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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.
PMCID: PMC2930251  PMID: 20729530
2.  Influence of Alcohol Use and Family History of Alcoholism on Neural Response to Alcohol Cues in College Drinkers 
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
PMCID: PMC3646913  PMID: 23667541
7.  Visual Image-Induced Craving for Ethanol (VICE): Development, Validation, and a Pilot fMRI Study 
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.
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.
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.
PMCID: PMC4031585  PMID: 24860218
Alcohol; craving; imaging; neurobiology; symptom provocation
8.  Neural Correlates of Verbal Learning in Adolescent Alcohol and Marijuana Users 
Addiction (Abingdon, England)  2010;106(3):564-573.
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.
Participants performed a verbal paired associates encoding task during fMRI scanning.
Adolescent subjects were recruited from local public schools and imaged at a University-based fMRI Center.
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.
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.
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.
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.
PMCID: PMC3423457  PMID: 21134014
adolescence; functional magnetic resonance imaging; verbal learning; cannabis; alcohol; binge drinking
9.  Activation in brain energy regulation and reward centers by food cues varies with choice of visual stimulus 
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.
Functional magnetic resonance imaging (fMRI) was used to compare brain activation in regions of interest between groups of food photographs.
10 healthy, nonobese women who were not dieting for weight loss.
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.
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.
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.
PMCID: PMC2697279  PMID: 19365394
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.
PMCID: PMC3066261  PMID: 21316465
alcohol; fMRI; cue reactivity; ventral striatum; dorsal striatum; HLM
11.  Prospective associations between brain activation to cocaine and no-go cues and cocaine relapse* 
Drug and alcohol dependence  2013;131(0):44-49.
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.
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.
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.
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.
PMCID: PMC3703628  PMID: 23683790
fMRI; cue; go no-go; urine drug screen; cocaine; relapse
12.  fMRI Response During Figural Memory Task Performance in College Drinkers 
Psychopharmacology  2013;231(1):10.1007/s00213-013-3219-1.
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.
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.
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).
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).
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.
PMCID: PMC3877735  PMID: 23949205
Alcohol; Adolescent; Young Adult; fMRI; Learning; Memory; Cognition
13.  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.
PMCID: PMC3359800  PMID: 22329835
abstinence; cue-reactivity; craving; heroin dependence; fMRI
14.  Alcohol Affects Neuronal Substrates of Response Inhibition but Not of Perceptual Processing of Stimuli Signalling a Stop Response 
PLoS ONE  2013;8(9):e76649.
Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour.
PMCID: PMC3783488  PMID: 24086758
15.  Distinct and convergent visual processing of high and low spatial-frequency information in faces 
We tested for differential brain response to distinct spatial-frequency (SF) components in faces. During an fMRI experiment, participants were presented with ‘hybrid’ faces containing superimposed low and high SF information from different identities. We used a repetition paradigm where faces at either SF range were independently repeated or changed across consecutive trials. In addition, we manipulated which SF band was attended. Our results suggest that repetition and attention affected partly overlapping occipito-temporal regions but did not interact. Changes of high SF faces increased responses of the right inferior occipital gyrus (IOG) and left inferior temporal gyrus (ITG), with the latter response being also modulated additively by attention. In contrast, the bilateral middle occipital gyrus (MOG) responded to repetition and attention manipulations of low SF. A common effect of high and low SF repetition was observed in the right fusiform gyrus (FFG). Follow-up connectivity analyses suggested direct influence of the MOG (low SF), IOG and ITG (high SF) on the FFG responses. Our results reveal that different regions within occipito-temporal cortex extract distinct visual cues at different SF ranges in faces, and that the outputs from these separate processes project forward to the right FFG, where the different visual cues may converge.
PMCID: PMC2600423  PMID: 17283203
attention; DCM; fMRI; human; occipito-temporal cortex; repetition
16.  Simultaneous and Concurrent Polydrug Use of Alcohol and Prescription Drugs: Prevalence, Correlates, and Consequences* 
Journal of studies on alcohol  2006;67(4):529-537.
In this study, we sought to examine the prevalence, correlates, and consequences associated with simultaneous polydrug use and concurrent polydrug use of alcohol and prescription drugs. For purposes of this investigation, simultaneous polydrug use referred to the co-ingestion of different drugs at the same time, and concurrent polydrug use referred to the use of different drugs on separate occasions within the past 12 months.
Undergraduate students attending a large public midwestern university in the United Sates were randomly selected to self-administer a Web survey. The sample consisted of 4,580 undergraduate students, with a mean (SD) age of 19.9 (2.0) years; the sample consisted of 50% women, and the racial breakdown was 65% while, 13% Asian, 7% black, 5% Hispanic, and 10% other race/ethnicity. The survey assessed simultaneous polydrug use and concurrent polydrug use of alcohol and four classes of prescription drugs: (1) pain medication, (2) stimulant medication, (3) sedative medication, and (4) sleeping medication.
The 12 month prevalence for polydrug use involving alcohol and abusable prescription drugs was 12.1% (including 6.9% simultaneous polydrug use). The majority of polydrug use involving alcohol and each class of prescription drugs was simultaneous polydrug use, with the exception of sleeping medication. Simultaneous polydrug use was more prevalent among undergraduate students who were male, were white, and reported early initiation of alcohol use. Simultaneous polydrug was associated with more alcohol-related and other drug use-related problems than concurrent polydrug use.
Based on the high prevalence and increased risk for consequences associated with simultaneous polydrug use of alcohol and prescription drugs, collegiate prevention efforts aimed at reducing substance abuse should clearly focus on co-ingestion of alcohol and prescription drugs.
PMCID: PMC1761923  PMID: 16736072
17.  Neural Substrates of Resisting Craving during Cigarette Cue Exposure 
Biological psychiatry  2007;62(6):642-651.
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.
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.
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.
Suppressing craving during cigarette cue exposure involves activation of limbic (and related) brain regions and deactivation of primary sensory and motor cortices.
PMCID: PMC1992815  PMID: 17217932
Nicotine Dependence; functional magnetic resonance imaging; cue-induced cigarette craving; cingulate cortex; visual cortex
18.  24-hr smoking abstinence potentiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum 
Psychopharmacology  2008;204(1):25-35.
Exposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence.
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).
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.
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).
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.
PMCID: PMC2810714  PMID: 19107465
cue-reactivity; craving; nicotine dependence; fMRI; smoking; dorsal striatum
19.  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
20.  Alcohol Sensitizes Cerebral Responses to the Odors of Alcoholic Drinks: An fMRI Study 
Small, priming doses of alcohol enhance desire to drink, and thus play a role in the loss of control of alcohol consumption. Using functional magnetic resonance imaging (fMRI), we previously showed that alcoholic drink odors (AO; subjects’ drinks of choice) induce greater nucleus accumbens (NAc) activity than non-appetitive odors (NApO; grass, leather) in subjects at risk for alcoholism. Here we hypothesized that priming exposure to alcohol would enhance responses to AO in the NAc and orbitofrontal cortex in comparison to NApO (grass, leather) and to the appetitive control odors (ApCO) of chocolate and grape.
Ten hazardous drinkers (mean age = 22.7; SD = 2.9, average drinks per drinking day = 5.9, SD = 2.3; drinking days/90 days = 50.4, SD = 13.7) were scanned on a 1.5T GE Signa MR scanner during intravenous infusion of lactated Ringer’s or 6% ethanol in lactated Ringer’s that was pharmacokinetically modeled to achieve a constant breath alcohol concentration (BrAC) of 50 mg% throughout imaging. During scanning, subjects sniffed AO, NApO, and ApCO.
Alcohol infusion enhanced the contrast between AO and NApO in the NAc, and in orbitofrontal, medial frontal, and precuneus/posterior cingulate regions. The contrast between AO and appetitive control odors (ApCO; chocolate and grape) was similarly larger in the orbital, medial frontal, precuneus, and posterior cingulate/retrosplenial areas, with the most robust finding being a potentiated response in the posterior cingulate/retrosplenial area. The orbital region is similar to an area previously shown to manifest satiety-related decreases in activity induced by food cues.
The results suggest that priming exposure to alcohol renders a limbic network more responsive to alcohol cues, potentially enhancing desire to drink.
PMCID: PMC2905852  PMID: 18540915
fMRI; Olfaction; Alcohol; Alcoholism; Orbitofrontal; Nucleus Accumbens; Posterior Cingulate
21.  Reward-related Brain Response and Craving Correlates of Marijuana Cue Exposure: A Preliminary Study in Treatment-Seeking Marijuana-Dependent Subjects 
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.
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.
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).
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.
PMCID: PMC3567235  PMID: 23188041
Cannabis; Marijuana Cues; Craving; Neuroimaging; Addiction; Brain Reward Circuitry
22.  Brain activity and desire for internet video game play 
Comprehensive psychiatry  2011;52(1):88-95.
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.
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.
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.
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.
PMCID: PMC3039876  PMID: 21220070
internet video game play; functional MRI; frontal cortex; parahippocampal gyrus; thalamus
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.
PMCID: PMC3349667  PMID: 22590530
24.  Neural mechanisms underlying the facilitation of naming in aphasia using a semantic task: an fMRI study 
BMC Neuroscience  2012;13:98.
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.
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.
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.
PMCID: PMC3477078  PMID: 22882806
Aphasia; Semantic verification; fMRI; Overt picture naming; Semantics
25.  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.
PMCID: PMC3836671  PMID: 24029699
fMRI; Marijuana IAT; habit; associative processes; memory associations; implicit cognition

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