Attentional Control and Brain Metabolite Levels in Methamphetamine Abusers Ruth Salo, Thomas E. Nordahl, Yutaka Natsuaki, Martin H. Leamon, Gantt P. Galloway, Christy Waters, Charles D. Moore, and Michael H. Buonocore Background: Methamphetamine abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. Methods: By using a computerized measure of selective attention and single-voxel proton magnetic resonance spectroscopy, we exam- ined the relationship between attentional control and brain metabolite levels in the anterior cingulate cortex (ACC) and primary visual cortex (PVC) in 36 currently abstinent methamphetamine abusers and 16 non–substance-using controls. Results: The methamphetamine abusers exhibited reduced attentional control (i.e., increased Stroop interference) compared with the controls (p = .04). Bonferroni-adjusted comparisons revealed that ACC levels of N-acetyl aspartate (NAA)– creatine and phosphocreatine (Cr) were lower and that levels of choline (Cho)–NAA were higher in the methamphetamine abusers compared with the controls, at the adjusted p value of .0125. Levels of NAA-Cr, but not of Cho-NAA, within the ACC correlated with measures of attentional control in the methamphet- amine abusers (r =-.41; p = .01) but not in controls (r = .22; p = .42). No significant correlations were observed in the PVC (methamphet- amine abusers, r = .19; p = .28, controls, r = .38; p = .15). Conclusions: Changes in neurochemicals within frontostriatal brain regions including ACC may contribute to deficits in attentional control among chronic methamphetamine abusers. Key Words: Anterior cingulate cortex, attention, imaging, metham- phetamine, MRS, NAA, Stroop I n the past decade, the use of the stimulant methamphet- amine has increased in the general population, with world- wide abuse of amphetamines surpassing that of cocaine and opiates combined (United Nations Office on Drugs and Crime 2004). Admissions to substance-abuse treatment programs in the United States with amphetamines as the primary substance of abuse increased fivefold in the decade for which latest figures are available, 1992–2002 (Office of Applied Studies, Substance Abuse and Mental Health Services Administration 2004). Al- though in the past methamphetamine abuse has been concen- trated in the western United States, many indicators point to abuse and dependence spreading across the country, into urban and rural areas in the south and northeast (Community Epide- miology Work Group 2004; National Drug Intelligence Center 2005). Compounding the problem is evidence that psychostimu- lants, such as methamphetamine, are neurotoxic to dopaminer- gic frontostriatal brain regions, with corresponding deficits in selective attention and cognitive control (Ernst et al. 2000; Nordahl et al. 2003; Salo et al. 2005; Sim et al. 2002; Simon et al. 2000). Damage after methamphetamine abuse to frontostriatal brain regions such as the striatum, prefrontal cortex, and anterior cingulate cortex (ACC) may contribute to the wide range of cognitive deficits observed in methamphetamine-abusing sub- jects (Ricaurte et al. 1984; Villemagne et al. 1998). Although early studies reported that acute doses of methamphetamine adminis- tered to drug-naive subjects actually produced improvements in cognitive processing (Kornetsky et al. 1959; Seashore and Ivy 1953; Soetens et al. 1995), it now is known that continued use of methamphetamine produces neural damage as well as cognitive sequelae of that damage (Nordahl et al. 2003; Rogers et al. 1995; Volkow et al. 2001). Cognitive impairments have been observed in methamphetamine abusers, with increased performance def- icits appearing on tasks that require the suppression of task- irrelevant information (Salo et al. 2005), decision making (Ka- lechstein et al. 2003; Paulus et al. 2003), and working memory (McKetin and Mattick 1998). Any combination of the cognitive impairments described in this paragraph may contribute and promote maintenance of the maladaptive actions that are asso- ciated with drug-seeking behavior (Porrino and Lyons 2000; Robbins and Everitt 1999). Study Rationale The goal of the present study was to examine the relationship between attentional control, as measured by a computerized single-trial version of the Stroop Attention Task, and brain metabolite levels, via proton magnetic resonance spectroscopy (MRS). The Stroop task is a powerful test of selective attention that requires subjects to engage cognitive control to inhibit a prepotent but task-irrelevant response (i.e., word reading) and execute the task-relevant response (color naming; Henik and Salo 2004; MacLeod 1991; Stroop 1935). Although several studies have used MRS to examine the effects of methamphetamine on neurometabolites (Ernst et al. 2000; Nordahl et al. 2002, 2005; Taylor et al. 2000), none to our knowledge have linked neuro- chemical levels to behavioral measures of cognition, such as the Stroop task. Thus, the current study generates novel information about the relationship between neurometabolite levels within targeted regions of interest and measures of cognition. This approach is essential to examine the degree to which metham- From the Department of Psychiatry and Behavioral Sciences (RS, TEN, MHL), Imaging Research Center (RS, TEN, YN, MHB), Department of Radiology (MHB), and Department of Biomedical Engineering (YN), University of California, Davis; California Pacific Medical Center (GPG), San Francisco; and Kaiser Chemical Dependence Recovery Program (CW, CDM), Sacra- mento, California. Address reprint requests to Ruth Salo, Ph.D., Imaging Research Center and Department of Psychiatry and Behavioral Sciences, University of California–Davis Medical Center, 4701 X Street, Sacramento, CA 95817; E-mail: resalo@ucdavis.edu. Received February 2, 2006; revised July 11, 2006; accepted July 13, 2006. BIOL PSYCHIATRY 2007;61:1272–1280 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.07.031 © 2007 Society of Biological Psychiatry