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1.  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.
PMCID: PMC2901019  PMID: 19915091
cognitive control; fMRI; orbitofrontal cortex; response inhibition; reversal learning
2.  The Association between Cue-Reactivity in the Precuneus and Level of Dependence on Nicotine and Alcohol* 
Drug and alcohol dependence  2014;141:21-26.
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.
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.
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).
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.
PMCID: PMC4166553  PMID: 24880692
precuneus; cigarettes; alcohol use disorder; fMRI; cue-reactivity; craving
3.  Risky Decision-making: Prefrontal Function and Mesocorticolimbic Resting-state Connectivity in Methamphetamine Users 
JAMA psychiatry  2014;71(7):812-820.
Various neuropsychiatric disorders, especially addictions, feature impairments in risky decision-making; clarifying the neural mechanisms underlying this problem can inform treatment.
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.
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.
Clinical research center at an academic institution.
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.
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.
PMCID: PMC4119006  PMID: 24850532
risk-taking; decision-making; prefrontal cortex; striatum; mesolimbic; fMRI; resting state
4.  Initial Evidence that Oprm1 Genotype Moderates Ventral and Dorsal Striatum Functional Connectivity During Alcohol Cues 
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.
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.
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.
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.
PMCID: PMC3808494  PMID: 23876228
OPRM1; fMRI; cue-reactivity; functional connectivity; dorsal striatum; ventral striatum
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.
PMCID: PMC3683582  PMID: 23240858
alcohol dependence; fMRI; functional connectivity; impulsivity; response inhibition; Stop Signal Task
7.  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.
PMCID: PMC3660101  PMID: 17351637
8.  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.
PMCID: PMC3225642  PMID: 22047731
Methamphetamine; Stroop; fMRI; cognitive control; prefrontal cortex; insula
9.  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.
PMCID: PMC3517177  PMID: 22623677
Response Inhibition; fMRI; Stop-signal Task; Dopamine; PET
10.  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.
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
11.  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.
PMCID: PMC3076289  PMID: 20437601
functional MRI (fMRI); social cognition; reward; learning

Results 1-11 (11)