- Email: [email protected]
Studying addiction in the age of neuroimaging
Drug and Alcohol Dependence 100 (2009) 182–185
Contents lists available at ScienceDirect
Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep
CPDD News and views
Studying addiction in the age of neuroimaging Marian W. Fischman lecture given at the 2008 meeting of CPDD夽 Edythe D. London ∗ Semel Institute of Neuroscience and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, United States
My talk today is about the discoveries that have come from my own work and that of others who have used brain imaging techniques over the past 30 years to understand the neural basis of drug addiction. Brain imaging allows us to relate drug actions to feelings, cognition, and the function of specific neural circuits. Such information is critical for our ability to develop rational therapies for addiction. 1. Development of brain imaging technologies The period of time from the midseventies to the present has been filled with transformative advances in brain imaging that moved forward the field of drug abuse research. The technique of positron emission tomography (PET), which allows noninvasive molecular imaging, was largely advanced in the 1970s, with the PET III built in 1974 after several prototypes (Hoffman et al., 1976). This work followed many decades of developments in positron imaging that included contributions of many individuals (see Brownell, 1999 for a historical review). Roughly simultaneously with the appearance of a commercial unit for human PET, the 2-deoxyglucose technique was developed, introducing metabolic mapping through measurement of rates of glucose metabolism throughout the brain (Sokoloff et al., 1977). The method was soon adapted for human studies following the synthesis of the radiotracer [18 F]fluorodeoxyglucose
夽 Supported in part by: P20DA022539, R01DA020726, and RL1DA024853. ∗ Tel.: +1 310 825 0606; fax: +1 310 825 0812. E-mail address: [email protected]. 0376-8716/$ – see front matter doi:10.1016/j.drugalcdep.2008.09.003
in 1976 (Ido et al., 1978), with the first human studies using this tracer performed in 1979 (Reivich et al., 1979). Metabolic mapping was then joined by PET neuroreceptor mapping, introduced in 1983, with the use of [11 C]N-methylspiperone (Wagner et al., 1983). Parallel to these developments in molecular imaging, another series of technological advances followed the discovery of magnetic resonance imaging (MRI) (Damadian, 1971; Lauterbur, 1973; Grannell and Mansfield, 1975). Achievements in this area included introduction of the Blood-Oxygen-Level-Dependent (BOLD) contrast method (Ogawa et al., 1990) and its application to studies of the human brain (Belliveau et al., 1991). These tools enabled many discoveries about the different factors that maintain addiction, including positive reinforcement, drug craving, negative affective states reinforcement, and dysfunction of inhibitory control systems. 2. Positive reinforcement, functional mapping and dopamine Studies on the acute effects of drugs of abuse on brain function were inspired by the knowledge that these drugs in general produce a positive affective state that reinforces their self-administration. PET imaging, with the 2-deoxyglucose method, was first applied in human studies of drug abuse after the responses to drugs of abuse were mapped in the rat brain (e.g., Fanelli et al., 1987; Kimes and London, 1989; London et al., 1987, 1988; London, 1989; Porrino et al., 1988; Weissman et al., 1987). In the first studies of humans, acute administration of morphine and cocaine, at euphorigenic doses, reduced cerebral
glucose metabolism globally with substantial cortical effects (London et al., 1990a,b), unlike the pattern of primarily subcortical effects that had been observed in rats (London et al., 1986). Cortical decrements in glucose metabolism, particularly in limbic cortex were also observed in monkeys (Lyons et al., 1996). Superimposed on the global reductions in cerebral glucose metabolism demonstrated using 2-deoxyglucose with PET, the BOLD fMRI method, which provides a finer time resolution, also revealed focal signal increases in many cortical and subcortical regions. Focal signal increases were demonstrated in pons, ventral tegmentum, thalamus, nucleus accumbens/subcallosal areas, caudate, putamen, basal forebrain, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal, temporal, parietal, and striate/extrastriate cortices, and focal signal decreases were noted in amygdala, temporal pole, and medial frontal cortex (Breiter et al., 1997). Animal studies have provided ample evidence that reward from selfadministration of drugs of abuse is due to dopamine release (Di Chiara and Imperato, 1988; Koob and Bloom, 1988). Studies using PET in human volunteers have extended this work, using [11 C]raclopride, a radiotracer that binds to D2-like dopamine receptors. For example, intravenous methylphenidate administration produces a decrease in striatal radiotracer binding (presumably due to competition by increased intrasynaptic dopamine) related to the subject’s self-report of being “high” (Volkow et al., 2004). Striatal dopamine release has also been demonstrated in human subjects after cigarette smoking (Brody et al., 2004; Scott et al., 2007); and this effect is under genetic control, as
E.D. London / Drug and Alcohol Dependence 100 (2009) 182–185
smokers who had at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype exhibited greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes (Brody et al., 2006). 3. Craving, corticolimbic circuits and dopamine Both functional and molecular neuroimaging studies have provided substantial information on the neural substrates of drug craving. Studies with [18 F]fluorodeoxyglucose (e.g., Grant et al., 1996; Bonson et al., 2002), [15 O]water (e.g., Childress et al., 1999; Kilts et al., 2001), and fMRI (e.g., Maas et al., 1998) allowed whole brain analyses of changes in brain activity associated with drug craving. In the first of these studies, exposure to cocainerelated cues led to increases in glucose metabolism of cortical areas, including the dorsolateral prefrontal cortex, the medial orbitofrontal cortex, and the temporal lobe (Grant et al., 1996). Cue-induced cocaine craving was also correlated with increase in glucose metabolism in the medial temporal lobe (amygdala), dorsolateral prefrontal cortex, and cerebellum. The findings suggest that a distributed neural network that integrates emotion with memory may link environmental cues to cocaine craving. Subsequent studies supported and extended these findings (e.g., Bonson et al., 2002; Childress et al., 1999; Kilts et al., 2001; Maas et al., 1998), including correlations of cue-induced cocaine craving with the change in glucose metabolism in the insula and orbitofrontal cortex (Bonson et al., 2002). Similar studies with drugs of abuse other than cocaine included studies of cigarette craving, in which craving was correlated with change in glucose metabolism in the insula and orbitofrontal cortex (Brody et al., 2002). Notably, the finding in the insula has gained special importance after observations that insula damage (through stroke) disrupted addiction to cigarette smoking (Naqvi et al., 2007). While reductions in striatal [11 C]raclopride binding (an indirect marker for dopamine release) have been implicated in drug-induced reward, such changes have also been related to craving for cocaine, induced by the presentation of cocaine-related visual cues (Volkow et al., 2006; Wong et al., 2006). In one study, the change in dopamine-receptor occupancy in the dorsal striatum was
highly correlated with craving for cocaine (Wong et al., 2006). Thus, imaging studies of cue-induced drug craving demonstrated a relationship to dopamine release, involvement of corticolimbic circuitry, and commonalities across drugs of abuse. 4. Negative affect and inhibitory control Aside from drug craving, another factor that influences and maintains addiction in some individuals is negative affect. In this regard, stimulant abusers who meet DSM-IV criteria for methamphetamine dependence show significant differences from healthy comparison subjects with respect to depressive symptoms and anxiety (London et al., 2004). Methamphetamine-dependent subjects, abstinent from illicit drugs of abuse for 4–7 days, also exhibit an abnormal pattern of cerebral glucose metabolism, including remarkably high relative activity in the amygdala and low activity in the medial prefrontal cortex. While activity in the prefrontal cortex, including the subgenual area, is inversely related to self-reported anxiety (low activity with high anxiety), activity in amygdala is positively correlated with self-reports of both anxiety and depression. In view of animal studies showing anatomical and functional links between function of the medial prefrontal cortex and amygdala (Heidbreder and Groenewegen, 2008), the pattern of abnormality in cerebral glucose metabolism in methamphetamine-dependent subjects is consistent with a loss of prefrontal inhibitory control. Such a deficit is in line with the view that addiction is maintained, in part or in some individuals, by impaired inhibitory control mechanisms. Impaired inhibition may contribute to an addicted individual’s failure to maintain desired abstinence, or to using more drug than intended. Although the relevance to drug-taking in the real world has not been well established, cognitive tasks are used in the laboratory to evaluate addicted individuals on several aspects of inhibitory control, such as motor-response inhibition (assessed by go/no go tasks, such as the Stop-Signal Task), ability to shift set (assessed by reversal learning tasks), and decision-making (assessed by delay discounting tasks and tests of risk-taking). In general, drug-abusing samples manifest impairments. For example, participants who have abused methamphetamine chronically exhibit a deficit in stopping ability on the Stop-Signal Task (Monterosso et al., 2005). Notably, performance on this task is linked to the integrity of the right lateral prefrontal cortex (Aron
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et al., 2004), where methamphetamine abusers exhibit gray matter volume deficits (Thompson et al., 2004; Monterosso et al., 2007). In addition to the aforementioned deficits in mood, cortical deficits and their contribution to impairing inhibitory circuits may contribute to other socially maladaptive behaviors observed in methamphetamine abusers, including hostility, aggression, and unmotivated violence (Cretzmeyer et al., 2003; Cohen et al., 2003; Hall et al., 1996; Maxwell, 2005). We therefore applied fMRI to studying the processing of emotional facial expressions (highly salient social cues) by methamphetamine-dependent subjects during early abstinence (Payer et al., 2008a). Methamphetamine-dependent subjects did not differ from a healthy control group in performance of a facematching task, while exhibiting less task-related activity in several cortical regions (i.e., ventrolateral prefrontal cortex, temporoparietal junction, anterior and posterior temporal cortex, and fusiform gyrus in the right hemisphere, and the cuneus in the left hemisphere) while showing more task-related activity in the dorsal anterior cingulate cortex and giving higher self-reports of interpersonal sensitivity. These data suggest that healthy individuals engage the right ventrolateral prefrontal cortex when processing negative facial expressions, possibly reflecting more inhibition of the dorsal anterior cingulate cortex than methamphetamine-dependent individuals. This heightened limbic sensitivity, and/or failure to regulate it, could contribute to socially inappropriate behaviors, such as violence and aggression, in those who abuse methamphetamine. More recently, we specifically asked whether methamphetamine-dependent subjects have a deficit in the ability of the prefrontal cortex to down-regulate the amygdala in response to emotional activation (Payer et al., 2008b). We used an fMRI paradigm in which verbal labeling of emotional facial expressions produced unintentional down-regulation of amygdala activity (Lieberman et al., 2007). Verbal labeling failed both to activate prefrontal cortex and to down-regulate amygdala activity in methamphetaminedependent women, while healthy women showed these effects. Using a test of psychophysiological interaction, healthy women also showed greater functional connectivity between prefrontal cortex and amygdala during affect labeling, consistent with the view that during the regulation of emotion by semantic labeling, an important mechanism for talking
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psychotherapies, methamphetaminedependent women are deficient in prefrontal cortical inhibition of the amygdala. 5. Summary The studies described above, as well as others which are beyond the scope of this lecture, have provided visual evidence that addiction is a brain disease. They have demonstrated a role of dopamine in the positive subjective responses to drugs of abuse and in craving. In addition, they have provided a fundamental understanding of the circuitry that mediates drug craving as well as negative affective states in addicts. Lastly, they have begun to show how inhibitory control during cognitive and emotional processing involves corticolimbic circuitry that may be an important target for treatment of drug abuse. This overview of how technology has advanced our knowledge of human addiction represents strong collaborative interactions between scientists trained in a variety of disciplines and across generations. I am indebted to my colleagues at the Intramural Research Program of NIDA and, for the past ten years, at UCLA for contributing to the work presented, and to NIDA for supporting our efforts. References Aron, A.R., Robbins, T.W., Poldrack, R.A., 2004. Inhibition and the right inferior frontal cortex. Trends Cogn Sci 8, 170–177. Belliveau, J.W., Kennedy Jr., D.N., McKinstry, R.C., Buchbinder, B.R., Weisskoff, R.M., Cohen, M.S., Vevea, J.M., Brady, T.J., Rosen, B.R., 1991. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254, 716–719. Bonson, K.R., Grant, S.J., Contoreggi, C.S., Links, J.M., Metcalfe, J., Weyl, H.L., Kurian, V., Ernst, M., London, E.D., 2002. Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26, 376–386. Breiter, H.C., Gollub, R.L., Weisskoff, R.M., Kennedy, D.N., Makris, N., Berke, J.D., Goodman, J.M., Kantor, H.L., Gastfriend, D.R., Riorden, J.P., Mathew, R.T., Rosen, B.R., Hyman, S.E., 1997. Acute effects of cocaine on human brain activity and emotion. Neuron 19, 591–611. Brody, A.L., Mandelkern, M.A., London, E.D., Childress, A.R., Lee, G.S., Bota, R.G., Ho, M.L., Saxena, S., Baxter, L.R., Madsen, D., Jarvik, M.E., 2002. Brain metabolic changes during cigarette craving. Arch. Gen. Psychiatry 59, 1162–1172. Brody, A.L., Mandelkern, M.A., Olmstead, R.E., Scheibal, D., Hahn, E., Shiraga, S., Zamora-Paja, E., Farahi, J., Saxena, S., London, E.D., McCracken, J.T., 2006. Gene variants of the brain dopamine reward pathway determine smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch. Gen. Psychiatry 63, 808–816. Brody, A.L., Olmstead, R.E., London, E.D., Farahi, J., Meyer, J.H., Grossman, P., Lee, G.S., Huang, J., Hahn, E., Mandelkern, M.A., 2004. Smoking-induced ventral striatal dopamine release. Am. J. Psychiatry 161, 1211–1218. Brownell, G.L., 1999. A History of Positron Imaging. http://www.mit.edu/∼glb.
E.D. London / Drug and Alcohol Dependence 100 (2009) 182–185 Childress, A.R., Mozley, P.D., McElgin, W., Fitzgerald, J., Reivich, M., O’Brien, C.P., 1999. Limbic activation during cue-induced cocaine craving. Am. J. Psychiatry 156, 11–18. Cohen, J.B., Dickow, A., Horner, K., Zweben, J.E., Balabis, J., Vandersloot, D., Reiber, C., 2003. Abuse and violence history of men and women in treatment for methamphetamine dependence. Am. J. Addict. 12, 377–385. Cretzmeyer, M., Sarrazin, M.V., Huber, D.L., Block, R.I., Hall, J.A., 2003. Treatment of methamphetamine abuse: research findings and clinical directions. J. Subst. Abuse Treat. 24, 267–277. Damadian, R., 1971. Tumor detection by nuclear magnetic resonance. Science 171, 1151–1153. Di Chiara, G., Imperato, A., 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl. Acad. Sci. U.S.A. 85, 5274–5278. Fanelli, R.F., Szikszay, M., Jasinski, D.R., London, E.D., 1987. Differential effects of mu and kappa opioid analgesics on cerebral glucose utilization in the rat. Brain Res. 422, 257–266. Grannell, P.K., Mansfield, P., 1975. Microscopy in vivo by nuclear magnetic resonance. Phys. Med. Biol. 20, 477–482. Grant, S., London, E.D., Newlin, D.B., Villemagne, V.L., Liu, X., Contoreggi, C., Phillips, R.L., Kimes, A.S., Margolin, A., 1996. Activation of memory circuits during cue-elicited cocaine craving. Proc. Natl. Acad. Sci. U.S.A. 93, 12040–12045. Hall, W., Hando, J., Darke, S., Ross, J., 1996. Psychological morbidity and route of administration among amphetamine users in Sydney, Australia. Addiction 91, 81–87. Heidbreder, C.A., Groenewegen, H.J., 2008. The medial prefrontal cortex in the rat: evidence for a dorsoventral distinction based upon functional and anatomical characteristics. J. Neurosci. Methods 169, 109–118. Hoffman, E.J., Phelps, M.E., Mullani, N.K., Higgins, C.S., Ter-Pogossian, M.M., 1976. Design and performance characteristics of a whole body transaxial tomograph. J. Nucl. Med. 1, 493–502. Ido, T., Wan, C.-N., Casella, V., Fowler, J.S., Wolf, A.P., Reivich, M., Kuhl, D.E., 1978. Labeled 2-deoxyD-glucose analogs. 18F-labeled 2-deoxy-2-fluoroD-glucose, 2-deoxy-2-fluoro-D-mannose and C14-2-deoxy-2-fluoro-D-glucose. J. Labell. Comp. Radiopharm 14, 175–182. Kilts, C.D., Schweitzer, J.B., Quinn, C.K., Gross, R.E., Faber, T.L., Muhammad, F., Ely, T.D., Hoffman, J.M., Drexler, K.P., 2001. Neural activity related to drug craving in cocaine addiction. Arch. Gen. Psychiatry 58, 334–341. Kimes, A.S., London, E.D., 1989. Glucose utilization in the rat brain during chronic morphine treatment & naloxone-precipitated morphine withdrawal. J. Pharmacol. Exp. Ther. 248, 538–545. Koob, G.F., Bloom, F.E., 1988. Cellular and molecular mechanism of drug dependence. Science 242, 715–723. Lauterbur, P.C., 1973. Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature 242, 190–191. Lieberman, M.D., Eisenberger, N.I., Crockett, M.J., Tom, S.M., Pfeifer, J.H., Way, B.M., 2007. Putting feelings into words: affect labeling disrupts amygdala activity in response to affective stimuli. Psychol. Sci. 8, 421–428. London, E.D., 1989. The effects of drug abuse on glucose metabolism. J. Neuropsychiatry Clin. Neurosci. 1 (Suppl. I), S30–S36. London, E.D., Broussolle, E.P.M., Links, J.M., Wong, D.F., Cascella, N.G., Dannals, R.F., Sano, M., Herning, R., Snyder, F.R., Rippetoe, L.R., Toung, T.J.K., Jaffe, J.H., Wagner Jr., H.N., 1990a. Morphineinduced metabolic changes in human brain. Studies with positron emission tomography and [18 F]-fluorodeoxyglucose. Arch. Gen. Psychiatry 47, 73–81. London, E.D., Cascella, N.G., Wong, D.F., Phillips, R.L., Dannals, R.F., Links, J., Herning, R., Grayson, R., Jaffe, J.H., Wagner Jr., H.N., 1990b. Cocaine-
induced reduction of glucose utilization in human brain. A study using positron emission tomography and [18 F]-fluorodeoxyglucose. Arch. Gen. Psychiatry 47, 567–574. London, E.D., Connolly, R.J., Szikszay, M., Wamsley, J.K., Dam, M., 1988. Effects of nicotine on local cerebral glucose utilization in the rat. J. Neurosci. 8, 3920–3928. London, E.D., Kimes, A.S., Fanelli, R.J., 1987. Cerebral metabolic effects of morphine in the rat. Substance Abuse 8, 43–52. London, E.D., Simon, S.L., Berman, S.M., Mandelkern, M.A., Lichtman, A.M., Bramen, J., Shinn, A.K., Miotto, K., Learn, J., Dong, Y., Matochik, J.A., Kurian, V., Newton, T., Woods, R., Rawson, R., Ling, W., 2004. Mood disturbances and regional cerebral metabolic abnormalities in recent methamphetamine abusers. Arch. Gen. Psychiatry 61, 73–84. London, E.D., Wilkerson, G., Goldberg, S.R., Risner, M.E., 1986. Effects of l-cocaine on local cerebral glucose utilization in the rat. Neurosci. Lett. 68, 73–78. Lyons, D., Friedman, D.P., Nader, M.A., Porrino, L.J., 1996. Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J. Neurosci. 16, 1230–1238. Maas, L.C., Lukas, S.E., Kaufman, M.J., Weiss, R.D., Daniels, S.L., Rogers, V.W., Kukes, T.J., Renshaw, P.F., 1998. Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. Am. J. Psychiatry 155, 124–126. Maxwell, J.C., 2005. Emerging research on methamphetamine. Curr. Opin. Psychiatry 18, 235–242. Monterosso, J.R., Aron, A.R., Cordova, X., Xu, J., London, E.D., 2005. Deficits in response inhibition associated with chronic methamphetamine abuse. Drug. Alcohol. Depend. 79, 273–277. Monterosso, J., Tabibnia, G., Chakrapani, S., Lee, B., Aron, A.R., Azizian, A., London, E.D., 2007. Does higher gray matter density in right inferior frontal gyrus predict better stop signal reaction time? Voxel-based morphometry in methamphetamine-dependent and healthy comparison subjects. In: Soc. Neurosci., Nov. 3–7, San Diego, CA. Naqvi, N.H., Rudrauf, D., Damasio, H., Bechara, A., 2007. Damage to the insula disrupts addiction to cigarette smoking. Science 315, 531–534. Ogawa, S., Lee, T.M., Kay, A.R., Tank, D.W., 1990. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc. Natl. Acad. Sci. U.S.A. 87, 9868–9872. Payer, D.E., Lieberman, M.D., Monterosso, J.R., Xu, J., Fong, T.W., London, E.D., 2008a. Differences in cortical activity between methamphetaminedependent and healthy individuals performing a facial affect matching task. Drug. Alcohol. Depend. 93, 93–102. Payer, D., Lieberman, M.D., Zorick, T., London, E.D., 2008b. Differences in brain correlates of emotion regulation between methamphetaminedependent and healthy men and women. In: Soc. Neurosci., Nov. 15–19, Washington, DC. Porrino, L.J., Domer, F.R., Crane, A.M., Sokoloff, L., 1988. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats. Neuropsychopharmacology 1, 109–118. Reivich, M., Kuhl, D., Wolf, A., Greenberg, J., Phelps, M., Ido, T., Cascella, V., Fowler, J., Hoffman, E., Alavi, A., Som, P., Sokoloff, L., 1979. The [18 F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ. Res. 44, 127–137. Scott, D.J., Domino, E.F., Heitzeg, M.M., Koeppe, R.A., Ni, L., Guthrie, S., Zubieta, J.K., 2007. Smoking modulation of mu-opioid and dopamine D2 receptor-mediated neurotransmission in humans. Neuropsychopharmacology 32, 450–457. Sokoloff, L., Reivich, M., Kennedy, C., Des Rosiers, M.H., Patlak, C.S., Pettigrew, K.D., Sakurada, O., Shinohara, M., 1977. The [14 C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in
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185 Weissman, A.D., Dam, M., London, E.D., 1987. Alterations in local cerebral glucose utilization induced by phencyclidine. Brain Res. 435, 29–40. Wong, D.F., Kuwabara, H., Schretlen, D., Bonson, K., Zhou, Y., Nandi, A., Brasic, J., Kimes, A.S., Kumar, A., Contoreggi, C., Links, J., Ernst, M., Rousset, O., Zukin, S., Grace, A., Rohde, C., Jasinski, D., London, E.D., 2006. Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving. Neuropsychopharmacology 31, 2716–2727 (Erratum: Neuropsychopharmacology 32, 256. J.S. Lee added as co-author).
Contents lists available at ScienceDirect
Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep
CPDD News and views
Studying addiction in the age of neuroimaging Marian W. Fischman lecture given at the 2008 meeting of CPDD夽 Edythe D. London ∗ Semel Institute of Neuroscience and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, United States
My talk today is about the discoveries that have come from my own work and that of others who have used brain imaging techniques over the past 30 years to understand the neural basis of drug addiction. Brain imaging allows us to relate drug actions to feelings, cognition, and the function of specific neural circuits. Such information is critical for our ability to develop rational therapies for addiction. 1. Development of brain imaging technologies The period of time from the midseventies to the present has been filled with transformative advances in brain imaging that moved forward the field of drug abuse research. The technique of positron emission tomography (PET), which allows noninvasive molecular imaging, was largely advanced in the 1970s, with the PET III built in 1974 after several prototypes (Hoffman et al., 1976). This work followed many decades of developments in positron imaging that included contributions of many individuals (see Brownell, 1999 for a historical review). Roughly simultaneously with the appearance of a commercial unit for human PET, the 2-deoxyglucose technique was developed, introducing metabolic mapping through measurement of rates of glucose metabolism throughout the brain (Sokoloff et al., 1977). The method was soon adapted for human studies following the synthesis of the radiotracer [18 F]fluorodeoxyglucose
夽 Supported in part by: P20DA022539, R01DA020726, and RL1DA024853. ∗ Tel.: +1 310 825 0606; fax: +1 310 825 0812. E-mail address: [email protected]. 0376-8716/$ – see front matter doi:10.1016/j.drugalcdep.2008.09.003
in 1976 (Ido et al., 1978), with the first human studies using this tracer performed in 1979 (Reivich et al., 1979). Metabolic mapping was then joined by PET neuroreceptor mapping, introduced in 1983, with the use of [11 C]N-methylspiperone (Wagner et al., 1983). Parallel to these developments in molecular imaging, another series of technological advances followed the discovery of magnetic resonance imaging (MRI) (Damadian, 1971; Lauterbur, 1973; Grannell and Mansfield, 1975). Achievements in this area included introduction of the Blood-Oxygen-Level-Dependent (BOLD) contrast method (Ogawa et al., 1990) and its application to studies of the human brain (Belliveau et al., 1991). These tools enabled many discoveries about the different factors that maintain addiction, including positive reinforcement, drug craving, negative affective states reinforcement, and dysfunction of inhibitory control systems. 2. Positive reinforcement, functional mapping and dopamine Studies on the acute effects of drugs of abuse on brain function were inspired by the knowledge that these drugs in general produce a positive affective state that reinforces their self-administration. PET imaging, with the 2-deoxyglucose method, was first applied in human studies of drug abuse after the responses to drugs of abuse were mapped in the rat brain (e.g., Fanelli et al., 1987; Kimes and London, 1989; London et al., 1987, 1988; London, 1989; Porrino et al., 1988; Weissman et al., 1987). In the first studies of humans, acute administration of morphine and cocaine, at euphorigenic doses, reduced cerebral
glucose metabolism globally with substantial cortical effects (London et al., 1990a,b), unlike the pattern of primarily subcortical effects that had been observed in rats (London et al., 1986). Cortical decrements in glucose metabolism, particularly in limbic cortex were also observed in monkeys (Lyons et al., 1996). Superimposed on the global reductions in cerebral glucose metabolism demonstrated using 2-deoxyglucose with PET, the BOLD fMRI method, which provides a finer time resolution, also revealed focal signal increases in many cortical and subcortical regions. Focal signal increases were demonstrated in pons, ventral tegmentum, thalamus, nucleus accumbens/subcallosal areas, caudate, putamen, basal forebrain, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal, temporal, parietal, and striate/extrastriate cortices, and focal signal decreases were noted in amygdala, temporal pole, and medial frontal cortex (Breiter et al., 1997). Animal studies have provided ample evidence that reward from selfadministration of drugs of abuse is due to dopamine release (Di Chiara and Imperato, 1988; Koob and Bloom, 1988). Studies using PET in human volunteers have extended this work, using [11 C]raclopride, a radiotracer that binds to D2-like dopamine receptors. For example, intravenous methylphenidate administration produces a decrease in striatal radiotracer binding (presumably due to competition by increased intrasynaptic dopamine) related to the subject’s self-report of being “high” (Volkow et al., 2004). Striatal dopamine release has also been demonstrated in human subjects after cigarette smoking (Brody et al., 2004; Scott et al., 2007); and this effect is under genetic control, as
E.D. London / Drug and Alcohol Dependence 100 (2009) 182–185
smokers who had at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype exhibited greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes (Brody et al., 2006). 3. Craving, corticolimbic circuits and dopamine Both functional and molecular neuroimaging studies have provided substantial information on the neural substrates of drug craving. Studies with [18 F]fluorodeoxyglucose (e.g., Grant et al., 1996; Bonson et al., 2002), [15 O]water (e.g., Childress et al., 1999; Kilts et al., 2001), and fMRI (e.g., Maas et al., 1998) allowed whole brain analyses of changes in brain activity associated with drug craving. In the first of these studies, exposure to cocainerelated cues led to increases in glucose metabolism of cortical areas, including the dorsolateral prefrontal cortex, the medial orbitofrontal cortex, and the temporal lobe (Grant et al., 1996). Cue-induced cocaine craving was also correlated with increase in glucose metabolism in the medial temporal lobe (amygdala), dorsolateral prefrontal cortex, and cerebellum. The findings suggest that a distributed neural network that integrates emotion with memory may link environmental cues to cocaine craving. Subsequent studies supported and extended these findings (e.g., Bonson et al., 2002; Childress et al., 1999; Kilts et al., 2001; Maas et al., 1998), including correlations of cue-induced cocaine craving with the change in glucose metabolism in the insula and orbitofrontal cortex (Bonson et al., 2002). Similar studies with drugs of abuse other than cocaine included studies of cigarette craving, in which craving was correlated with change in glucose metabolism in the insula and orbitofrontal cortex (Brody et al., 2002). Notably, the finding in the insula has gained special importance after observations that insula damage (through stroke) disrupted addiction to cigarette smoking (Naqvi et al., 2007). While reductions in striatal [11 C]raclopride binding (an indirect marker for dopamine release) have been implicated in drug-induced reward, such changes have also been related to craving for cocaine, induced by the presentation of cocaine-related visual cues (Volkow et al., 2006; Wong et al., 2006). In one study, the change in dopamine-receptor occupancy in the dorsal striatum was
highly correlated with craving for cocaine (Wong et al., 2006). Thus, imaging studies of cue-induced drug craving demonstrated a relationship to dopamine release, involvement of corticolimbic circuitry, and commonalities across drugs of abuse. 4. Negative affect and inhibitory control Aside from drug craving, another factor that influences and maintains addiction in some individuals is negative affect. In this regard, stimulant abusers who meet DSM-IV criteria for methamphetamine dependence show significant differences from healthy comparison subjects with respect to depressive symptoms and anxiety (London et al., 2004). Methamphetamine-dependent subjects, abstinent from illicit drugs of abuse for 4–7 days, also exhibit an abnormal pattern of cerebral glucose metabolism, including remarkably high relative activity in the amygdala and low activity in the medial prefrontal cortex. While activity in the prefrontal cortex, including the subgenual area, is inversely related to self-reported anxiety (low activity with high anxiety), activity in amygdala is positively correlated with self-reports of both anxiety and depression. In view of animal studies showing anatomical and functional links between function of the medial prefrontal cortex and amygdala (Heidbreder and Groenewegen, 2008), the pattern of abnormality in cerebral glucose metabolism in methamphetamine-dependent subjects is consistent with a loss of prefrontal inhibitory control. Such a deficit is in line with the view that addiction is maintained, in part or in some individuals, by impaired inhibitory control mechanisms. Impaired inhibition may contribute to an addicted individual’s failure to maintain desired abstinence, or to using more drug than intended. Although the relevance to drug-taking in the real world has not been well established, cognitive tasks are used in the laboratory to evaluate addicted individuals on several aspects of inhibitory control, such as motor-response inhibition (assessed by go/no go tasks, such as the Stop-Signal Task), ability to shift set (assessed by reversal learning tasks), and decision-making (assessed by delay discounting tasks and tests of risk-taking). In general, drug-abusing samples manifest impairments. For example, participants who have abused methamphetamine chronically exhibit a deficit in stopping ability on the Stop-Signal Task (Monterosso et al., 2005). Notably, performance on this task is linked to the integrity of the right lateral prefrontal cortex (Aron
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et al., 2004), where methamphetamine abusers exhibit gray matter volume deficits (Thompson et al., 2004; Monterosso et al., 2007). In addition to the aforementioned deficits in mood, cortical deficits and their contribution to impairing inhibitory circuits may contribute to other socially maladaptive behaviors observed in methamphetamine abusers, including hostility, aggression, and unmotivated violence (Cretzmeyer et al., 2003; Cohen et al., 2003; Hall et al., 1996; Maxwell, 2005). We therefore applied fMRI to studying the processing of emotional facial expressions (highly salient social cues) by methamphetamine-dependent subjects during early abstinence (Payer et al., 2008a). Methamphetamine-dependent subjects did not differ from a healthy control group in performance of a facematching task, while exhibiting less task-related activity in several cortical regions (i.e., ventrolateral prefrontal cortex, temporoparietal junction, anterior and posterior temporal cortex, and fusiform gyrus in the right hemisphere, and the cuneus in the left hemisphere) while showing more task-related activity in the dorsal anterior cingulate cortex and giving higher self-reports of interpersonal sensitivity. These data suggest that healthy individuals engage the right ventrolateral prefrontal cortex when processing negative facial expressions, possibly reflecting more inhibition of the dorsal anterior cingulate cortex than methamphetamine-dependent individuals. This heightened limbic sensitivity, and/or failure to regulate it, could contribute to socially inappropriate behaviors, such as violence and aggression, in those who abuse methamphetamine. More recently, we specifically asked whether methamphetamine-dependent subjects have a deficit in the ability of the prefrontal cortex to down-regulate the amygdala in response to emotional activation (Payer et al., 2008b). We used an fMRI paradigm in which verbal labeling of emotional facial expressions produced unintentional down-regulation of amygdala activity (Lieberman et al., 2007). Verbal labeling failed both to activate prefrontal cortex and to down-regulate amygdala activity in methamphetaminedependent women, while healthy women showed these effects. Using a test of psychophysiological interaction, healthy women also showed greater functional connectivity between prefrontal cortex and amygdala during affect labeling, consistent with the view that during the regulation of emotion by semantic labeling, an important mechanism for talking
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psychotherapies, methamphetaminedependent women are deficient in prefrontal cortical inhibition of the amygdala. 5. Summary The studies described above, as well as others which are beyond the scope of this lecture, have provided visual evidence that addiction is a brain disease. They have demonstrated a role of dopamine in the positive subjective responses to drugs of abuse and in craving. In addition, they have provided a fundamental understanding of the circuitry that mediates drug craving as well as negative affective states in addicts. Lastly, they have begun to show how inhibitory control during cognitive and emotional processing involves corticolimbic circuitry that may be an important target for treatment of drug abuse. This overview of how technology has advanced our knowledge of human addiction represents strong collaborative interactions between scientists trained in a variety of disciplines and across generations. I am indebted to my colleagues at the Intramural Research Program of NIDA and, for the past ten years, at UCLA for contributing to the work presented, and to NIDA for supporting our efforts. References Aron, A.R., Robbins, T.W., Poldrack, R.A., 2004. Inhibition and the right inferior frontal cortex. Trends Cogn Sci 8, 170–177. Belliveau, J.W., Kennedy Jr., D.N., McKinstry, R.C., Buchbinder, B.R., Weisskoff, R.M., Cohen, M.S., Vevea, J.M., Brady, T.J., Rosen, B.R., 1991. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254, 716–719. Bonson, K.R., Grant, S.J., Contoreggi, C.S., Links, J.M., Metcalfe, J., Weyl, H.L., Kurian, V., Ernst, M., London, E.D., 2002. Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26, 376–386. Breiter, H.C., Gollub, R.L., Weisskoff, R.M., Kennedy, D.N., Makris, N., Berke, J.D., Goodman, J.M., Kantor, H.L., Gastfriend, D.R., Riorden, J.P., Mathew, R.T., Rosen, B.R., Hyman, S.E., 1997. Acute effects of cocaine on human brain activity and emotion. Neuron 19, 591–611. Brody, A.L., Mandelkern, M.A., London, E.D., Childress, A.R., Lee, G.S., Bota, R.G., Ho, M.L., Saxena, S., Baxter, L.R., Madsen, D., Jarvik, M.E., 2002. Brain metabolic changes during cigarette craving. Arch. Gen. Psychiatry 59, 1162–1172. Brody, A.L., Mandelkern, M.A., Olmstead, R.E., Scheibal, D., Hahn, E., Shiraga, S., Zamora-Paja, E., Farahi, J., Saxena, S., London, E.D., McCracken, J.T., 2006. Gene variants of the brain dopamine reward pathway determine smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch. Gen. Psychiatry 63, 808–816. Brody, A.L., Olmstead, R.E., London, E.D., Farahi, J., Meyer, J.H., Grossman, P., Lee, G.S., Huang, J., Hahn, E., Mandelkern, M.A., 2004. Smoking-induced ventral striatal dopamine release. Am. J. Psychiatry 161, 1211–1218. Brownell, G.L., 1999. A History of Positron Imaging. http://www.mit.edu/∼glb.
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