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1.  fMRI BOLD Response in High-risk College Students (Part 1): During Exposure to Alcohol, Marijuana, Polydrug and Emotional Picture Cues† 
Aim: This functional magnetic resonance imaging (fMRI) study examined reactivity to alcohol, polydrug, marijuana and emotional picture cues in students who were referred to a college alcohol and drug assistance program. Methods: The fMRI data of 10 participants (5 females; 5 males) were collected while they viewed standardized emotional and appetitive cues. Results: Positive and negative emotional cues produced greater activity than neutral cues in the expected brain areas. Compared with neutral cues, alcohol cues produced greater brain activation in the right insula, left anterior cingulate, left caudate and left prefrontal cortex (Z = 2.01, 1.86, 1.82, 1.81, respectively; P < 0.05). Drug cues produced significantly greater left prefrontal activity compared with neutral cues, with polydrug cues activating the right insula and marijuana cues activating left anterior cingulate. Conclusions: Students at-risk for alcohol abuse showed neural reactivity to alcohol cues in four brain regions, which is consistent with their greater use of alcohol. Insula activation to appetitive cues may be an early marker of risk for progression to alcohol/drug abuse.
doi:10.1093/alcalc/agq042
PMCID: PMC2930251  PMID: 20729530
2.  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
3.  Action simulation in hallucination-prone adolescents 
Theoretical and empirical accounts suggest that impairments in self-other discrimination processes are likely to promote the expression of hallucinations. Studies using a variety of paradigms involving self-performed actions argue in favor of perspective taking confusion in hallucination-prone subjects. However, our understanding of such processes during adolescence is still at an early stage. The present study thus aims (1) to delineate the neural correlates sustaining mental simulation of actions involving self-performed actions (first-person perspective; 1PP) and other-performed actions (third-person perspective; 3PP) during adolescence (2) to identify atypical activation patterns during 1PP/3PP mental simulation of actions in hallucination-prone adolescents (3) to examine whether differential risk for schizophrenia (clinical vs. genetic) is also associated with differential impairments in the 1PP/3PP mental simulation of actions during adolescence. Twenty-two typically developing controls (Control group; 6 females), 12 hallucination-prone adolescents [auditory hallucination (AH) group; 7 females] and 13 adolescents with 22q11.2 Deletion Syndrome (22q11.2DS group; 4 females) were included in the study. During the fMRI task, subjects were presented with a cue (self-other priming cues) indicating to perform the task using either a first person perspective (“you”-1PP) or a third person perspective (“best friend”-3PP) and then they were asked to mentally simulate actions based on the type of cue. Hallucination-proneness was assessed using a self-report questionnaire [Cardiff Anomalous Perception Scale (CAPS)]. Our results indicated that atypical patterns of cerebral activation, particularly in the key areas of self-other distinction, were found in both groups at risk for auditory hallucinations (AHs and 22q11.2DS). More precisely, adolescents in the AH group presented decreased activations in the right middle occipital gyrus BA19, left cingulate gyrus BA31, and right precuneus BA31 for the 3PP > 1PP contrast. Adolescents in the 22q11.2DS group presented decreased activations in the right superior occipital gyrus BA19, left caudate tail and left precuneus BA7 for the 3PP > 1PP contrast. In comparison to the Control group, only the 22q11.2DS adolescents showed a decreased activation for other-related cues (prime other > prime self contrast) in areas of visual imagery, episodic memory and social cognition. This study characterizes the neural correlates of mental imagery for actions during adolescence, and suggests that a differential risk for hallucination-proneness (clinical vs. genetic) is associated to similar patterns of atypical activations in key areas sustaining self-other discrimination processes. These observations may provide relevant information for future research and prevention strategies with regards to hallucination-proneness during adolescence.
doi:10.3389/fnhum.2013.00329
PMCID: PMC3701149  PMID: 23847502
auditory hallucinations; 22q11.2; action simulation; perspective-taking
4.  Multimodal imaging of repetition priming: Using fMRI, MEG, and intracranial EEG to reveal spatiotemporal profiles of word processing 
NeuroImage  2010;53(2):707-717.
Repetition priming is a core feature of memory processing whose anatomical correlates remain poorly understood. In this study, we use advanced multimodal imaging (functional magnetic resonance imaging (fMRI) and magnetoencephalography; MEG) to investigate the spatiotemporal profile of repetition priming. We use intracranial electroencephalography (iEEG) to validate our fMRI/MEG measurements. Twelve controls completed a semantic judgment task with fMRI and MEG that included words presented once (new, ‘N’) and words that repeated (old, ‘O’). Six patients with epilepsy completed the same task during iEEG recordings. Blood-oxygen level dependent (BOLD) responses for N vs O words were examined across the cortical surface and within regions of interest. MEG waveforms for N vs O words were estimated using a noise-normalized minimum norm solution, and used to interpret the timecourse of fMRI. Spatial concordance was observed between fMRI and MEG repetition effects from 350–450ms within bilateral occipitotemporal and medial temporal, left prefrontal, and left posterior temporal cortex. Additionally, MEG revealed widespread sources within left temporoparietal regions, whereas fMRI revealed bilateral reductions in occipitotemporal and left superior frontal, and increases in inferior parietal, precuneus, and dorsolateral prefrontal activity. BOLD suppression in left posterior temporal, left inferior prefrontal, and right occipitotemporal cortex correlated with MEG repetition-related reductions. IEEG responses from all three regions supported the timecourse of MEG and localization of fMRI. Furthermore, iEEG decreases to repeated words were associated with decreased gamma power in several regions, providing evidence that gamma oscillations are tightly coupled to cognitive phenomena and reflect regional activations seen in the BOLD signal.
doi:10.1016/j.neuroimage.2010.06.069
PMCID: PMC2930128  PMID: 20620212
fMRI; magnetoencepholography; intracranial EEG; memory; language; gamma
5.  Functional MRI of inhibitory processing in abstinent adolescent marijuana users 
Psychopharmacology  2007;194(2):173-183.
Background
Marijuana intoxication appears to impair response inhibition, but it is unclear if impaired inhibition and associated brain abnormalities persist after prolonged abstinence among adolescent users. We hypothesized that brain activation during a go/no-go task would show persistent abnormalities in adolescent marijuana users after 28 days of abstinence.
Methods
Adolescents with (n=16) and without (n=17) histories of marijuana use were compared on blood oxygen level dependent (BOLD) response to a go/no-go task during functional magnetic resonance imaging (fMRI) after 28 days of monitored abstinence. Participants had no neurological problems or Axis I diagnoses other than cannabis abuse/dependence.
Results
Marijuana users did not differ from non-users on task performance but showed more BOLD response than non-users during inhibition trials in right dorsolateral prefrontal, bilateral medial frontal, bilateral inferior and superior parietal lobules, and right occipital gyri, as well as during “go” trials in right prefrontal, insular, and parietal cortices (p<0.05, clusters>943 μl). Differences remained significant even after controlling for lifetime and recent alcohol use.
Conclusions
Adolescent marijuana users relative to non-users showed increased brain processing effort during an inhibition task in the presence of similar task performance, even after 28 days of abstinence. Thus, increased brain processing effort to achieve inhibition may predate the onset of regular use or result from it. Future investigations will need to determine whether increased brain processing effort is associated with risk to use.
doi:10.1007/s00213-007-0823-y
PMCID: PMC2269705  PMID: 17558500
Marijuana; Cannabis; Functional magnetic resonance imaging; Adolescence; Response inhibition; Abstinence
6.  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
7.  Neural Correlates of Verbal Learning in Adolescent Alcohol and Marijuana Users 
Addiction (Abingdon, England)  2010;106(3):564-573.
Aims
Alcohol and marijuana are the most widely used intoxicants among adolescents, yet their potential unique and interactive influences on the developing brain are not well established. Brain regions subserving learning and memory undergo continued maturation during adolescence, and may be particularly susceptible to substance-related neurotoxic damage. Here, we characterize brain response during verbal learning among adolescent users of alcohol and marijuana.
Design
Participants performed a verbal paired associates encoding task during fMRI scanning.
Setting
Adolescent subjects were recruited from local public schools and imaged at a University-based fMRI Center.
Participants
Participants were 74 16- to 18-year-olds, divided into four groups: (1) 22 controls with limited alcohol and marijuana experience, (2) 16 binge drinkers, (3) 8 marijuana users, and (4) 28 binge drinking marijuana users.
Measurements
Diagnostic interview assured that all teens were free from neurologic or psychiatric disorders; urine toxicology and breathalyzer verified abstinence for 22–28 days before scanning; a verbal paired associates task was administered during fMRI.
Findings
Groups demonstrated no differences in performance on the verbal encoding task, yet exhibited different brain response patterns. A main effect of drinking pointed to decreased inferior frontal but increased dorsal frontal and parietal fMRI response among binge drinkers (corrected p < .05). There was no main effect of marijuana use. Binge drinking × marijuana interactions were found in bilateral frontal regions (corrected p < .05), where users of either alcohol or marijuana showed greater response than non-users, but users of both substances resembled non-users.
Conclusions
Adolescent substance users demonstrated altered fMRI response relative to nonusing controls, yet binge drinking appeared associated with more differences in activation than marijuana use. Alcohol and marijuana may have interactive effects that alter these differences, particularly in prefrontal brain regions.
doi:10.1111/j.1360-0443.2010.03197.x
PMCID: PMC3423457  PMID: 21134014
adolescence; functional magnetic resonance imaging; verbal learning; cannabis; alcohol; binge drinking
8.  fMRI Response During Figural Memory Task Performance in College Drinkers 
Psychopharmacology  2013;231(1):10.1007/s00213-013-3219-1.
Rationale
18-25-year-olds show the highest rates of alcohol use disorders (AUD) and heavy drinking, which may have critical neurocognitive implications. Regions subserving memory may be particularly susceptible to alcohol-related impairments.
Objective
We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine the neural correlates of visual encoding and recognition among heavy drinking college students. We predicted that heavy drinkers would show worse memory performance and increased frontal/parietal activation and decreased hippocampal response during encoding.
Methods
Participants were 23 heavy drinkers and 33 demographically matched light drinkers, ages 18-20, characterized using quantity/frequency of drinking and AUD diagnosis. Participants performed a figural encoding and recognition task during fMRI. BOLD response during encoding was modeled based on whether each stimulus was subsequently recognized or forgotten (i.e., correct vs. incorrect encoding).
Results
There were no group differences in behavioral performance. Compared to light drinkers, heavy drinkers showed: 1) greater BOLD response during correct encoding in right hippocampus/medial temporal, right dorsolateral prefrontal, left inferior frontal, and bilateral posterior parietal cortices; 2) less left inferior frontal activation and greater bilateral precuneus deactivation during incorrect encoding; and 3) less bilateral insula response during correct recognition (clusters >10,233ul, p<.05 whole-brain).
Conclusions
This is the first investigation of the neural substrates of figural memory among heavy drinking older adolescents. Heavy drinkers demonstrated compensatory hyperactivation of memory-related areas during correct encoding, greater deactivation of default mode regions during incorrect encoding, and reduced recognition-related response. Results could suggest use of different encoding and recognition strategies among heavy drinkers.
doi:10.1007/s00213-013-3219-1
PMCID: PMC3877735  PMID: 23949205
Alcohol; Adolescent; Young Adult; fMRI; Learning; Memory; Cognition
9.  STABILITY OF FMRI STRIATAL RESPONSE TO ALCOHOL CUES: A HIERARCHICAL LINEAR MODELING APPROACH 
NeuroImage  2011;56(1):61-68.
In functional magnetic resonance imaging (fMRI) studies of alcohol-dependent individuals, alcohol cues elicit activation of the ventral and dorsal aspects of the striatum (VS and DS), which are believed to underlie aspects of reward learning critical to the initiation and maintenance of alcohol dependence. Cue-elicited striatal activation may represent a biological substrate through which treatment efficacy may be measured. However, to be useful for this purpose, VS or DS activation must first demonstrate stability across time. Using hierarchical linear modeling (HLM), this study tested the stability of cue-elicited activation in anatomically and functionally defined regions of interest in bilateral VS and DS. Nine non-treatment-seeking alcohol-dependent participants twice completed an alcohol cue reactivity task during two fMRI scans separated by 14 days. HLM analyses demonstrated that, across all participants, alcohol cues elicited significant activation in each of the regions of interest. At the group level, these activations attenuated slightly between scans, but session-wise differences were not significant. Within-participants stability was best in the anatomically defined right VS and DS and in a functionally defined region that encompassed right caudate and putamen (intraclass correlation coefficients of .75, .81, and .76, respectively). Thus, within this small sample, alcohol cue-elicited fMRI activation had good reliability in the right striatum, though a larger sample is necessary to ensure generalizability and further evaluate stability. This study also demonstrates the utility of HLM analytic techniques for serial fMRI studies, in which separating within-participants variance (individual changes in activation) from between-participants factors (time or treatment) is critical.
doi:10.1016/j.neuroimage.2011.02.004
PMCID: PMC3066261  PMID: 21316465
alcohol; fMRI; cue reactivity; ventral striatum; dorsal striatum; HLM
10.  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
11.  Prospective associations between brain activation to cocaine and no-go cues and cocaine relapse* 
Drug and alcohol dependence  2013;131(0):44-49.
Background
The ability to predict potential for relapse to substance use following treatment could be very useful in targeting aftercare strategies. Recently, a number of investigators have focused on using neural activity measured by fMRI to predict relapse propensity. The purpose of the present study was to use fMRI to investigate prospective associations between brain reactivity to cocaine and response inhibition cues and relapse to cocaine use.
Methods
Thirty cocaine-dependent participants with clean cocaine urine drug screens (UDS) completed a baseline fMRI scan, including a cocaine-cue reactivity task and a go/no-go response inhibition task. After participating in a brief clinical trial of D-cycloserine for the facilitation of cocaine cue extinction, they returned for a one-week follow-up UDS. Associations between baseline activation to cocaine and inhibition cues and relapse to cocaine use were explored.
Results
Positive cocaine UDS was significantly associated with cocaine cue activation in the right putamen and insula, as well as bilateral occipital regions. Associations between positive cocaine UDS and activation to no-go cues were concentrated in the postcentral gyri, a region involved in response execution.
Conclusions
Although preliminary, these results suggest that brain imaging may be a useful tool for predicting risk for relapse in cocaine-dependent individuals. Further, larger-scale naturalistic studies are needed to corroborate and extend these findings.
doi:10.1016/j.drugalcdep.2013.04.008
PMCID: PMC3703628  PMID: 23683790
fMRI; cue; go no-go; urine drug screen; cocaine; relapse
12.  Functional Imaging of Implicit Marijuana Associations during performance on an Implicit Association Test (IAT) 
Behavioural brain research  2013;256:10.1016/j.bbr.2013.09.013.
This research evaluated the neural correlates of implicit associative memory processes (habit-based processes) through the imaging (fMRI) of a marijuana Implicit Association Test. Drug-related associative memory effects have been shown to consistently predict level of drug use. To observe differences in neural activity of associative memory effects, this study compared 13 heavy marijuana users and 15 non-using controls, ranging in age from 18 to 25, during performance of a marijuana Implicit Association Test (IAT). Group by condition interactions in the putamen, caudate, and right inferior frontal gyrus were observed. Relative to non-users, marijuana users showed greater bilateral activity in the dorsal striatum (caudate and putamen) during compatible trials focused on perceived positive outcomes of use. Alternatively, relative to the marijuana-using group, the non-users showed greater activity in the right inferior frontal gyrus during incompatible trials, which require more effortful processing of information. Further, relative to fixation, heavy users showed bilateral activity in the caudate and putamen, hippocampus and some frontal regions during compatible trials and no significant activity during incompatible trials. The non-using group showed greater activity in frontal regions during incompatible trials relative to fixation and no significant activity during compatible trials. These findings are consistent with a dual process framework of appetitive behaviors proposing that (1) implicit associations underlying habit are mediated through neural circuitry dependent on the striatum, and (2) deliberative/controlled behaviors are mediated through circuitry more dependent on the prefrontal cortex.
doi:10.1016/j.bbr.2013.09.013
PMCID: PMC3836671  PMID: 24029699
fMRI; Marijuana IAT; habit; associative processes; memory associations; implicit cognition
13.  Visual Image-Induced Craving for Ethanol (VICE): Development, Validation, and a Pilot fMRI Study 
Background:
Craving induction in a controlled environment is helpful in the research of craving mechanism and its role in development of alcohol dependence (AD). We describe a novel tool Visual Image-induced Craving for Ethanol (VICE) and its effects on brain activation with pilot functional magnetic resonance imaging (fMRI).
Materials and Methods:
Alcohol-related visual cues (ARCs) in 5 scenarios were photographed, which included pictures of bars, alcoholic beverage bottles, pouring of alcohol into glasses, glasses filled with alcohol, and scenes of people sipping alcohol, counterbalanced with neutral pictures (involving water, milk etc.,). Craving scores were obtained from 15 hospitalized patients with AD to validate this tool. In the pilot fMRI (3-Tesla) study, 5 patients were examined using VICE in a symptom provocation model. Group level-fixed effect analysis of brain activation differences was done using SPM8.
Results:
VICE showed a high internal consistency with Cronbach's α coefficient of 0.86, which confirmed its reliability. Concurrent validity of VICE was demonstrated via its convergence with the Penn Alcohol Craving Scale. ARCs had significantly greater mean craving scores than neutral cues in all the 5 scenarios (intentional validity). In the pilot fMRI, patients were found to have greater activation while viewing ARCs compared to the neutral cues in right insular cortex and deficient activation in right orbitofrontal cortex.
Conclusions:
The VICE is a reliable and valid measure of alcohol craving with promising clinical and translational research implications. Preliminary fMRI findings indicate it can be used as a symptom provocation tool for fMRI experiments.
doi:10.4103/0253-7176.130984
PMCID: PMC4031585  PMID: 24860218
Alcohol; craving; imaging; neurobiology; symptom provocation
14.  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
15.  Human ecstasy (MDMA) polydrug users have altered brain activation during semantic processing 
Psychopharmacology  2012;227(1):41-54.
Rationale
Ecstasy (MDMA) polydrug users have verbal memory performance that is statistically significantly lower than comparison control subjects. Studies have correlated long-term MDMA use with altered brain activation in regions that play a role in verbal memory.
Objectives
The aim of our study was to examine the association of lifetime ecstasy use with semantic memory performance and brain activation in ecstasy polydrug users.
Methods
23 abstinent ecstasy polydrug users (age=24.57) and 11 controls (age=22.36) performed a two-part fMRI semantic encoding and recognition task. To isolate brain regions activated during each semantic task, we created statistical activation maps in which brain activation was greater for word stimuli than for non-word stimuli (corrected p<0.05).
Results
During the encoding phase, ecstasy polydrug users had greater activation during semantic encoding bilaterally in language processing regions, including Brodmann Areas 7, 39, and 40. Of this bilateral activation, signal intensity with a peak T in the right superior parietal lobe was correlated with lifetime ecstasy use (rs=0.43, p=0.042). Behavioral performance did not differ between groups.
Conclusions
These findings demonstrate that ecstasy polydrug users have increased brain activation during semantic processing. This increase in brain activation in the absence of behavioral deficits suggests that ecstasy polydrug users have reduced cortical efficiency during semantic encoding, possibly secondary to MDMA-induced 5-HT neurotoxicity. Although pre-existing differences cannot be ruled out, this suggests the possibility of a compensatory mechanism allowing ecstasy polydrug users to perform equivalently to controls, providing additional support for an association of altered cerebral neurophysiology with MDMA exposure.
doi:10.1007/s00213-012-2936-1
PMCID: PMC3615064  PMID: 23241648
16.  Neural mechanisms underlying the facilitation of naming in aphasia using a semantic task: an fMRI study 
BMC Neuroscience  2012;13:98.
Background
Previous attempts to investigate the effects of semantic tasks on picture naming in both healthy controls and people with aphasia have typically been confounded by inclusion of the phonological word form of the target item. As a result, it is difficult to isolate any facilitatory effects of a semantically-focused task to either lexical-semantic or phonological processing. This functional magnetic resonance imaging (fMRI) study examined the neurological mechanisms underlying short-term (within minutes) and long-term (within days) facilitation of naming from a semantic task that did not include the phonological word form, in both participants with aphasia and age-matched controls.
Results
Behavioral results showed that a semantic task that did not include the phonological word form can successfully facilitate subsequent picture naming in both healthy controls and individuals with aphasia. The whole brain neuroimaging results for control participants identified a repetition enhancement effect in the short-term, with modulation of activity found in regions that have not traditionally been associated with semantic processing, such as the right lingual gyrus (extending to the precuneus) and the left inferior occipital gyrus (extending to the fusiform gyrus). In contrast, the participants with aphasia showed significant differences in activation over both the short- and the long-term for facilitated items, predominantly within either left hemisphere regions linked to semantic processing or their right hemisphere homologues.
Conclusions
For control participants in this study, the short-lived facilitation effects of a prior semantic task that did not include the phonological word form were primarily driven by object priming and episodic memory mechanisms. However, facilitation effects appeared to engage a predominantly semantic network in participants with aphasia over both the short- and the long-term. The findings of the present study also suggest that right hemisphere involvement may be supportive rather than maladaptive, and that a large distributed perisylvian network in both cerebral hemispheres supports the facilitation of naming in individuals with aphasia.
doi:10.1186/1471-2202-13-98
PMCID: PMC3477078  PMID: 22882806
Aphasia; Semantic verification; fMRI; Overt picture naming; Semantics
17.  A Word by Any Other Intonation: FMRI Evidence for Implicit Memory Traces for Pitch Contours of Spoken Words in Adult Brains 
PLoS ONE  2013;8(12):e82042.
Objectives
Intonation may serve as a cue for facilitated recognition and processing of spoken words and it has been suggested that the pitch contour of spoken words is implicitly remembered. Thus, using the repetition suppression (RS) effect of BOLD-fMRI signals, we tested whether the same spoken words are differentially processed in language and auditory brain areas depending on whether or not they retain an arbitrary intonation pattern.
Experimental design
Words were presented repeatedly in three blocks for passive and active listening tasks. There were three prosodic conditions in each of which a different set of words was used and specific task-irrelevant intonation changes were applied: (i) All words presented in a set flat monotonous pitch contour (ii) Each word had an arbitrary pitch contour that was set throughout the three repetitions. (iii) Each word had a different arbitrary pitch contour in each of its repetition.
Principal findings
The repeated presentations of words with a set pitch contour, resulted in robust behavioral priming effects as well as in significant RS of the BOLD signals in primary auditory cortex (BA 41), temporal areas (BA 21 22) bilaterally and in Broca's area. However, changing the intonation of the same words on each successive repetition resulted in reduced behavioral priming and the abolition of RS effects.
Conclusions
Intonation patterns are retained in memory even when the intonation is task-irrelevant. Implicit memory traces for the pitch contour of spoken words were reflected in facilitated neuronal processing in auditory and language associated areas. Thus, the results lend support for the notion that prosody and specifically pitch contour is strongly associated with the memory representation of spoken words.
doi:10.1371/journal.pone.0082042
PMCID: PMC3876977  PMID: 24391713
18.  Activation in brain energy regulation and reward centers by food cues varies with choice of visual stimulus 
Objective
To develop a noninvasive method of studying brain mechanisms involved in energy homeostasis and appetite regulation in humans by using visual food cues that are relevant to individuals attempting weight loss.
Design
Functional magnetic resonance imaging (fMRI) was used to compare brain activation in regions of interest between groups of food photographs.
Participants
10 healthy, nonobese women who were not dieting for weight loss.
Measurements
Independent raters viewed food photographs and evaluated whether the foods depicted should be eaten by individuals attempting a calorically-restricted diet. Based on their responses, we categorized photographs into “non-fattening” and “fattening” food groups, the latter characterized by obviously high caloric content and usually also high fat or high sugar content. Blood oxygen level-dependent (BOLD) response was measured by fMRI while participants viewed photographs of “fattening” foods, “non-fattening” foods, and non-food objects.
Results
Viewing photographs of fattening food compared to non-food objects resulted in significantly greater activation in the brainstem; hypothalamus; left amygdala; left dorsolateral prefrontal cortex; left orbitofrontal cortex; right insular cortex; bilateral striatum, including the nucleus accumbens, caudate nucleus, and putamen; bilateral thalamus; and occipital lobe. By comparison, only the occipital region had greater activation by non-fattening food than by object photographs. Combining responses to all food types resulted in attenuation of activation in the brainstem, hypothalamus, and striatum.
Conclusion
These findings suggest that, in nonobese women, neural circuits engaged in energy homeostasis and reward processing are selectively attuned to representations of high-calorie foods that are perceived as fattening. Studies to investigate hormonal action or manipulation of energy balance may benefit from fMRI protocols that contrast energy-rich food stimuli with non-food or low-calorie food stimuli.
doi:10.1038/ijo.2009.56
PMCID: PMC2697279  PMID: 19365394
19.  Repetition Suppression and Multi-Voxel Pattern Similarity Differentially Track Implicit and Explicit Visual Memory 
The Journal of Neuroscience  2013;33(37):14749-14757.
Repeated exposure to a visual stimulus is associated with corresponding reductions in neural activity, particularly within visual cortical areas. It has been argued that this phenomenon of repetition suppression is related to increases in processing fluency or implicit memory. However, repetition of a visual stimulus can also be considered in terms of the similarity of the pattern of neural activity elicited at each exposure—a measure that has recently been linked to explicit memory. Despite the popularity of each of these measures, direct comparisons between the two have been limited, and the extent to which they differentially (or similarly) relate to behavioral measures of memory has not been clearly established. In the present study, we compared repetition suppression and pattern similarity as predictors of both implicit and explicit memory. Using functional magnetic resonance imaging, we scanned 20 participants while they viewed and categorized repeated presentations of scenes. Repetition priming (facilitated categorization across repetitions) was used as a measure of implicit memory, and subsequent scene recognition was used as a measure of explicit memory. We found that repetition priming was predicted by repetition suppression in prefrontal, parietal, and occipitotemporal regions; however, repetition priming was not predicted by pattern similarity. In contrast, subsequent explicit memory was predicted by pattern similarity (across repetitions) in some of the same occipitotemporal regions that exhibited a relationship between priming and repetition suppression; however, explicit memory was not related to repetition suppression. This striking double dissociation indicates that repetition suppression and pattern similarity differentially track implicit and explicit learning.
doi:10.1523/JNEUROSCI.4889-12.2013
PMCID: PMC3771032  PMID: 24027275
20.  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
21.  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
22.  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
23.  Regional Brain Responses in Nulliparous Women to Emotional Infant Stimuli 
PLoS ONE  2012;7(5):e36270.
Infant cries and facial expressions influence social interactions and elicit caretaking behaviors from adults. Recent neuroimaging studies suggest that neural responses to infant stimuli involve brain regions that process rewards. However, these studies have yet to investigate individual differences in tendencies to engage or withdraw from motivationally relevant stimuli. To investigate this, we used event-related fMRI to scan 17 nulliparous women. Participants were presented with novel infant cries of two distress levels (low and high) and unknown infant faces of varying affect (happy, sad, and neutral) in a randomized, counter-balanced order. Brain activation was subsequently correlated with scores on the Behavioral Inhibition System/Behavioral Activation System scale. Infant cries activated bilateral superior and middle temporal gyri (STG and MTG) and precentral and postcentral gyri. Activation was greater in bilateral temporal cortices for low- relative to high-distress cries. Happy relative to neutral faces activated the ventral striatum, caudate, ventromedial prefrontal, and orbitofrontal cortices. Sad versus neutral faces activated the precuneus, cuneus, and posterior cingulate cortex, and behavioral activation drive correlated with occipital cortical activations in this contrast. Behavioral inhibition correlated with activation in the right STG for high- and low-distress cries relative to pink noise. Behavioral drive correlated inversely with putamen, caudate, and thalamic activations for the comparison of high-distress cries to pink noise. Reward-responsiveness correlated with activation in the left precentral gyrus during the perception of low-distress cries relative to pink noise. Our findings indicate that infant cry stimuli elicit activations in areas implicated in auditory processing and social cognition. Happy infant faces may be encoded as rewarding, whereas sad faces activate regions associated with empathic processing. Differences in motivational tendencies may modulate neural responses to infant cues.
doi:10.1371/journal.pone.0036270
PMCID: PMC3349667  PMID: 22590530
24.  Marijuana-Using Drivers, Alcohol-Using drivers and Their Passengers: Prevalence and Risk Factors Among Underage College Students 
JAMA pediatrics  2014;168(7):618-624.
Importance
Driving after marijuana use increases the risk of a motor vehicle crash. Understanding this behavior among young drivers and how it may differ from alcohol-related driving behaviors could inform prevention efforts.
Objective
To describe prevalence, sex differences, and risk factors associated with underage college students’ driving after using marijuana, driving after drinking alcohol, or riding with a driver using these substances.
Design, Setting, Participants
Cross-sectional telephone survey of a random sample of 315 first-year college students (aged 18-20 years) from 2 large public universities, who were participating in an ongoing longitudinal study. At recruitment, 52.8% of eligible individuals consented to participate; retention was 93.2% one year later when data for this report was collected.
Main Outcome Measure(s)
Self-reported past-28-day driving after marijuana use, riding with a marijuana-using driver, driving after alcohol use, and riding with an alcohol-using driver.
Results
In the prior month, 20.3% of students had used marijuana. Among marijuana-using students, 43.9% of males and 8.7% of females drove after using marijuana (p<0.001) and 51.2% of male and 34.8% of female students rode as a passenger with a marijuana-using driver (p=0.21). Most students (65.1%) drank alcohol, and among this group 12.0% of male students and 2.7% of female students drove after drinking (p=0.01), with 20.7% and 11.5% (p=0.07), respectively, reporting riding with a drinking driver. Controlling for demographics and substance use behaviors, driving after substance use was associated with at least a 2-fold increase in risk of being a passenger with another user; the reverse was also true. A 1% increase in the reported percentage of friends using marijuana was associated with a 2% increased risk of riding with a marijuana using driver (95% CI=1.01-1.03). Among students using any substances, past 28-day use of only marijuana was associated with a 6.24-fold increased risk of driving after substance use compared to using only alcohol (95% CI=1.89-21.7).
Conclusions and Relevance
Driving and riding after marijuana use is common among underage, marijuana-using college students. This is concerning given recent legislation that may increase marijuana availability.
doi:10.1001/jamapediatrics.2013.5300
PMCID: PMC4090688  PMID: 24820649
25.  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

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