heroin cohorts, and likely does not play a role in the WMH differences identified between groups. However, the control cohort likely had fewer nicotine-dependent subjects and this could have resulted in group differences in comparisons between control and drugabusing cohorts since a putative relationship has been reported between nicotine dependence and WMH (Dager and Friedman, 2000). Although an increased prevalence of WMH has been reported in a number of psychiatric disorders (Coffey et al., 1988, 1989; Krishnan et al., 1988; Garber et al., 1989; Breitner et al., 1990; Dupont et al., 1990; Fontaine et al., 1990; Jernigan et al., 1990; Swayze et al., 1990; Figiel et al., 1991; Botteron et al., 1992, 1995; Aylward et al., 1994; Keshavan et al., 1996; McDonald et al., 1999), it is not clear whether the cocaine and opiate abuse, which are associated with relatively high rates of psychiatric comorbidity, share the same pathophysiology for WMH with other psychiatric disorders. In conclusion, we reported on increased prevalence of WMH lesions among cocaine- and opiate-dependent groups relative to a healthy comparison group, and more severe WMH lesions in cocaine-dependent subjects than in opiate-dependent subjects. There was a potential sex effect, with women less prone to the development of WMH. These findings could be potentially used for subgrouping drug-dependent populations or as a severity index when the clinical significance of WMH is assessed. Future prospective studies with measurement of serial changes in WMH, with collateral studies of clinical or cognitive function, will be needed to develop a better understanding of the clinical implications of the current findings.

Acknowledgements This work was supported, in part, by grants from the National Institute on Drug Abuse (DA09448, DA14178, DA50038, DA00329, DA14674, DA11231), the National Institute of Mental Health (MH58681), the National Institute on Alcohol Abuse and Alcoholism (K23AA13149), the Poitras Foundation (P.F.R.), and NARSAD (I.K.L., P.F.R.) and a VA Career Development Award (CCS).

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