Alcohol and Alcoholism Advance Access originally published online on February 16, 2007
Alcohol and Alcoholism 2007 42(5):417-422; doi:10.1093/alcalc/agl117
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Brain substrates of craving to alcohol cues in subjects with alcohol use disorder
1 Department of Psychology, Brain Research Institute, Chungnam National University, Daejeon, South Korea
2 Army Substance Abuse Program, US Army, South Korea
3 School of Social Work, University of Texas Austin, TX, USA
* Author to whom correspondence should be addressed at: Jin-Hun Sohn, Department of Psychology, Chungnam National University, Daejeon, 305-764, South Korea, Tel: +82 42 821 6369; Fax: +82 42 821 8875; E-mail: jhsohn{at}cnu.ac.kr
Received 24 November 2006; ; accepted 6 December 2006
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ABSTRACT |
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Aims: This study's purpose was to identify the neural substrates and mechanisms responsible for craving among subjects with alcohol use disorders (AUDs) using functional magnetic resonance imaging (fMRI). Methods: Alcohol abusers with AUD (n = 9) and demographically similar non-abusers (n = 9) participated in this study. After given 5 cc of alcohol, subjects were exposed to different types of stimuli [i.e. alcohol, non-alcoholic beverage, and visual control pictures and one rest (cross-hair)]. Craving levels were rated through self-report on a Likert scale immediately after the presentation of visual cues. Results: Brain activations in the fusiform gyri, temporal gyri, parahipocampal gyrus, uncus, frontal gyri, and precuneus were correlated with the level of craving among subjects with AUD in response to alcohol cues. Conclusions: In conclusion, specific brain regions were identified that are associated with craving among subjects with AUD.
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Introduction |
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Alcohol and other drug abuse facilitate dopamine release in the ventral striatum which includes the nucleus accumbens, a core region of the brain reward system (Heinz et al., 2004
). Neurons located in the nucleus accumbens extend to both the amygdala and the frontal cortex areas (Anton, 1999). One of the frontal cortex areas is the dorsolateral prefrontal cortex (DLPFC) where the reward memory of alcohol use is thought to be located (Kalivas et al., 1998). Situations or stimuli previously associated with alcohol use may activate the reward system and induce craving (Anton, 1999). Since craving plays a role to trigger compulsive drug/substance use among active users and relapse among those in recovery there is a need for improved understanding of underlying neurobiological mechanisms (Schneider et al., 2001).
Neuroimaging techniques, e.g. functional magnetic resonance imaging (fMRI) and PET, have helped to identify the brain regions associated with craving. It has been known that viewing cocaine images is associated with a relative increase in regional brain activity (Grant et al., 1996; Breiter et al., 1997; Childress et al., 1999). Brain regions known to be involved in reward (the nucleus accumbens), arousal (the medial temporal lobes, cingulate gyrus), memory (the DLPFC), and sensory integration (thalamus) were activated during the exposure to cocaine cues.
Relatively few studies to date have identified the brain areas associated with alcohol craving. Modell and Mountz (1995) reported increased blood flow in the right caudate nucleus during a craving condition in alcoholics. George et al. (2001) evaluated regional brain activity in both alcoholics and social drinkers using both taste and visual cues. Alcoholics had increases in brain activation in the anterior thalamus and left DLPFC, while the social drinkers did not. Recently, Tapert et al. (2003) identified the relationship between a self-reported desire to drink and brain response using visual cues in adolescents with alcohol use disorder (AUD). They found a strong desire for drinking to be associated with both left temporal and right thalamic responses. Myrick et al. (2004) reported activation on the prefrontal cortex and anterior limbic regions in alcoholics during exposure to alcohol cues. These studies identified the differences in brain activation areas between the two groups, alcoholics and the control group. However, reported results were inconsistent. A more recent study by Myrick et al. (2004) reported a positive correlation between the level of craving and brain activations. Brain activations in the left nucleus accumbens, the anterior cingulate and the left orbitofrontal cortex were correlated positively with cravings in alcoholics.
Initially, we examined differences in craving and brain activations between AUDs and non-alcoholic control subjects when exposed to a variety of visual alcohol cues.
Secondly, using the methodology of the Myrick et al. (2004) study, this study was conducted to extend the results of these earlier researchers to include both alcoholics and alcohol abusers.
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Methods |
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Participants
Eighteen right-handed never married male and female college students participated in the study: nine were diagnosed with AUD [i.e. DSM-IV (American Psychiatric Association, 1994) criteria for alcohol abuse or dependence]. The Korean version of Alcohol Use Disorders Identification Test (AUDIT-K) (Lee, 2000
), National Alcoholism Screening Test (NAST) (Kim et al., 1991), and a Structured Clinical Interview based on the DSM-IV (Hahn et al., 2000) were administered to evaluate substance use among alcoholic subjects. Based on AUDIT-K and NAST results, all alcoholic subjects met the DSM-IV criteria for AUDs. A score >15 points on the AUDIT-K is considered sufficient to meet the DSM-IV criteria for AUDs (Park et al., 2000). A positive response to more than one item on the NAST is considered sufficient to meet DSM-IV criteria for AUDs (Park et al., 2000). The control group was composed of nine subjects who were demographically similar, having no previous history of substance use disorder (Table 1).
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All the participants were screened to rule out other psychiatric or co-occurring mental disorders using self-report and mental health history. The exclusion criteria incorporated any history of a serious head injury, serious medical problems, neurological disorders, Axis I psychiatric disorders other than AUD, and the current use of psychotropic medication. The complete procedure was explained to all subjects prior to execution. All subjects signed the participation consent forms and were required to be alcohol-free 24 h prior to fMRI scanning. The experimental procedure was comprehensively reviewed and conducted in strict compliance with the Institutional Review Committee.
Stimuli
Alcoholic picture cues were selected from the Normative Appetitive Picture System (NAPS; Breiner et al., 1995). To avoid the duplication of visual cues, 12 additional pictures were needed to supplement the original 11 pictures. Additional images were selected and downloaded from website advertisements. Those images consisted of Korean beer and mild liquor. These additional images were then pre-tested to assure a craving response could be produced. Pictures with non-alcoholic theme were selected from the NAPS. Control pictures were duplications of liquor pictures with blurred distortions for the subjects not to perceive any objects in the pictures but gaze at the picture stimuli. These distortions were made to match the alcohol picture cues in both colour and hue with non-recognizable alcohol cues. This was done in order to identify continued brain activity based solely on alcohol-associated cues by ruling out the activity resulting from visual effects, e.g. colour or hue.
Procedures
Once subjects arrived, they were individually instructed on the experimental procedure they would be expected to follow. Prior to cue exposure, they were asked to rate their craving level using the Obsessive Compulsive Drinking Scale (OCDS) (Choi et al., 2002) and a one-item Likert scale (range from 1 to 7 points). Prior to entering the scanner room, subjects practiced the procedure exactly in the same manner as was expected while in the scanner. Then, they were given 5 cc of alcohol (negligible blood alcohol levels) and were asked again to rate their level of craving using only the Likert scale.
The stimulus period was 9 min long and consisted of six separate runs through the cue sequence as shown in Figure 1. Four blocks of visual cues were contained in a single run. The four blocks of visual cues in a run were associated with alcohol, non-alcoholic beverage, and visual control pictures and one rest (cross-hair). One block had four individual pictures, with a visual exposure period of 18 s for each block presentation. Blocks were counterbalanced to control time and order effects across subjects. Subjects were again given 6 s to rate their craving levels after each block.
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The stimulus was created in the Streamdx 1.0 (KAIST, Korea) and then projected onto a screen using a mirror. After each block, subjects were instructed to rate their level of craving in real time during visual exposure. Subjects did this by indicating the appropriate point on the 1–7 scale with a computer mouse.
Imaging parameters
Imaging was conducted on a 3.0 T whole-body ISOL Technology FORTE scanner (ISOL Technology, Korea) equipped with whole-body gradients and a quadrature head coil. Single-shot echo-planar fMRI scans were acquired in 35 continuous slices, parallel to the anterior commissure–posterior commissure line. The parameters for fMRI include the following: the repetition time/echo time [TR/TE] were 3000/30 ms, respectively, flip angle 80, field of view 240 mm, matrix 64 x 64, slice thickness 4 mm, and in-plane resolution 3.75 mm. Three dummy scans from the beginning of the run were excluded to decrease the effect of non-steady state longitudinal magnetization. T1-weighted anatomic images were obtained with a 3-D FLAIR sequence (TR/TE = 280/14 ms, flip angle = 60, FOV = 240 mm, matrix = 256 x 256, slice thickness = 4 mm).
Data analysis
The fMRI data were analysed with SPM99 (Wellcome Department of Cognitive Neurology, London, UK). All functional images were realigned with the image taken proximate to the anatomical study by using affine transformation routines built into SPM99. The realigned scans were co-registered to the participant's anatomical images obtained within each session, and normalized to SPM99's template image that uses the space defined by the Montreal Neurologic Institute, which is very similar to the Talairach and Tournoux's (1988) atlas. Motion correction was done using Sinc interpolation. Time series data were filtered with 240 s high-pass filter, to remove artefacts due to cardio-respiratory and other cyclical influences. The functional map was smoothened with a 7 mm isotropic Gaussian kernel prior to statistical analysis. Statistical analysis was done individually and as a group using the general linear model and the theory of Gaussian random fields implemented in SPM99. Using the subtraction procedure, activated areas in the brain during alcoholic beverage pictures compared to non-alcoholic beverage pictures were colour-coded by t-score. The double subtraction method was used to test the effect of difference between two groups (i.e. the AUD group vs control group).
Finally, regression between craving scores and brain activity measured during the alcohol pictures in the AUD group was performed to investigate if brain activity significantly correlated with the levels of craving. Finally, regression analysis between craving scores and brain activity in response to alcohol-related visual cues in the AUD group was performed to investigate a possible correlation with craving levels.
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Results |
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Behavioural results
Table 2 shows the OCDS score and the mean levels of pre-and post-sip alcohol craving in each group. The independent t-test showed a statistically significant difference between two groups in the OCDS scores, pre-sip and post-sip alcohol craving. Figure 2 illustrates the levels of craving while in the scanner when the AUD and control subjects were exposed to alcoholic beverage pictures, non-alcoholic beverage pictures, visual control pictures, and cross-hair. The AUD group showed significantly higher levels of craving during visual cues.
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fMRI results
To identify brain areas generated by alcohol cues, we directly compared brain activation during exposure to alcohol cues to that of beverage cues. In this comparison, we were able to subtract brain activation generated by the neutral (control) beverage cues from brain activation generated by the alcohol cues. Theoretically, the remaining brain activation areas are considered to be related to the alcohol-specific content of the pictures (George et al., 2001
). Figure 3 illustrates brain areas significantly activated in the AUD group and control group during exposure to alcohol cues compared to beverage cues. In the AUD group, significant activation was observed in the left cingulate gyrus, bilateral inferior parietal lobe, left superior temporal gyrus, right middle frontal gyrus, right fusiform gyrus, right medial frontal gyrus, right posterior cingulate, and left insula. In the control group, only the right culmen in the cerebellum was significantly activated (corrected P < 0.05).
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Figure 4 reveals the contrasting effects between the AUD and control groups using the double subtraction method. These areas include the right medial frontal gyrus and right inferior parietal lobe in the AUD group compared to the control group. Significant activation was observed in the right posterior cingulate and right culmen in the control group when compared with that of the AUD group (corrected P < 0.05).
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Figure 5 shows brain areas correlated with the level of craving among AUD subjects in response to the alcohol cues. Significant activation was shown in the bilateral fusiform gyri, bilateral lingual gyri, right middle temporal gyrus, left inferior temporal gyrus, left parahippocampal gyrus, left postcentral gyrus, left precentral gyrus, right uncus, right paracentral, right superior frontal gyrus, bilateral middle frontal gyri, bilateral superior temporal gyri, and left precuneus (corrected P < 0.05). The Talairach coordinates and t-scores of each activated area are shown in Table 3.
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Discussion |
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TOPABSTRACTIntroductionMethodsResultsDiscussionReferences |
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The purpose of the study was to find the brain substrates associated with craving in subjects with AUD. After exposure to alcohol cues, brain activations were examined in both AUD and control subjects via fMRI. Also after exposure, craving responses of both AUD and control subjects were compared.
Analysis of the behavioural data showed comparisons between the mean level of craving reported by AUD subjects to be significantly higher than that reported by control subjects after exposure to alcohol cues. These results support the concept that exposure to environmental stimuli associated with drinking (such as pictures, smells, and places of ingestion) can strongly stimulate the urge or desire to consume alcohol in alcohol-dependent individuals (Myrick et al., 2004).
Activation was significantly greater in AUD subjects than control subjects in the frontal cortex, limbic regions, and other brain areas during exposure to alcohol cues in comparison to beverage cues. Consistent with this study, a number of previous neuroimaging studies using cue stimulation identified the areas of brain activation. The brain areas known to be activated when exposed to cue stimulation of cocaine, opiates, nicotine, or alcohol include the cingulate gyrus (Breiter et al., 1997; Myrick et al., 2004), parietal lobe (Grant et al., 1996; Breiter et al., 1997; Garavan et al., 2000), temporal gyrus (Grant et al., 1996; Breiter et al., 1997; Garavan et al., 2000; Schneider et al., 2001), frontal gyrus (Grant et al., 1996; Breiter et al., 1997; Garavan et al., 2000; George et al., 2001), fusiform gyrus (Braus et al., 2001), posterior cingulate (Garavan et al., 2000), and insula (Breiter et al., 1997; Wang et al., 1999; Garavan et al., 2000; Myrick et al., 2004).
In this study, the brain areas directly associated with the level of craving in the AUD subjects include the fusiform gyri, temporal gyri, parahipocampal gyrus, uncus, frontal gyri, and precuneus. Our result support the contention that limbic activation is one component of cue-induced craving and thus it may be involved in appetitive craving for addictive drugs or for natural rewards (Childress et al., 1999). The parahippocampal gyrus, which has efferent fibres to the nucleus accumbens and amygdala, is a primary input source for the hippocampus (Breiter et al., 1997). Sell et al. (2000) found that the hippocampal activity was correlated with self-reports of feeling high, i.e. with euphoric effects of heroin in opiate addicts. They further suggested that the hippocampus has a significant role in learning and memory that may contribute to drug addiction. The hippocampus is implicated in learning about the relationship between the external cues and internal states (White, 1996). Therefore, activation of the hippocampus might be anticipated when AUD subjects connected the environmental cues to the internal states associated with alcohol use.
Our result confirms frontal involvement in alcohol craving on cue-induced drug craving (George et al., 2001; Grant et al., 1996; Maas et al., 1998; Volkow et al., 1999; Garavan et al., 2000). Garavan et al. (2000) suggested the participation of a working memory circuit while in the craving state. It is possible to assume that the engagement of alcohol abuser's attention and his or her subsequent alcohol-related ruminations associated with alcohol cues are mediated within a working memory system (Garavan et al., 2000) when the AUD subjects experienced craving for alcohol.
Activation of the right precuneus was also correlated with levels of self-reported craving in this study. The right precuneus is strongly implicated in episodic memory retrieval (i.e. conscious recall of past experiences) (Shallice et al., 1994). When AUD subjects experienced alcohol craving, it has been assumed that visual memories associated with the alcohol use are reprocessed in this region and serve as conditioned stimuli that provoke conditioned responses (Sell et al., 2000).
The study had a number of limitations. The first was sample size. Although efforts were made to match the two groups by important demographic variables; age, education level, and handedness for comparison purposes, the sample size remained relatively small. A second limitation was the race composition of subjects selected. All subjects were Asian. These two factors (sample size and race composition) taken together limit the generalizability of study results to the broader universal population.
In conclusion, specific brain regions were found to be directly associated with craving. The present findings indicated that brain activation regions implicated in several forms of memory (working, episodic, emotional) are directly related to craving.
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ACKNOWLEDGEMENTS |
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This research was supported as a Brain Neuroinformatics Research Program sponsored by Ministry of Commerce, Industry and Energy.
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