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1.  Risk-Taking Behavior: Dopamine D2/D3 Receptors, Feedback, and Frontolimbic Activity 
Cerebral Cortex (New York, NY)  2013;25(1):236-245.
Decision-making involves frontolimbic and dopaminergic brain regions, but how prior choice outcomes, dopamine neurotransmission, and frontostriatal activity are integrated to affect choices is unclear. We tested 60 healthy volunteers using the Balloon Analogue Risk Task (BART) during functional magnetic resonance imaging. In the BART, participants can pump virtual balloons to increase potential monetary reward or cash out to receive accumulated reward; each pump presents greater risk and potential reward (represented by the pump number). In a separate session, we measured striatal D2/D3 dopamine receptor binding potential (BPND) with positron emission tomography in 13 of the participants. Losses were followed by fewer risky choices than wins; and during risk-taking after loss, amygdala and hippocampal activation exhibited greater modulation by pump number than after a cash-out event. Striatal D2/D3 BPND was positively related to the modulation of ventral striatal activation when participants decided to cash out and negatively to the number of pumps in the subsequent trial; but negatively related to the modulation of prefrontal cortical activation by pump number when participants took risk, and to overall earnings. These findings provide in vivo evidence for a potential mechanism by which dopaminergic neurotransmission may modulate risk-taking behavior through an interactive system of frontal and striatal activity.
doi:10.1093/cercor/bht218
PMCID: PMC4259280  PMID: 23966584
decision-making; dopamine receptors; fMRI; pet; risk-taking; striatum
2.  VARENICLINE, NALTREXONE, AND THEIR COMBINATION FOR HEAVY-DRINKING SMOKERS: PRELIMINARY NEUROIMAGING FINDINGS 
Rationale
Heavy drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.
Objective
The present study used a double-blind, randomized, 2×2 medication design, testing varenicline alone (VAR; 1mg twice daily), naltrexone alone (NTX; 25mg once daily), varenicline plus naltrexone, and placebo for effects on neural activation to cigarette cues in a sample (n=40) of heavy drinking daily smokers (≥10 cigarettes/day).
Methods
All participants were tested after a 10–12 day titration period designed to reach steady state on the target medication. Participants underwent functional neuroimaging (fMRI) for examination of brain responses to visual smoking-related (vs. neutral) cues.
Results
Region of interest (ROI) analyses of brain responses to cigarette vs. neutral cues indicated that the combination of VAR+NTX was associated with reduced activation of the bilateral anterior cingulate cortex as compared to placebo and to NTX alone. Exploratory whole-brain analyses also indicated significant differences in brain activation during cigarette cues in the active medications versus placebo condition. All medications suppressed left nucleus accumbens activation relative to placebo, suggesting the possibility that both medications, either alone or in combination, reduce neural signals associated with appetitive behavior.
Conclusions
Although preliminary, these neuroimaging findings indicate that clinical studies of the combination of VAR+NTX for heavy drinkers trying to quit smoking may be warranted.
doi:10.3109/00952990.2014.927881
PMCID: PMC4365972  PMID: 24949564
Naltrexone; varenicline; heavy drinker; smoker; craving; fMRI
3.  The Effect Of Alcohol Priming On Neural Markers Of Alcohol Cue-Reactivity 
Background
Priming doses of alcohol are associated with increased desire to drink and disinhibitory effects on subsequent control over drinking. Despite the importance of alcohol priming in the cue-reactivity literature, the effects of priming on brain responses to alcohol cues remains unclear. Further, evidence suggests this relationship may be moderated by OPRM1 genotype.
Methods
Twenty individuals with alcohol dependence (6 females; 90% Caucasian; mean age=29.4) who were prospectively genotyped on the OPRM1 gene underwent two functional magnetic resonance imaging (fMRI) sessions, before and after a priming dose of alcohol, each including a gustatory alcohol cue reactivity paradigm and self-reported craving measures.
Results
Self-reported alcohol craving generally increased and remained higher for alcohol versus water cue presentations across pre- and post-priming scans. Compared to alcohol cues delivered during the post-priming scan, alcohol cues delivered pre-priming were associated with greater activation in regions including the hippocampus, amygdala, inferior frontal gyrus, temporal cortex, and occipital cortex. Controlling for alcoholism severity increased statistical significance of activation in these regions. Follow-up analyses revealed a positive correlation between alcoholism severity and pre- versus post-priming alcohol cue-reactivity primarily in frontal regions. OPRM1 genotype was also found to moderate alcohol cue-reactivity across scans.
Conclusion
This study provides initial evidence of alcohol cue-elicited habituation in fronto-temporal regions, despite continued craving, following a priming dose of alcohol. Further, it provides preliminary evidence for moderating roles of alcoholism severity and OPRM1 genotype on priming-related changes in cue-reactivity, adding to our understanding of the function of alcohol priming in alcohol dependence.
doi:10.3109/00952990.2015.1044608
PMCID: PMC4651007  PMID: 26125586
fMRI; cue-reactivity; priming; alcohol; alcoholism
4.  Distinct representations of configural and part information across multiple face-selective regions of the human brain 
Frontiers in Psychology  2015;6:1710.
Several regions of the human brain respond more strongly to faces than to other visual stimuli, such as regions in the amygdala (AMG), superior temporal sulcus (STS), and the fusiform face area (FFA). It is unclear if these brain regions are similar in representing the configuration or natural appearance of face parts. We used functional magnetic resonance imaging of healthy adults who viewed natural or schematic faces with internal parts that were either normally configured or randomly rearranged. Response amplitudes were reduced in the AMG and STS when subjects viewed stimuli whose configuration of parts were digitally rearranged, suggesting that these regions represent the 1st order configuration of face parts. In contrast, response amplitudes in the FFA showed little modulation whether face parts were rearranged or if the natural face parts were replaced with lines. Instead, FFA responses were reduced only when both configural and part information were reduced, revealing an interaction between these factors, suggesting distinct representation of 1st order face configuration and parts in the AMG and STS vs. the FFA.
doi:10.3389/fpsyg.2015.01710
PMCID: PMC4635218  PMID: 26594191
occipito-temporal cortex; FFA; amygdala; STS; face; configuration; parts; holistic representation
5.  Striatal D1- and D2-type Dopamine Receptors Are Linked to Motor Response Inhibition in Human Subjects 
The Journal of Neuroscience  2015;35(15):5990-5997.
Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [11C]NNC-112 and [18F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition.
doi:10.1523/JNEUROSCI.4850-14.2015
PMCID: PMC4397600  PMID: 25878272
dopamine; impulsivity; PET imaging
6.  Varenicline, Low Dose naltrexone, and their combination for heavy-drinking smokers: Human laboratory findings 
Psychopharmacology  2014;231(19):3843-3853.
Rationale
Heavy drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.
Objectives
The present study used a double-blind, randomized, 2×2 medication design, testing varenicline alone (VAR; 1mg twice daily), low dose naltrexone alone (L-NTX; 25mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n=130) of heavy drinking daily smokers (≥10 cigarettes/day).
Methods
All participants were tested after a 9-day titration period designed to reach steady state on the target medication. Testing was completed at 12-hrs of nicotine abstinence, after consuming a standard dose of alcohol (target Breath Alcohol Concentration = 0.06 g/dl), and after smoking the first cigarette of the day.
Results
The combination of VAR+L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol “high,” and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period.
Conclusions
These preliminary findings indicate that clinical studies of the combination of VAR+L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers.
doi:10.1007/s00213-014-3519-0
PMCID: PMC4161630  PMID: 24733235
Naltrexone; varenicline; heavy drinker; smoker; human lab; craving
7.  The Association between Cue-Reactivity in the Precuneus and Level of Dependence on Nicotine and Alcohol* 
Drug and alcohol dependence  2014;141:21-26.
Background
Given numerous reports implicating involvement of the precuneus in cue-reactivity paradigms, the goal of this investigation was to examine the relationship between activation of the precuneus in response to drug cues and measures of subjective craving and severity of dependence in volunteers who were comorbid for alcohol and nicotine abuse.
Methods
Forty research participants, who all reported heavy drinking and daily smoking, were recruited (15 women; 70% Caucasian; mean age = 31.2 years) for a functional magnetic resonance imaging (fMRI) session involving a cigarette video-cues task and an alcohol taste-cues task. Mean precuneus activation from both tasks during cue presentation was subjected to bivariate correlation analyses with indices of dependence severity and subjective craving.
Results
Precuneus activation in the contrast of Cigarette Cues vs. Control Cues was positively correlated with scores on the Fagerström Test of Nicotine Dependence (r=0.389, p=0.016), and activation in the Alcohol Cues vs. Control Cues contrast was positively correlated with Alcohol Dependence Scale scores (r=0.338, p=0.038). No correlations with subjective craving were observed (ps>0.05).
Conclusions
These findings indicate that the precuneus is involved in cue reactivity for both cigarettes and alcohol, and that this involvement is moderated by severity of drug dependence. The precuneus may be a cortical locus for neuroplastic changes related to drug dependence.
doi:10.1016/j.drugalcdep.2014.04.026
PMCID: PMC4166553  PMID: 24880692
precuneus; cigarettes; alcohol use disorder; fMRI; cue-reactivity; craving
8.  Cigarette Exposure, Dependence, and Craving Are Related to Insula Thickness in Young Adult Smokers 
Neuropsychopharmacology  2014;39(8):1816-1822.
The age period spanning late adolescence to emergent adulthood is associated with the highest prevalence of cigarette smoking in the United States, and is also a time of continued brain development. Nonetheless, although prior research has shown group differences in brain structure associated with smoking status in adults, few studies have examined how smoking and associated behavioral states relate to brain structure in this age group. Neuroimaging and lesion studies have suggested that the insula, a cortical region that integrates heterogeneous signals about internal states and contributes to executive functions, plays an important role in cigarette smoking behavior. Using high-resolution structural magnetic resonance imaging, we therefore measured cortical thickness of the insula in 18 smokers and 24 nonsmokers between the ages of 16 and 21 years. There were no group differences in insula thickness, but cigarette exposure (pack-years) was negatively associated with thickness in right insula. Cigarette dependence and the urge to smoke were negatively related to cortical thickness in the right ventral anterior insula. Although the results do not demonstrate causation, they do suggest that there are effects of cigarette exposure on brain structure in young smokers, with a relatively short smoking history. It is possible that changes in the brain due to prolonged exposure or to the progression of dependence lead to more extensive structural changes, manifested in the reported group differences between adult smokers and nonsmokers. Structural integrity of the insula may have implications for predicting long-term cigarette smoking and problems with other substance abuse in this population.
doi:10.1038/npp.2014.48
PMCID: PMC4059909  PMID: 24584328
9.  Risky Decision-making: Prefrontal Function and Mesocorticolimbic Resting-state Connectivity in Methamphetamine Users 
JAMA psychiatry  2014;71(7):812-820.
Importance
Various neuropsychiatric disorders, especially addictions, feature impairments in risky decision-making; clarifying the neural mechanisms underlying this problem can inform treatment.
Objective
To determine how methamphetamine-dependent and control subjects differ in brain activation during a risky decision-making task, resting-state functional connectivity within mesolimbic and executive control circuits, and the relationships between these measures.
Design
A case-control, functional magnetic resonance imaging study of methamphetamine-dependent and healthy comparison participants at rest and when performing the Balloon Analogue Risk Task, which involves the choice to pump a balloon or to cash out in the context of uncertain risk.
Setting
Clinical research center at an academic institution.
Participants
Twenty-five methamphetamine-dependent and 27 control subjects.
Main Outcomes and Measures
1) Parametric modulation of activation in the striatum and right dorsolateral prefrontal cortex, i.e., the degree to which activation changed as a linear function of risk and potential reward, both indexed by pump number; and 2) resting-state functional connectivity, measured in whole brain with seeds in the midbrain and right dorsolateral prefrontal cortex. Relationships between these outcomes were also tested.
Results
Parametric modulation of cortical and striatal activation by pump number during risk-taking differed with group. It was stronger in the ventral striatum but weaker in the right dorsolateral prefrontal cortex in methamphetamine-dependent participants than controls. Methamphetamine-dependent subjects also exhibited greater resting-state functional connectivity of the midbrain with the putamen, amygdala, and hippocampus. This connectivity was negatively related to modulation of right dorsolateral prefrontal cortex activation by risk level during risky decision-making. In controls, parametric modulation of right dorsolateral prefrontal cortex activation by risk during decision-making was positively related to resting-state functional connectivity of the right dorsolateral prefrontal cortex with the striatum.
Conclusions and Relevance
Maladaptive decision-making by methamphetamine users may reflect circuit-level dysfunction, underlying deficits in task-based activation. Heightened resting-state connectivity within the mesocorticolimbic system, coupled with reduced prefrontal cortical connectivity, may create a bias toward reward-driven behavior over cognitive control in methamphetamine users. Interventions to improve this balance may enhance treatments for stimulant dependence and other disorders that involve maladaptive decision-making.
doi:10.1001/jamapsychiatry.2014.399
PMCID: PMC4119006  PMID: 24850532
risk-taking; decision-making; prefrontal cortex; striatum; mesolimbic; fMRI; resting state
10.  Initial Evidence that Oprm1 Genotype Moderates Ventral and Dorsal Striatum Functional Connectivity During Alcohol Cues 
Background
Endogenous opioids and striatal dopamine have been implicated in cue-induced alcohol craving and have been hypothesized to play a role in goal-directed, as opposed to habitual, alcohol use. This initial study examines dorsal and ventral-striatal functional connectivity during alcohol cue processing as a function of the A118G single nucleotide polymorphism (SNP) of the mu opioid receptor (OPRM1) gene.
Method
Seventeen individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing an alcohol taste-cues task. Psychophysiological interaction (PPI) analyses investigated associations of the OPRM1 genotype with ventral and dorsal striatum functional connectivity, using the ventral striatum and the caudate as the seed region, respectively.
Results
Compared to A-allele homozygotes, G-allele carriers of the OPRM1 gene showed (a) greater activation of the insula and orbitofrontal cortex and (b) stronger negative fronto-striatal functional connectivity for both ventral and dorsal striatal seed regions during processing of alcohol versus water cues.
Conclusions
These preliminary findings suggest that, relative to A-allele homozygotes, G-allele carriers show unstable frontal regulation over reward and/or habit-driven inputs from the striatum resulting from greater reward sensitivity combined with limited self-control resources.
doi:10.1111/acer.12136
PMCID: PMC3808494  PMID: 23876228
OPRM1; fMRI; cue-reactivity; functional connectivity; dorsal striatum; ventral striatum
12.  FRONTO-STRIATAL FUNCTIONAL CONNECTIVITY DURING RESPONSE INHIBITION IN ALCOHOL DEPENDENCE 
Addiction biology  2012;18(3):593-604.
Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the µ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing a Stop Signal Task (SST). The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction (PPI) analyses. Analyses revealed greater alcohol dependence severity associated with weaker functional connectivity between the putamen and prefrontal regions (e.g., the anterior insula, anterior cingulate, and medial prefrontal cortex) during response inhibition. Further, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses.
doi:10.1111/adb.12013
PMCID: PMC3683582  PMID: 23240858
alcohol dependence; fMRI; functional connectivity; impulsivity; response inhibition; Stop Signal Task
13.  Differential development of high-level visual cortex correlates with category-specific recognition memory 
Nature neuroscience  2007;10(4):512-522.
High-level visual cortex in humans includes functionally defined regions that preferentially respond to objects, faces and places. It is unknown how these regions develop and whether their development relates to recognition memory. We used functional magnetic resonance imaging to examine the development of several functionally defined regions including object (lateral occipital complex, LOC)-, face (‘fusiform face area’, FFA; superior temporal sulcus, STS)- and place (‘parahippocampal place area’, PPA)-selective cortices in children (ages 7–11), adolescents (12–16) and adults. Right FFA and left PPA volumes were substantially larger in adults than in children. This development occurred by expansion of FFA and PPA into surrounding cortex and was correlated with improved recognition memory for faces and places, respectively. In contrast, LOC and STS volumes and object-recognition memory remained constant across ages. Thus, the ventral stream undergoes a prolonged maturation that varies temporally across functional regions, is determined by brain region rather than stimulus category, and is correlated with the development of category-specific recognition memory.
doi:10.1038/nn1865
PMCID: PMC3660101  PMID: 17351637
14.  Prefrontal hypoactivation during cognitive control in early abstinent methamphetamine-dependent subjects 
Psychiatry research  2011;194(3):287-295.
Individuals who abuse methamphetamine (MA) perform at levels below those of healthy controls on tests that require cognitive control. As cognitive control deficits may influence the success of treatment for addiction, we sought to help clarify the neural correlates of this deficit. MA-dependent (n=10, abstinent 4–7 days) and control subjects (n=18) performed a color-word Stroop task, which requires cognitive control, during functional MRI (fMRI). The task included a condition in which participants were required to respond to one stimulus dimension while ignoring another conflicting dimension, and another condition without conflict. We compared the groups on performance and neural activation in the two conditions. MA-dependent subjects made more errors and responded more slowly than controls. Controlling for response times in the incongruent condition, voxel-wise mixed effects analyses (whole-brain corrected) demonstrated that MA-dependent subjects had less activation than control subjects in the right inferior frontal gyrus, supplementary motor cortex/anterior cingulate gyrus and the anterior insular cortex during the incongruent condition only. MA-dependent subjects did not exhibit greater activation in any brain region in either of the Stroop conditions. These preliminary findings suggest that hypofunction in cortical areas that are important for executive function underlies cognitive control deficits associated with MA dependence.
doi:10.1016/j.pscychresns.2011.04.010
PMCID: PMC3225642  PMID: 22047731
Methamphetamine; Stroop; fMRI; cognitive control; prefrontal cortex; insula
15.  Striatal dopamine D2/D3 receptors mediate response inhibition and related activity in frontostriatal neural circuitry in humans 
Impulsive behavior is thought to reflect a trait-like characteristic that can have broad consequences for an individual’s success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D2-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D2-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D2/D3 dopamine-receptor ligand [18F]fallypride, and blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D2/D3-receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time), and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D2/D3 receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D2-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.
doi:10.1523/JNEUROSCI.4284-11.2012
PMCID: PMC3517177  PMID: 22623677
Response Inhibition; fMRI; Stop-signal Task; Dopamine; PET
16.  Effect of Modafinil on Learning and Task-Related Brain Activity in Methamphetamine-Dependent and Healthy Individuals 
Neuropsychopharmacology  2011;36(5):950-959.
Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function. Therefore, medications that improve cognition in these subjects may improve the success of therapy for their addiction, especially when cognitive behavioral therapies are used. Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers. We therefore conducted a randomized, double-blind, placebo-controlled, cross-over study, using functional magnetic resonance imaging, to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent, MA-dependent, and healthy control participants. Modafinil (200 mg) and placebo were administered orally (one single dose each), in counterbalanced fashion, 2 h before each of two testing sessions. Under placebo conditions, MA-dependent participants showed worse learning performance than control participants. Modafinil boosted learning in MA-dependent participants, bringing them to the same performance level as control subjects; the control group did not show changes in performance with modafinil. After controlling for performance differences, MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants. The findings suggest that modafinil improves learning in MA-dependent participants, possibly by enhancing neural function in regions important for learning and cognitive control. These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence.
doi:10.1038/npp.2010.233
PMCID: PMC3077264  PMID: 21289606
modafinil; fMRI; methamphetamine; anterior cingulate; learning; drug abuse; addiction & substance abuse; learning & memory; imaging, clinical or preclinical; psychopharmacology; modafinil; fMRI; methamphetamine; anterior cingulate; learning
17.  Neural Components Underlying Behavioral Flexibility in Human Reversal Learning 
Cerebral Cortex (New York, NY)  2009;20(8):1843-1852.
The ability to flexibly respond to changes in the environment is critical for adaptive behavior. Reversal learning (RL) procedures test adaptive response updating when contingencies are altered. We used functional magnetic resonance imaging to examine brain areas that support specific RL components. We compared neural responses to RL and initial learning (acquisition) to isolate reversal-related brain activation independent of cognitive control processes invoked during initial feedback-based learning. Lateral orbitofrontal cortex (OFC) was more activated during reversal than acquisition, suggesting its relevance for reformation of established stimulus–response associations. In addition, the dorsal anterior cingulate (dACC) and right inferior frontal gyrus (rIFG) correlated with change in postreversal accuracy. Because optimal RL likely requires suppression of a prior learned response, we hypothesized that similar regions serve both response inhibition (RI) and inhibition of learned associations during reversal. However, reversal-specific responding and stopping (requiring RI and assessed via the stop-signal task) revealed distinct frontal regions. Although RI-related regions do not appear to support inhibition of prepotent learned associations, a subset of these regions, dACC and rIFG, guide actions consistent with current reward contingencies. These regions and lateral OFC represent distinct neural components that support behavioral flexibility important for adaptive learning.
doi:10.1093/cercor/bhp247
PMCID: PMC2901019  PMID: 19915091
cognitive control; fMRI; orbitofrontal cortex; response inhibition; reversal learning
18.  Reward Processing in Autism 
The social motivation hypothesis of autism posits that infants with autism do not experience social stimuli as rewarding, thereby leading to a cascade of potentially negative consequences for later development. While possible downstream effects of this hypothesis such as altered face and voice processing have been examined, there has not been a direct investigation of social reward processing in autism. Here we use functional magnetic resonance imaging to examine social and monetary rewarded implicit learning in children with and without autism spectrum disorders (ASD). Sixteen males with ASD and sixteen age- and IQ-matched typically developing (TD) males were scanned while performing two versions of a rewarded implicit learning task. In addition to examining responses to reward, we investigated the neural circuitry supporting rewarded learning and the relationship between these factors and social development. We found diminished neural responses to both social and monetary rewards in ASD, with a pronounced reduction in response to social rewards (SR). Children with ASD also demonstrated a further deficit in frontostriatal response during social, but not monetary, rewarded learning. Moreover, we show a relationship between ventral striatum activity and social reciprocity in TD children. Together, these data support the hypothesis that children with ASD have diminished neural responses to SR, and that this deficit relates to social learning impairments.
doi:10.1002/aur.122
PMCID: PMC3076289  PMID: 20437601
functional MRI (fMRI); social cognition; reward; learning
19.  Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2 
Science translational medicine  2010;2(56):56ra80.
Genetic studies are rapidly identifying variants that shape risk for disorders of human cognition, but the question of how such variants predispose to neuropsychiatric disease remains. Noninvasive human brain imaging allows assessment of the brain in vivo, and the combination of genetics and imaging phenotypes remains one of the only ways to explore functional genotype-phenotype associations in human brain. Common variants in contactin-associated protein-like 2 (CNTNAP2), a neurexin superfamily member, have been associated with several allied neurodevelopmental disorders, including autism and specific language impairment, and CNTNAP2 is highly expressed in frontal lobe circuits in the developing human brain. Using functional neuroimaging, we have demonstrated a relationship between frontal lobar connectivity and common genetic variants in CNTNAP2. These data provide a mechanistic link between specific genetic risk for neurodevelopmental disorders and empirical data implicating dysfunction of long-range connections within the frontal lobe in autism. The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such asautism in part through modulation of frontal lobe connectivity.
doi:10.1126/scitranslmed.3001344
PMCID: PMC3065863  PMID: 21048216

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