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1.  fMRI BOLD Response of High-risk College Students (Part 2): During Memory Priming of Alcohol, Marijuana and Polydrug Picture Cues 
Aims: This study examined brain activity using functional magnetic resonance imaging (fMRI) and reaction time (RT) during an implicit repetition priming memory task involving alcohol, polydrug, marijuana and emotional picture cues. Methods: Participants were 5 male and 5 female high-risk college students who had just participated in a cue exposure study (Ray et al., this issue). fMRI and RT data were collected while participants made decisions about previously seen and new picture cues. Results: Both behavioral RT and brain imaging data revealed strong memory priming for drug and alcohol cues. Neurologically, a repetition priming effect (suppression in neural activity for repeated cues) was observed in response to alcohol cues in the left prefrontal, bilateral occipital, and bilateral occipitotemporal regions, as well as right insula and right precuneus (Z ranged from 3.03 to 3.31 P < 0.05). Polydrug cues elicited priming in the occipital and temporal areas, and marijuana cues in the occipital area. Conclusions: Prefrontal and insular cortex involvement both in reactivity to alcohol cues (Ray et al., this issue) and subsequent implicit memory processing of these cues, as found in this study, suggests their potential role in the maintenance of high-risk alcohol use behaviors.
doi:10.1093/alcalc/agq043
PMCID: PMC2930252  PMID: 20729527
2.  Sex Differences in Neural Responses to Stress and Alcohol Context Cues 
Human brain mapping  2010;32(11):1998-2013.
Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. The present study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (p<.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the right dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala and hippocampus than women, whereas women showed greater alcohol-cue related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion modulation regions, including the medial OFC, ventromedial PFC, left superior-medial PFC and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal and ventral) in men, supporting its involvement in alcohol ‘urge’ in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences, and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.
doi:10.1002/hbm.21165
PMCID: PMC3236497  PMID: 21162046
Sex differences; Stress; Alcohol cue; Reward; Brain fMRI; Prefrontal Cortex
3.  Exploring the Relationship Between Depressive and Anxiety Symptoms and Neuronal Response to Alcohol Cues 
Background
Depressive and anxiety symptoms tend to co-occur with heavy drinking. Specifically, their presence may exacerbate the severity and intractability of heavy drinking. Similarly, heavy drinking may increase the risk for and experience of depressive and anxiety symptoms. Although depressive and anxiety symptoms have been significantly correlated with alcohol craving in cue-exposure paradigms, physiological responses have not always mapped onto emotional responses. Therefore, this study sought to examine the role of depressive and anxiety symptoms using a more basic science approach, through examining functional brain changes.
Methods
Seventy nontreatment seeking, heavy drinking adults were recruited through a college campus (n = 45 men; mean age = 22.8). They completed measures of drinking, smoking, depressive symptoms, anxiety symptoms, and a functional magnetic resonance imaging (fMRI) cue-exposure paradigm.
Results
As hypothesized, depressive symptoms were positively correlated with activation during the alcohol (vs. appetitive control) cue in the insula, cingulate, ventral tegmentum, striatum, and thalamus (cluster-corrected p < 0.05, z = 2.3). Similarly, anxiety symptoms were positively correlated with activation during the alcohol (vs. appetitive control) cue in the striatum, thalamus, insula, and inferior frontal, mid-frontal, and cingulate gyri (cluster-corrected p < 0.05, z = 2.3).
Conclusions
Significant correlations were found between depressive symptoms, anxiety symptoms, and differential brain activation in response to an alcohol versus an appetitive control cue in an fMRI paradigm. Moreover, the pattern of activation mapped onto expected regions. This study strongly supports the posited relationships between depressive symptoms, anxiety symptoms, and differential brain activation in an alcohol cue-exposure paradigm with a sample of heavy drinking adults.
doi:10.1111/j.1530-0277.2009.01104.x
PMCID: PMC2911356  PMID: 20028366
Heavy Drinking; Depressive Symptoms; Anxiety Symptoms; Neuroimaging; Craving
4.  Smoking-Cue Induced Brain Activation In Adolescent Light Smokers 
Purpose
Using fMRI, we examined whether or not adolescents with low levels of nicotine exposure (light smokers) display neural activation in areas shown to be involved with addiction in response to smoking-related stimuli.
Design/Setting/Participants
Twelve adolescent light smokers (aged 13 to17, smoked 1 to 5 cigarettes per day) and 12 non-smokers (ages 13 to 17, never smoked a cigarette) from the San Francisco Bay Area underwent fMRI scanning. During scanning they viewed blocks of photographic smoking and control cues. Smoking cues consisted of pictures of people smoking cigarettes and smoking-related objects such as lighters and ashtrays. Neutral cues consisted of everyday objects and people engaged in everyday activities.
Findings
For smokers, smoking cues elicited greater activation than neutral cues in the mesolimbic reward circuit (left anterior cingulate (T=7.88, p<.001), right hippocampus (T=6.62, p<.001) and right parahippocampal gyrus (T=4.70, p<.001)). We found activation from smoking cues versus neutral cues within both the left and right frontal medial orbital regions (T=5.09, p<.001 and T=3.94, p=.001 respectively), which may be unique to adolescents. Non-smokers showed no significant difference in activation between smoking-related cues and neutral cues.
Conclusions
Our finding that smoking cues produced activation in adolescent light smokers in brain regions seen in adult and heavy teen smokers suggests that even at low levels of smoking, adolescents exhibit heightened reactivity to smoking cues. This paper adds to the existing literature suggesting that nicotine dependence may begin with exposure to low levels of nicotine, underscoring the need for early intervention among adolescent smokers.
doi:10.1016/j.jadohealth.2010.09.016
PMCID: PMC3058837  PMID: 21185518
fMRI; adolescent nicotine addiction; adolescent smoking; brain imaging
5.  Influence of Alcohol Use and Family History of Alcoholism on Neural Response to Alcohol Cues in College Drinkers 
Background
Heavy drinkers show altered functional magnetic resonance imaging (fMRI) response to alcohol cues. Little is known about alcohol cue reactivity among college age drinkers, who show the greatest rates of alcohol use disorders. Family history of alcoholism (FHP) is a risk factor for problematic drinking, but the impact on alcohol cue reactivity is unclear. We investigated the influence of heavy drinking and family history of alcoholism on alcohol cue-related fMRI response among college students.
Method
Participants were 19 family history negative (FHN) light drinkers, 11 FHP light drinkers, 25 FHN heavy drinkers, and 10 FHP heavy drinkers, ages 18–21. During fMRI scanning, participants viewed alcohol images, non-alcohol beverage images, and degraded control images, with each beverage image presented twice. We characterized blood oxygen level-dependent (BOLD) contrast for alcohol vs. non-alcohol images, and examined BOLD response to repeated alcohol images to understand exposure effects.
Results
Heavy drinkers exhibited greater BOLD response than light drinkers in posterior visual association regions, anterior cingulate, medial frontal cortex, hippocampus, amygdala, and dorsal striatum, and hyperactivation to repeated alcohol images in temporo-parietal, frontal, and insular regions (clusters > 8127 μl, p < .05). FHP individuals showed increased activation to repeated alcohol images in temporo-parietal regions, fusiform and hippocampus. There were no interactions between family history and drinking group.
Conclusions
Our results parallel findings of hyperactivation to alcohol cues among heavy drinkers in regions subserving visual attention, memory, motivation, and habit. Heavy drinkers demonstrated heightened activation to repeated alcohol images, which could influence continued drinking. Family history of alcoholism was associated with greater response to repeated alcohol images in regions underlying visual attention, recognition, and encoding, which could suggest aspects of alcohol cue reactivity that are independent of personal drinking. Heavy drinking and family history of alcoholism may have differential impacts on neural circuitry involved in cue reactivity.
doi:10.1111/j.1530-0277.2012.01879.x
PMCID: PMC3548054  PMID: 23078363
fMRI; alcohol; adolescence; cue reactivity; brain
6.  Reward-related Brain Response and Craving Correlates of Marijuana Cue Exposure: A Preliminary Study in Treatment-Seeking Marijuana-Dependent Subjects 
Objective
Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry [e.g., amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex (OFC)] triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brain’s response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects.
Methods
Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire-Short Form. Subsequently, BOLD functional MRI data were acquired during exposure to alternating 20 second blocks of marijuana-related versus matched nondrug visual cues.
Results
Brain activation during marijuana cue exposure was significantly greater in bilateral amygdala and hippocampus. Significant positive correlations between craving scores and brain activation were found in ventral striatum, and medial and lateral OFC (p<0.0001).
Conclusions
This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving, and extends the current literature on marijuana cue reactivity. Further, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.
doi:10.1097/ADM.0b013e318273863a
PMCID: PMC3567235  PMID: 23188041
Cannabis; Marijuana Cues; Craving; Neuroimaging; Addiction; Brain Reward Circuitry
7.  Neural substrates of smoking cue reactivity: A meta-analysis of fMRI studies 
Neuroimage  2011;60(1):252-262.
Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.
doi:10.1016/j.neuroimage.2011.12.024
PMCID: PMC3288122  PMID: 22206965
smoking; cue reactivity; fMRI; meta-analysis; tobacco; addiction
8.  Neural Circuitry of Impulsivity in a Cigarette Craving Paradigm 
Impulsivity has been shown to play a pivotal role in the onset, pattern of consumption, relapse and, most notably, craving of illicit and licit drugs such as cigarette smoking. The goal of this study was to examine the neurobiological influence of trait impulsivity during cue-induced cigarette craving. Thirty-one chronic smokers passively viewed appetitive smoking-related and neutral images while being scanned and reported their feelings of craving. They completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. We conducted functional connectivity analyses using the psycho-physiological interaction method. During the processing of smoking stimuli, participants presented increased activations in the cingulate and prefrontal cortices. We observed a significant positive relationship between impulsivity scores and reported craving. A negative correlation was observed between the impulsivity score and activity in the posterior cingulate cortex (PCC). The insula, dorsal anterior cingulate cortex (dACC) as well as the dorsolateral prefrontal cortex (DLPFC) presented a negative connectivity with the PCC. Consistent with the view that the PCC is related to the ability to resist cigarette craving, our results suggest that high impulsive smokers have greater difficulty in controlling their cravings, and that this weakness may be mediated by lower PCC activity. Moreover, we argue that the less PCC activity, the greater the probability of a stronger emotional, physiological, and biased attentional response to smoking cues mediated by insula, dACC, and DLPFC activity. This is the first study on this topic, and so, results will need to be replicated in both licit and illicit drug abusers. Our findings also highlight a need for more emphasis on the PCC in drug addiction research, as it is one of the most consistently activated regions in functional magnetic resonance imaging studies examining the neural correlates of cue-induced alcohol, drug, and tobacco cravings.
doi:10.3389/fpsyt.2013.00067
PMCID: PMC3712893  PMID: 23874307
craving; impulsivity; cigarette smoking; neural correlates; fMRI
9.  Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers 
PLoS ONE  2010;5(7):e11509.
Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.
doi:10.1371/journal.pone.0011509
PMCID: PMC2901385  PMID: 20634975
10.  Cue-Elicited Craving in Heroin Addicts at Different Abstinent Time: An fMRI Pilot Study 
Substance Use & Misuse  2012;47(6):631-639.
Objective: We evaluated the effect of short-term and long-term heroin abstinence on brain responses to heroin-related cues using functional magnetic resonance imaging (fMRI). Methods: Eighteen male heroin addicts following short-term abstinence and 19 male heroin addicts following long-term abstinence underwent fMRI scanning while viewing heroin-related and neutral images. Cue-elicited craving and withdrawal symptoms in the subjects were measured. Results: Following short-term abstinence, greater activation was found in response to heroin cues compared to neutral cues in bilateral temporal, occipital, posterior cingulate, anterior cingulate, thalamus, cerebellum, and left hippocampus. In contrast, activations in bilateral temporal and occipital and deactivations in bilateral frontal, bilateral parietal, left posterior cingulate, insula, thalamus, dorsal striatum, and bilateral cerebellum were observed following long-term abstinence. Direct comparisons between conditions showed greater brain reactivity in response to smoking cues following short-term abstinence. In addition, short-term abstinence had more serious withdrawal symptoms than the long-term. Conclusion: The present findings indicate that compared to short-term, long-term abstinence manifests less serious withdrawal symptoms and significantly decreases neural responses to heroin-related cues in brain regions subserving visual sensory processing, attention, memory, and action planning. These findings suggest that long-term abstinence can decrease the salience of conditioned cues, thereby reducing the risk of relapses. The study's limitations are noted.
doi:10.3109/10826084.2011.646381
PMCID: PMC3359800  PMID: 22329835
abstinence; cue-reactivity; craving; heroin dependence; fMRI
11.  Brain activity and desire for internet video game play 
Comprehensive psychiatry  2011;52(1):88-95.
Objective
Recent studies have suggested that the brain circuitry mediating cue induced desire for video games is similar to that elicited by cues related to drugs and alcohol. We hypothesized that desire for internet video games during cue presentation would activate similar brain regions to those which have been linked with craving for drugs or pathological gambling.
Methods
This study involved the acquisition of diagnostic MRI and fMRI data from 19 healthy male adults (ages 18–23 years) following training and a standardized 10-day period of game play with a specified novel internet video game, “War Rock” (K-network®). Using segments of videotape consisting of five contiguous 90-second segments of alternating resting, matched control and video game-related scenes, desire to play the game was assessed using a seven point visual analogue scale before and after presentation of the videotape.
Results
In responding to internet video game stimuli, compared to neutral control stimuli, significantly greater activity was identified in left inferior frontal gyrus, left parahippocampal gyrus, right and left parietal lobe, right and left thalamus, and right cerebellum (FDR <0.05, p<0.009243). Self-reported desire was positively correlated with the beta values of left inferior frontal gyrus, left parahippocampal gyrus, and right and left thalamus. Compared to the general players, members who played more internet video game (MIGP) cohort showed significantly greater activity in right medial frontal lobe, right and left frontal pre-central gyrus, right parietal post-central gyrus, right parahippocampal gyrus, and left parietal precuneus gyrus. Controlling for total game time, reported desire for the internet video game in the MIGP cohort was positively correlated with activation in right medial frontal lobe and right parahippocampal gyrus.
Discussion
The present findings suggest that cue-induced activation to internet video game stimuli may be similar to that observed during cue presentation in persons with substance dependence or pathological gambling. In particular, cues appear to commonly elicit activity in the dorsolateral prefrontal, orbitofrontal cortex, parahippocampal gyrus, and thalamus.
doi:10.1016/j.comppsych.2010.04.004
PMCID: PMC3039876  PMID: 21220070
internet video game play; functional MRI; frontal cortex; parahippocampal gyrus; thalamus
12.  24-hr smoking abstinence potentiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum 
Psychopharmacology  2008;204(1):25-35.
Rationale
Exposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence.
Objectives
In the present study we evaluated the effect of 24-hr smoking abstinence on brain responses to smoking-related cues using functional magnetic resonance imaging (fMRI).
Methods
Eighteen adult smokers underwent fMRI scanning following smoking as usual (satiated condition) and following 24-hr abstinence (abstinent condition). During scanning they viewed blocks of photographic smoking and control cues.
Results
Following abstinence, greater activation was found in response to smoking cues compared to control cues in parietal (BA 7/31), frontal (BA 8/9), occipital (BA 19) and central (BA 4) cortical regions and in dorsal striatum (putamen) and thalamus. In contrast, no smoking cue > control cue activations were observed following smoking as usual. Direct comparisons between conditions (satiated vs. abstinent) showed greater brain reactivity in response to smoking cues following abstinence. In addition, positive correlations between pre-scan craving in the abstinent condition and smoking cue activation were observed in right dorsomedial prefrontal cortex (dmPFC) including superior frontal gyrus (BA 6/10), anterior cingulate gyrus (BA 32) and supplementary motor area (BA 6).
Conclusions
The present findings indicate smoking abstinence significantly potentiates neural responses to smoking-related cues in brain regions subserving visual sensory processing, attention and action planning. Moreover, greater abstinence-induced craving was significantly correlated with increased smoking cue activation in dmPFC areas involved in action planning and decision making. These findings suggest that drug abstinence can increase the salience of conditioned cues which is consistent with incentive-motivation models of addiction.
doi:10.1007/s00213-008-1436-9
PMCID: PMC2810714  PMID: 19107465
cue-reactivity; craving; nicotine dependence; fMRI; smoking; dorsal striatum
13.  Effects of a GABA-ergic medication combination and initial alcohol withdrawal severity on cue-elicited brain activation among treatment-seeking alcoholics 
Psychopharmacology  2013;227(4):627-637.
Rationale
Many studies have reported medication effects on alcohol cue-elicited brain activation or associations between such activation and subsequent drinking. However, few have combined the methodological rigor of a randomized clinical trial (RCT) with follow-up assessments to determine whether cue-elicited activation predicts relapse during treatment, the crux of alcoholism.
Objectives
This study analyzed functional magnetic resonance imaging (fMRI) data from 48 alcohol-dependent subjects enrolled in a six-week RCT of an investigational pharmacotherapy.
Methods
Subjects were randomized, based on their level of alcohol withdrawal (AW) at study entry, to receive either a combination of gabapentin (up to 1200 mg for 39 days) and flumazenil infusions (two days) or two placebos. Midway through the RCT, subjects were administered an fMRI alcohol cue reactivity task.
Results
There were no main effects of medication or initial AW status on cue-elicited activation, but these factors interacted, such that the gabapentin-flumazenil/higher AW and placebo/lower AW groups, which had previously been shown to have relatively reduced drinking, demonstrated greater dorsal anterior cingulate cortex (dACC) activation to alcohol cues. Further analysis suggested that this finding represented differences in task-related deactivation and was associated with greater control over alcohol-related thoughts. Among study completers, regardless of medication or AW status, greater left dorsolateral prefrontal cortex (DLPFC) activation predicted more post-scan heavy drinking.
Conclusions
These data suggest that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.
doi:10.1007/s00213-013-2996-x
PMCID: PMC3664140  PMID: 23389755
alcoholism; anticonvulsant; craving; neuroimaging; relapse
14.  Brain Reactivity to Smoking Cues Prior to Smoking Cessation Predicts Ability to Maintain Tobacco Abstinence 
Biological psychiatry  2010;67(8):722-729.
Background
Developing means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured prior to a quit attempt, could identify smokers with heightened relapse vulnerability.
Methods
Twenty-one nicotine-dependent women underwent fMRI prior to quitting smoking, during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence versus slip: smoking 1 cigarette after attaining abstinence). Pre-quit fMRI and ES measurements in these groups were compared.
Results
Slip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Smoking cue-induced insula and dorsal anterior cingulate cortex (dACC) reactivity correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of smoking-related cue-induced emotions.
Conclusions
These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified prior to quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality.
doi:10.1016/j.biopsych.2009.12.034
PMCID: PMC2954596  PMID: 20172508
Insula; Dorsal anterior cingulate cortex; fMRI; emotional Stroop task; tobacco; relapse
15.  Anatomical differences and network characteristics underlying smoking cue reactivity 
NeuroImage  2010;54(1):131-141.
A distributed network of brain regions is linked to drug-related cue responding. However, the relationships between smoking cue-induced phasic activity and possible underlying differences in brain structure, tonic neuronal activity and connectivity between these brain areas are as yet unclear. Twenty-two smokers and 22 controls viewed smoking-related and neutral pictures during a functional arterial spin labeling scanning session. T1, resting functional, and diffusion tensor imaging data were also collected. Six brain areas, dorsal lateral prefrontal cortex (dlPFC), dorsal medial prefrontal cortex (dmPFC), dorsal anterior cingulate cortex/cingulate cortex, rostral anterior cingulate cortex (rACC), occipital cortex, and insula/operculum, showed significant smoking cue-elicited activity in smokers when compared with controls and were subjected to secondary analysis for resting state functional connectivity (rsFC), structural, and tonic neuronal activity. rsFC strength between rACC and dlPFC was positively correlated with the cue-elicited activity in dlPFC. Similarly, rsFC strength between dlPFC and dmPFC was positively correlated with the cue-elicited activity in dmPFC while rsFC strength between dmPFC and insula/operculum was negatively correlated with the cue-elicited activity in both dmPFC and insula/operculum, suggesting these brain circuits may facilitate the response to the salient smoking cues. Further, the gray matter density in dlPFC was decreased in smokers and correlated with cue-elicited activity in the same brain area, suggesting a neurobiological mechanism for the impaired cognitive control associated with drug use. Taken together, these results begin to address the underlying neurobiology of smoking cue salience, and may speak to novel treatment strategies and targets for therapeutic interventions.
doi:10.1016/j.neuroimage.2010.07.063
PMCID: PMC2962771  PMID: 20688176
Smoking cue; anatomical; ASL; DTI; VBM; resting state functional connectivity
16.  Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study 
Addiction Biology  2010;15(4):491-503.
Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.
doi:10.1111/j.1369-1600.2010.00242.x
PMCID: PMC3014110  PMID: 20840335
Addiction; cue reactivity; fMRI; impulse control disorder; nicotine dependence; pathological gambling
17.  fMRI Reactivity to High-Calorie Food Pictures Predicts Short- and Long-Term Outcome in a Weight-Loss Program 
Neuroimage  2012;59(3):2709-2721.
Behavioral studies have suggested that food cues have stronger motivating effects in obese than in normal-weight individuals, which may be a risk factor underlying obesity. Previous cross-sectional neuroimaging studies have suggested that this difference is mediated by increased reactivity to food cues in parts of the reward system in obese individuals. To date, however, only a few prospective neuroimaging studies have been conducted to examine whether individual differences in brain activation elicited by food cues can predict differences in weight change. We used functional magnetic resonance imaging (fMRI) to investigate activation in reward-system as well as other brain regions in response to viewing high-calorie food vs. control pictures in 25 obese individuals before and after a 12-week psychosocial weight-loss treatment and at 9-mo follow-up. In those obese individuals who were least successful in losing weight during the treatment, we found greater pre-treatment activation to high-calorie food vs. control pictures in brain regions implicated in reward-system processes, such as the nucleus accumbens, anterior cingulate, and insula. We found similar correlations with weight loss in brain regions implicated by other studies in vision and attention, such as superior occipital cortex, inferior and superior parietal lobule, and prefrontal cortex. Furthermore, less successful weight maintenance at 9-mo follow-up was predicted by greater post-treatment activation in such brain regions as insula, ventral tegmental area, putamen, and fusiform gyrus. In summary, we found that greater activation in brain regions mediating motivational and attentional salience of food cues in obese individuals at the start of a weight-loss program was predictive of less success in the program and that such activation following the program predicted poorer weight control over a 9-mo follow-up period.
PMCID: PMC3287079  PMID: 22332246
obesity; fMRI; food cues; weight loss; weight maintenance; reward system
18.  Assessing Cue-Induced Brain Response as a Function of Abstinence Duration in Heroin-Dependent Individuals: An Event-Related fMRI Study 
PLoS ONE  2013;8(5):e62911.
The brain activity induced by heroin-related cues may play a role in the maintenance of heroin dependence. Whether the reinforcement or processing biases construct an everlasting feature of heroin addiction remains to be resolved. We used an event-related fMRI paradigm to measure brain activation in response to heroin cue-related pictures versus neutral pictures as the control condition in heroin-dependent patients undergoing short-term and long-term abstinence. The self-reported craving scores were significantly increased after cue exposure in the short-term abstinent patients (t = 3.000, P = 0.008), but no increase was found in the long-term abstinent patients (t = 1.510, P = 0.149). However, no significant differences in cue-induced craving changes were found between the two groups (t = 1.193, P = 0.850). Comparing between the long-term abstinence and short-term abstinence groups, significant decreases in brain activation were detected in the bilateral anterior cingulated cortex, left medial prefrontal cortex, caudate, middle occipital gyrus, inferior parietal lobule and right precuneus. Among all of the heroin dependent patients, the abstinence duration was negatively correlated with brain activation in the left medial prefrontal cortex and left inferior parietal lobule. These findings suggest that long-term abstinence may be useful for heroin-dependent patients to diminish their saliency value of heroin-related cues and possibly lower the relapse vulnerability to some extent.
doi:10.1371/journal.pone.0062911
PMCID: PMC3646913  PMID: 23667541
19.  Disrupted Ventromedial Prefrontal Function, Alcohol Craving, and Subsequent Relapse Risk 
JAMA psychiatry (Chicago, Ill.)  2013;70(7):727-739.
Importance
Alcohol dependence is a chronic relapsing illness; stress, alcohol-related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear.
Objectives
To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues.
Design
Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group.
Settings
Inpatient treatment setting in a community mental health center and hospital-based research unit.
Patients
Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons.
Intervention
Twelve-step recovery–based addiction treatment for the patient group.
Main Outcomes and Measures
Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity).
Results
Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue–induced and stress-induced craving in early recovering AD patients (x=6, y=43, z= −6; P <.01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P <.01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F=6.42; P <.01, whole-brain corrected).
Conclusions and Relevance
Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse.
doi:10.1001/jamapsychiatry.2013.762
PMCID: PMC3788824  PMID: 23636842
20.  Reduced Metabolism in Brain “Control Networks” following Cocaine-Cues Exposure in Female Cocaine Abusers 
PLoS ONE  2011;6(2):e16573.
Objective
Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved.
Method
To test this we compared brain metabolism (using PET and 18FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video.
Results
Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreased metabolism (−8.6%±10) whereas males tended to increase it (+5.5%±18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus).
Conclusions
Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from “control networks” (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.
doi:10.1371/journal.pone.0016573
PMCID: PMC3043072  PMID: 21373180
21.  Association Between Nicotine Dependence Severity, BOLD Response to Smoking Cues, and Functional Connectivity 
Neuropsychopharmacology  2013;38(12):2363-2372.
Enhanced motivational salience towards smoking cues is a consequence of chronic nicotine use, but the degree to which this value increases beyond that of other appetitive cues is unknown. In addition, it is unclear how connectivity between brain regions influences cue reactivity and how cue reactivity and functional connectivity are related to nicotine dependence severity. This study examined neural responses during the presentation of smoking cues and appetitive control cues, as well as functional connectivity in 116 smokers with a range of nicotine dependence severity. Smoking cues elicited greater response above baseline than food cues in orbitofrontal cortex (OFC) and supplementary motor area (SMA) and less deactivation below baseline in middle frontal gyrus, inferior parietal lobe, and middle temporal gyrus. Psychophysiological interaction (PPI) analysis using right OFC as a seed revealed increased connectivity with somatosensory cortex and lateral inferior parietal lobe during smoking cues compared with food cues. Similarly, a PPI analysis using left insula as a seed showed stronger connectivity with somatosensory cortex, right insula, OFC, and striatum. Finally, relationships with nicotine dependence scores showed enhanced response in insula and dorsal anterior cingulate cortex in the smoking vs food comparison, and increased connectivity between insula and circuits involved in motivated behavior. Combined, these results suggest that smokers engage attentional networks and default mode networks involved in self-referential processing to a greater degree during smoking cues. In addition, individuals with greater nicotine dependence severity show increased engagement of sensorimotor and motor preparation circuits, suggesting increased reliance on habitual behavior.
doi:10.1038/npp.2013.134
PMCID: PMC3799055  PMID: 23708507
abuse; biological psychiatry; craving; functional connectivity; imaging; clinical or preclinical; insula; nicotine dependence; psychiatry & behavioral sciences; craving; insula; functional connectivity; nicotine dependence
22.  Dissociable Neural Effects of Stimulus Valence and Preceding Context during the Inhibition of Responses to Emotional Faces 
Human brain mapping  2009;30(9):2821-2833.
Socially appropriate behavior requires the concurrent inhibition of actions that are inappropriate in the context. This self-regulatory function requires an interaction of inhibitory and emotional processes that recruits brain regions beyond those engaged by either process alone. In this study, we isolated brain activity associated with response inhibition and emotional processing in 24 healthy adults using event-related functional magnetic resonance imaging (fMRI) and a go/no-go task that independently manipulated the context preceding no-go trials (i.e., number of go trials) and the valence (i.e., happy, sad, and neutral) of the face stimuli used as trial cues. Parallel quadratic trends were seen in correct inhibitions on no-go trials preceded by increasing numbers of go trials and associated activation for correct no-go trials in inferior frontal gyrus pars opercularis, pars triangularis, and pars orbitalis, temporoparietal junction, superior parietal lobule, and temporal sensory association cortices. Conversely, the comparison of happy versus neutral faces and sad versus neutral faces revealed valence-dependent activation in the amygdala, anterior insula cortex, and posterior midcingulate cortex. Further, an interaction between inhibition and emotion was seen in valence-dependent variations in the quadratic trend in no-go activation in the right inferior frontal gyrus and left posterior insula cortex. These results suggest that the inhibition of response to emotional cues involves the interaction of partly dissociable limbic and frontoparietal networks that encode emotional cues and use these cues to exert inhibitory control over the motor, attention, and sensory functions needed to perform the task, respectively.
doi:10.1002/hbm.20706
PMCID: PMC2733937  PMID: 19086020
fMRI; motor inhibition; emotion; response context; prefrontal cortex; amygdala
23.  Neural Substrates of Resisting Craving during Cigarette Cue Exposure 
Biological psychiatry  2007;62(6):642-651.
Background
In cigarette smokers, the most commonly-reported areas of brain activation during visual cigarette cue exposure are: the prefrontal, anterior cingulate, and visual cortices. We sought to determine changes in brain activity in response to cigarette cues when smokers actively resist craving.
Methods
Forty-two tobacco dependent smokers underwent functional magnetic resonance imaging, during which they were presented with videotaped cues. Three cue presentation conditions were tested: cigarette cues with subjects allowing themselves to crave (cigarette cue crave), cigarette cues with the instruction to resist craving (cigarette cue resist), and matched neutral cues.
Results
Activation was found in the cigarette cue resist (compared to the cigarette cue crave) condition in the left dorsal anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and precuneus. Lower MR signal for the cigarette cue resist condition was found in the cuneus bilaterally, left lateral occipital gyrus, and right post-central gyrus. These relative activations and deactivations were more robust when the cigarette cue resist condition was compared to the neutral cue condition.
Conclusions
Suppressing craving during cigarette cue exposure involves activation of limbic (and related) brain regions and deactivation of primary sensory and motor cortices.
doi:10.1016/j.biopsych.2006.10.026
PMCID: PMC1992815  PMID: 17217932
Nicotine Dependence; functional magnetic resonance imaging; cue-induced cigarette craving; cingulate cortex; visual cortex
24.  From cue to meaning: Brain mechanisms supporting the construction of expectations of pain 
Pain  2013;155(1):129-136.
The brain mechanisms by which sensory cues become transformed into expectations of impending events are a critical component of cognitive tuning of sensory processing. However, distinctions between the afferent processing of cue-related activity itself versus those mechanisms supporting the contextual meaning imparted to the cue remain limited. Do sensory cues with equal meaning engage similar patterns of brain activations even if they are delivered in separate modalities? To address this question, we used functional magnetic resonance imaging of an expectation paradigm in which cues were delivered with visual or innocuous thermal stimuli. Cues were designed to be highly meaningful since they predicted the delivery of high and low painful stimuli. As expected, the cues themselves activated unimodal sensory cortices. This cue modality-specific activation was transformed into a pattern of activity reflecting cue meaning. Cues signaling high pain produced greater activity in the left dorsolateral prefrontal cortex and anterior cingulate cortex. Such activity is consistent with the graded encoding of the magnitude of expected pain. In contrast, cues signaling low pain produced greater activity in the right intraparietal sulcus. This activation may reflect processes directing spatial attention to the stimulated body region in order to more accurately evaluate the relatively weak, low pain stimulus. Taken together, these findings indicate that cues arising from different sensory modalities ultimately engage common brain mechanisms that reflect the meaning of the cue. This meaning-related activity is presumably critical for preparing sensory systems to optimally process afferent information.
doi:10.1016/j.pain.2013.09.014
PMCID: PMC3947355  PMID: 24055334
25.  Brain fMRI Responses to Smoking-Related Images Prior to and During Extended Smoking Abstinence 
Background
Reactivity to smoking-related cues may play a role in the maintenance of smoking behavior and may change depending on smoking status. Whether smoking cue-related functional MRI (fMRI) reactivity differs between active smoking and extended smoking abstinence states currently is unknown.
Methods
We used fMRI to measure brain reactivity in response to smoking-related versus neutral images in 13 tobacco-dependent subjects prior to a smoking cessation attempt and again during extended smoking abstinence (52 ± 11 days) aided by nicotine replacement therapy.
Results
Pre-quit smoking cue induced fMRI activity patterns paralleled those reported in prior smoking cue reactivity fMRI studies. Greater fMRI activity was detected during extended smoking abstinence than during the pre-quit assessment subcortically in the caudate nucleus and cortically in prefrontal (BA 6, 9, 44, 46), primary somatosensory (BA 1,2,3), temporal (BA 22, 41, 42), parietal (BA 7, 40) anterior cingulate (BA 24, 32), and posterior cingulate (BA 31) cortex.
Conclusions
These data suggest that during extended smoking abstinence, fMRI reactivity to smoking versus neutral stimuli persists in brain areas involved in attention, somatosensory processing, motor planning, and conditioned cue responding. In some brain regions, fMRI smoking cue reactivity is increased during extended smoking abstinence in comparison to the pre-quit state, which may contribute to persisting relapse vulnerability.
doi:10.1037/a0017797
PMCID: PMC3742373  PMID: 19968401
abstinence; addiction; caudate nucleus; fMRI; nicotine

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