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1.  Distinct roles of three frontal cortical areas in reward-guided behavior 
Functional magnetic resonance imaging (fMRI) was used to measure activity in three frontal cortical areas, lateral orbitofrontal cortex (lOFC), medial orbitofrontal cortex/ventromedial frontal cortex (mOFC/vmPFC), and anterior cingulate cortex (ACC) when expectations about type of reward, and not just reward presence or absence, could be learned. Two groups of human subjects learned twelve stimulus-response pairings. In one group (Consistent), correct performances of a given pairing were always reinforced with a specific reward outcome whereas in the other group (Inconsistent), correct performances were reinforced with randomly selected rewards. MOFC/vmPFC and lOFC were not distinguished by simple differences in relative preference for positive and negative outcomes. Instead lOFC activity reflected updating of reward-related associations specific to reward type; lOFC was active whenever informative outcomes allowed updating of reward-related associations regardless of whether the outcomes were positive or negative and the effects were greater when consistent stimulus-outcome and response-outcome mappings were present. A psycho-physiological interaction (PPI) analysis demonstrated changed coupling between lOFC and brain areas for visual object representation, such as perirhinal cortex, and reward-guided learning, such as amygdala, ventral striatum, and habenula /mediodorsal thalamus. By contrast mOFC/vmPFC activity reflected expected values of outcomes and occurrence of positive outcomes, irrespective of consistency of outcome mappings. The third frontal cortical region, ACC, reflected the use of reward type information to guide response selection. ACC activity reflected the probability of selecting the correct response, was greater when consistent outcome mappings were present, and was related to individual differences in propensity to select the correct response.
doi:10.1523/JNEUROSCI.6456-10.2011
PMCID: PMC3224993  PMID: 21976525
2.  The Essential Role of Primate Orbitofrontal Cortex in Conflict-Induced Executive Control Adjustment 
The Journal of Neuroscience  2014;34(33):11016-11031.
Conflict in information processing evokes trial-by-trial behavioral modulations. Influential models suggest that adaptive tuning of executive control, mediated by mid-dorsal lateral prefrontal cortex (mdlPFC) and anterior cingulate cortex (ACC), underlies these modulations. However, mdlPFC and ACC are parts of distributed brain networks including orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), and superior-dorsal lateral prefrontal cortex (sdlPFC). Contributions of these latter areas in adaptive tuning of executive control are unknown. We trained monkeys to perform a matching task in which they had to resolve the conflict between two behavior-guiding rules. Here, we report that bilateral lesions in OFC, but not in PCC or sdlPFC, impaired selection between these competing rules. In addition, the behavioral adaptation that is normally induced by experiencing conflict disappeared in OFC-lesioned, but remained normal in PCC-lesioned or sdlPFC-lesioned monkeys. Exploring underlying neuronal processes, we found that the activity of neurons in OFC represented the conflict between behavioral options independent from the other aspects of the task. Responses of OFC neurons to rewards also conveyed information of the conflict level that the monkey had experienced along the course to obtain the reward. Our findings indicate dissociable functions for five closely interconnected cortical areas suggesting that OFC and mdlPFC, but not PCC or sdlPFC or ACC, play indispensable roles in conflict-dependent executive control of on-going behavior. Both mdlPFC and OFC support detection of conflict and its integration with the task goal, but in contrast to mdlPFC, OFC does not retain the necessary information for conflict-induced modulation of future decisions.
doi:10.1523/JNEUROSCI.1637-14.2014
PMCID: PMC4131015  PMID: 25122901
conflict; executive control; lesion study; orbitofrontal cortex
3.  Altered functional connectivity within the central reward network in overweight and obese women 
Nutrition & Diabetes  2015;5(1):e148-.
Background/Objectives:
Neuroimaging studies in obese subjects have identified abnormal activation of key regions of central reward circuits, including the nucleus accumbens (NAcc), in response to food-related stimuli. We aimed to examine whether women with elevated body mass index (BMI) show structural and resting state (RS) functional connectivity alterations within regions of the reward network.
Subjects/Methods:
Fifty healthy, premenopausal women, 19 overweight and obese (high BMI=26–38 kg m−2) and 31 lean (BMI=19–25 kg m−2) were selected from the University of California Los Angeles' Oppenheimer Center for Neurobiology of Stress database. Structural and RS functional scans were collected. Group differences in grey matter volume (GMV) of the NAcc, oscillation dynamics of intrinsic brain activity and functional connectivity of the NAcc to regions within the reward network were examined.
Results:
GMV of the left NAcc was significantly greater in the high BMI group than in the lean group (P=0.031). Altered frequency distributions were observed in women with high BMI compared with lean group in the left NAcc (P=0.009) in a medium-frequency (MF) band, and in bilateral anterior cingulate cortex (ACC) (P=0.014, <0.001) and ventro-medial prefrontal cortex (vmPFC) (P=0.034, <0.001) in a high-frequency band. Subjects with high BMI had greater connectivity of the left NAcc with bilateral ACC (P=0.024) and right vmPFC (P=0.032) in a MF band and with the left ACC (P=0.03) in a high frequency band.
Conclusions:
Overweight and obese women in the absence of food-related stimuli show significant structural and functional alterations within regions of reward-related brain networks, which may have a role in altered ingestive behaviors.
doi:10.1038/nutd.2014.45
PMCID: PMC4314578  PMID: 25599560
4.  Neurobiology of Decision-Making in Adolescents 
Behavioural brain research  2010;217(1):67-76.
The study examined the relationship between risk-taking behavior during selection of monetary rewards and activations in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), brain regions that are associated with decision-making. Thirty-three adolescents with no personal or family history of any psychiatric illness were administered the Wheel of Fortune (WOF) task using a functional magnetic resonance imaging protocol. The WOF is a computerized two-choice, probabilistic monetary reward task. Selection of a reward, particularly a low-probability/high-magnitude reward choice, induced greater activations in dorsal ACC, ventrolateral OFC and mPFC than the control condition. Although similar findings have been reported by earlier studies, the results from this study were not impacted by reaction times and expected values and persisted even after controlling for sociodemographic factors. Post-hoc analysis revealed greater activation of ACC and mPFC in response to selection of rewards of larger magnitude than those of smaller magnitude when the probability of reward was maintained constant. Adolescents with greater frequency of high-risk behavior (defined as low-probability/high magnitude reward choice) had lower activation of ACC, OFC and mPFC than those who engaged in this behavior less frequently. These findings suggest individual differences in prefrontal cortical function with regards to decision-making process in adolescents.
doi:10.1016/j.bbr.2010.09.033
PMCID: PMC3004983  PMID: 20933020
Neurobiology; choice; selection; adolescents; decision-making; rewards
5.  Symptom dimensions are associated with reward processing in unmedicated persons at risk for psychosis 
There is growing evidence that reward processing is disturbed in schizophrenia. However, it is uncertain whether this dysfunction predates or is secondary to the onset of psychosis. Studying 21 unmedicated persons at risk for psychosis plus 24 healthy controls (HCs) we used a incentive delay paradigm with monetary rewards during functional magnetic resonance imaging. During processing of reward information, at-risk individuals performed similarly well to controls and recruited the same brain areas. However, while anticipating rewards, the high-risk sample exhibited additional activation in the posterior cingulate cortex, and the medio- and superior frontal gyrus, whereas no significant group differences were found after rewards were administered. Importantly, symptom dimensions were differentially associated with anticipation and outcome of the reward. Positive symptoms were correlated with the anticipation signal in the ventral striatum (VS) and the right anterior insula (rAI). Negative symptoms were inversely linked to outcome-related signal within the VS, and depressive symptoms to outcome-related signal within the medial orbitofrontal cortex (mOFC). Our findings provide evidence for a reward-associated dysregulation that can be compensated by recruitment of additional prefrontal areas. We propose that stronger activations within VS and rAI when anticipating a reward reflect abnormal processing of potential future rewards. Moreover, according to the aberrant salience theory of psychosis, this may predispose a person to positive symptoms. Additionally, we report evidence that negative and depressive symptoms are differentially associated with the receipt of a reward, which might demonstrate a broader vulnerability to motivational and affective symptoms in persons at-risk for psychosis.
doi:10.3389/fnbeh.2014.00382
PMCID: PMC4235359  PMID: 25477792
reward; salience processing; psychosis; ventral striatum; anterior insula; dopamine; at-risk mental state; functional magnetic resonance imaging (fMRI)
6.  Developmental effects of decision-making on sensitivity to reward: An fMRI study 
Studies comparing neural correlates of reward processing across development yield inconsistent findings. This challenges theories characterizing adolescents as globally hypo- or hypersensitive to rewards. Developmental differences in reward sensitivity may fluctuate based on reward magnitude, and on whether rewards require decision-making. We examined whether these factors modulate developmental differences in neural response during reward anticipation and/or receipt in 26 adolescents (14.05±2.37yrs) and 26 adults (31.25±8.23yrs). Brain activity was assessed with fMRI during reward anticipation, when subjects made responses with-vs.-without decision-making, to obtain large–vs.–small rewards, and during reward receipt. When reward-receipt required decision-making, neural activity did not differ by age. However, when reward receipt did not require decision-making, neural activity varied by development, reward magnitude, and stage of the reward task. During anticipation, adolescents, but not adults, exhibited greater activity in the insula, extending into putamen, and cingulate gyrus for large-vs.-small incentives. During feedback, adults, but not adolescents, exhibited greater activity in the precuneus for large-vs.-small incentives. These data indicate that age-related differences in reward sensitivity cannot be characterized by global hypo- or hyper-responsivity. Instead, neural responding in striatum, prefrontal cortex and precuneus is influenced by both situational demands and developmental factors. This suggests nuanced maturational effects in adolescent reward sensitivity.
doi:10.1016/j.dcn.2012.04.002
PMCID: PMC3427023  PMID: 22591860
reward; incentive; brain; fMRI; development; adolescents; decision-making
7.  Prefrontal Cortex and Drug Abuse Vulnerability: Translation to Prevention and Treatment Interventions 
Brain research reviews  2010;65(2):124-149.
Vulnerability to drug abuse is related to both reward seeking and impulsivity, two constructs thought to have a biological basis in the prefrontal cortex (PFC). This review addresses similarities and differences in neuroanatomy, neurochemistry and behavior associated with PFC function in rodents and primates. Emphasis is placed on monoamine and amino acid neurotransmitter systems located in anatomically distinct subregions: medial prefrontal cortex (mPFC); lateral prefrontal cortex (lPFC); anterior cingulate cortex (ACC); and orbitofrontal cortex (OFC). While there are complex interconnections and overlapping functions among these regions, each is thought to be involved in various functions related to health-related risk behaviors and drug abuse vulnerability. Among the various functions implicated, evidence suggests that mPFC is involved in reward processing, attention and drug reinstatement; lPFC is involved in decision-making, behavioral inhibition and attentional gating; ACC is involved in attention, emotional processing and self-monitoring; and OFC is involved in behavioral inhibition, signaling of expected outcomes and reward/punishment sensitivity. Individual differences factors (e.g., age and sex) influence functioning of these regions, which, in turn, impacts drug abuse vulnerability. Implications for the development of drug abuse prevention and treatment strategies aimed at engaging PFC inhibitory processes that may reduce risk-related behaviors are discussed, including the design of effective public service announcements, cognitive exercises, physical activity, direct current stimulation, feedback control training and pharmacotherapies. A major challenge in drug abuse prevention and treatment rests with improving intervention strategies aimed at strengthening PFC inhibitory systems among at-risk individuals.
doi:10.1016/j.brainresrev.2010.09.001
PMCID: PMC3005953  PMID: 20837060
Anterior cingulate cortex; Dopamine; Drug abuse; GABA; Glutamate; Impulsivity; Lateral prefrontal cortex; Medial prefrontal cortex; Norepinephrine; Orbitofrontal cortex; Serotonin
8.  The Value of Success: Acquiring Gains, Avoiding Losses, and Simply Being Successful 
PLoS ONE  2011;6(9):e25307.
A large network of spatially contiguous, yet anatomically distinct regions in medial frontal cortex is involved in reward processing. Although it is clear these regions play a role in critical aspects of reward-related learning and decision-making, the individual contributions of each component remains unclear. We explored dissociations in reward processing throughout several key regions in the reward system and aimed to clarify the nature of previously observed outcome-related activity in a portion of anterior medial orbitofrontal cortex (mOFC). Specifically, we tested whether activity in anterior mOFC was related to processing successful actions, such that this region would respond similarly to rewards with and without tangible benefits, or whether this region instead encoded only quantifiable outcome values (e.g., money). Participants performed a task where they encountered monetary gains and losses (and non-gains and non-losses) during fMRI scanning. Critically, in addition to the outcomes with monetary consequences, the task included trials that provided outcomes without tangible benefits (participants were simply told that they were correct or incorrect). We found that anterior mOFC responded to all successful outcomes regardless of whether they carried tangible benefits (monetary gains and non-losses) or not (controls). These results support the hypothesis that anterior mOFC processes rewards in terms of a common currency and is capable of providing reward-based signals for everything we value, whether it be primary or secondary rewards or simply a successful experience without objectively quantifiable benefits.
doi:10.1371/journal.pone.0025307
PMCID: PMC3178646  PMID: 21966494
9.  Measuring extrastriatal dopamine release during a reward learning task 
Human brain mapping  2011;34(3):575-586.
Objectives
Reward learning is critical for survival. Animal research emphasizes the role of dopaminergic (DA) mesocorticolimbic pathways in reward learning, but few studies have evaluated extrastriatal DA functioning in humans. The purpose of this study was to examine presynaptic DA release in extrastriatal regions of the reward circuit by measuring displacement of the high affinity D2/D3 radioligand [18F]Fallypride during a reward task.
Design
Ten healthy volunteers underwent a [18F]Fallypride Positron Emission Tomography protocol while performing a reward task, allowing us to assess participants’ ability to modulate behavior as a function of reward. DA receptor ligand displacement was correlated with task performance and self-reported anhedonia.
Observations
Parametric t-maps revealed significant decrease in [18F]Fallypride binding in the medial orbitofrontal cortex (mOFC), ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC), indicating endogenous DA release in these regions. Increasing anhedonic symptoms correlated with DA release in the left vmPFC, left dACC, and right dACC emerged (all rs > 0.65, ps < 0.05). Similarly, reduced reward learning correlated with higher DA release in left vmPFC, right vmPFC, and left dACC (all rs < −0.64, ps < 0.05). Left dACC (r = 0.66, p = 0.04) and left vmPFC (r = 0.74, p = 0.01) DA release showed a significant positive correlation with impaired tendency to modulate behaviour as a function of prior positive reinforcements.
Conclusions
These findings support the hypothesis that DA release in mOFC, vmPFC and dACC regions plays an important role in reinforcement learning in the human brain.
doi:10.1002/hbm.21456
PMCID: PMC3366062  PMID: 22109979
Positron emission tomography; PET; Reward learning; Extrastriatal Reward Circuit; Dopamine; [18F]Fallypride; Anhedonia
10.  Substrates of neuropsychological functioning in stimulant dependence: a review of functional neuroimaging research 
Brain and Behavior  2012;2(4):499-523.
Stimulant dependence is associated with neuropsychological impairments. Here, we summarize and integrate the existing neuroimaging literature on the neural substrates of neuropsychological (dys)function in stimulant dependence, including cocaine, (meth-)amphetamine, ecstasy and nicotine dependence, and excessive caffeine use, comparing stimulant abusers (SAs) to nondrug using healthy controls (HCs). Despite some inconsistencies, most studies indicated altered brain activation in prefrontal cortex (PFC) and insula in response to reward and punishment, and higher limbic and anterior cingulate cortex (ACC)/PFC activation during craving and attentional bias paradigms in SAs compared with HCs. Impulsivity in SAs was associated with lower ACC and presupplementary motor area activity compared with HCs, and related to both ventral (amygdala, ventrolateral PFC, insula) and dorsal (dorsolateral PFC, dorsal ACC, posterior parietal cortex) systems. Decision making in SAs was associated with low dorsolateral PFC activity and high orbitofrontal activity. Finally, executive function in SAs was associated with lower activation in frontotemporal regions and higher activation in premotor cortex compared with HCs. It is concluded that the lower activations compared with HCs are likely to reflect the neural substrate of impaired neurocognitive functions, whereas higher activations in SAs compared with HCs are likely to reflect compensatory cognitive control mechanisms to keep behavioral task performance to a similar level as in HCs. However, before final conclusions can be drawn, additional research is needed using neuroimaging in SAs and HCs using larger and more homogeneous samples as well as more comparable task paradigms, study designs, and statistical analyses.
doi:10.1002/brb3.65
PMCID: PMC3432971  PMID: 22950052
Addiction; fMRI; functional imaging; magnetic resonance imaging; stimulant dependence; stimulants
11.  Limbic responses to reward cues correlate with antisocial trait density in heavy drinkers 
Neuroimage  2011;60(1):644-652.
Antisocial traits are common among alcoholics— particularly in certain subtypes. Although people with antisocial tendencies show atypical brain activation in some emotion and reward paradigms, how the brain reward systems of heavy drinkers (HD) are influenced by antisocial traits remains unclear. We used subjects’ preferred alcohol drink odors (AO), appetitive (ApCO) and non-appetitive (NApO) control odors in functional magnetic resonance imaging (fMRI) to determine if reward system responses varied as a function of antisocial trait density (ASD). In this retrospective analysis, we examined 30 HD who had participated in imaging twice: once while exposed to clamped intravenous alcohol infusion targeted to 50 mg%, and once during placebo saline infusion. Under placebo, there were positive correlations between ASD and blood oxygenation level dependent (BOLD) activation in the [AO > ApCO] contrast in the left dorsal putamen, while negative correlations were present in medial orbitofrontal cortex (OFC) and the bilateral amygdala. A similar pattern was observed in the correlation with the [AO > NApO] contrast. This inverse relationship between ASD and activation to alcohol odors in OFC and amygdala was specific to AO. However, negative correlations between ASD and the [ApCO > NApO] contrast were also present in the insula, putamen, and medial frontal cortex. These data suggest that frontal and limbic reward circuits of those with significant ASD are less responsive to reward cues in general, and particularly to alcohol cues in medial OFC and amygdala. These findings are broadly consistent with the reward deficiency syndrome hypothesis, although positive correlation in the striatum suggests regional variability.
doi:10.1016/j.neuroimage.2011.12.043
PMCID: PMC3288676  PMID: 22227139
alcoholism; alcohol use disorder; ethanol; personality disorder; prefrontal; orbital
12.  Behavioral and neural evidence of incentive bias for immediate rewards relative to preference-matched delayed rewards 
Several theories of self-control (including intertemporal bargaining Ainslie (1992) and self-signaling Bodner and Prelec (2001)) imply that intertemporal decisions can be more farsighted than would be predicted by the incentive associated with rewards outside a decision context. We examined this hypothesis using behavior and functional neuroimaging. First, subjects expressed preferences between amounts of money delayed by four months and smaller amounts available that day. This allowed us to establish “indifference pairs” individualized to each participant -- immediate and delayed amounts that were equally preferred. Participants subsequently performed a reaction time fMRI task (Knutson et al, 2001a) that provided them with distinct opportunities to win each of the rewards that comprised the indifference pairs. Anatomical Region of Interest analysis as well as whole-brain analysis indicated greater response recruited by the immediate rewards (relative to the preference matched delayed rewards) in regions previously implicated as sensitive to incentive value using the same task (including bilateral putamen, bilateral anterior insula and midbrain). RT to the target was also faster during the immediate relative to delayed reward trials (p < .01), and individual differences in RT between immediate versus delayed reward trials correlated with variance in MR signal in those clusters that responded preferentially to immediate rewards (r = .33, p < .05). These findings indicate a discrepancy in incentive associated with the immediate versus the preference-matched delayed rewards. This discrepancy may mark the contribution of self-control processes that are recruited during decision-making, but that are absent when rewards are individually anticipated.
doi:10.1523/JNEUROSCI.4261-09.2009
PMCID: PMC2821568  PMID: 19940177
Reward; Limbic; Decision; Motivation; fMRI; delayed gratification
13.  The convergence of information about rewarding and aversive stimuli in single neurons 
Neuroscientists, psychologists, clinicians, and economists have long been interested in how individuals weigh information about potential rewarding and aversive stimuli to make decisions and to regulate their emotions. However, we know relatively little about how appetitive and aversive systems interact in the brain, as most prior studies have investigated only one valence of reinforcement. Previous work has suggested that primate orbitofrontal cortex (OFC) represents information about the reward value of stimuli. We therefore investigated whether OFC also represents information about aversive stimuli, and, if so, whether individual neurons process information about both rewarding and aversive stimuli. Monkeys performed a trace-conditioning task in which different novel abstract visual stimuli (conditioned stimuli, CSs) predicted the occurrence of one of three unconditioned stimuli (USs): a large liquid reward, a small liquid reward, or an aversive air-puff. Three lines of evidence suggest that information about rewarding and aversive stimuli converges in individual neurons in OFC. First, OFC neurons often responded to both rewarding and aversive USs, despite their different sensory features. Second, OFC neural responses to CSs often encoded information about both potential rewarding and aversive stimuli, even though these stimuli differed in both valence and sensory modality. Finally, OFC neural responses were correlated with monkeys’ behavioral use of information about both rewarding and aversive CS-US associations. These data indicate that processing of appetitive and aversive stimuli converges at the single cell level in OFC, providing a possible substrate for executive and emotional processes that require using information from both appetitive and aversive systems.
doi:10.1523/JNEUROSCI.1815-09.2009
PMCID: PMC2782596  PMID: 19759296
orbitofrontal cortex; monkey; reward; punishment; aversive stimuli; Macaque
14.  Reward circuit connectivity relates to delay discounting in children with attention-deficit/hyperactivity disorder 
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that has poor long-term outcomes and remains a major public health concern. Recent theories have proposed that ADHD arises from alterations in multiple neural pathways. Alterations in reward circuits are hypothesized as one core dysfunction, leading to altered processing of anticipated rewards. The nucleus accumbens (NAcc) is particularly important for reward processes; task-based fMRI studies have found atypical activation of this region while the participants performed a reward task. Understanding how reward circuits are involved with ADHD may be further enhanced by considering how the NAcc interacts with other brain regions. Here we used the technique of resting-state functional connectivity MRI (rs-fcMRI) to examine the alterations in the NAcc interactions and how they relate to impulsive decision making in ADHD. Using rs-fcMRI, this study: examined differences in functional connectivity of the NAcc between children with ADHD and control children; correlated the functional connectivity of NAcc with impulsivity, as measured by a delay discounting task; and combined these two initial segments to identify the atypical NAcc connections that were associated with impulsive decision making in ADHD. We found that functional connectivity of NAcc was atypical in children with ADHD and the ADHD-related increased connectivity between NAcc and the prefrontal cortex was associated with greater impulsivity (steeper delayed-reward discounting). These findings are consistent with the hypothesis that atypical signaling of the NAcc to the prefrontal cortex in ADHD may lead to excessive approach and failure in estimating future consequences; thus, leading to impulsive behavior.
doi:10.1016/j.euroneuro.2012.10.015
PMCID: PMC3581744  PMID: 23206930
Attention Deficit Hyperactivity Disorder; reward; nucleus accumbens; fMRI; delay discounting; functional connectivity
15.  Neural Substrates of Abstinence-Induced Cigarette Cravings in Chronic Smokers 
Craving is a hallmark of drug dependence, including dependence on nicotine. Many studies have examined the neural substrates of cravings elicited by smoking-related cues. Less is known about the neural basis of unprovoked, abstinence-induced cravings, despite the contributions of such cravings to smoking relapse. To fill this gap, we used arterial spin labeled (ASL) perfusion MRI to characterize the neural substrates of abstinence-induced cravings to smoke. Fifteen chronic smokers were scanned during a resting state on two separate occasions: (1) smoking satiety and (2) abstinence (following ≥ 12 hours of smoking deprivation), in counterbalanced order. Smoking abstinence state (vs. satiety) was associated with increased cerebral blood flow (CBF) in anterior cingulate cortex (ACC)/medial orbitofrontal cortex (OFC) and left OFC. Abstinence-induced cravings to smoke were predicted by CBF increases (abstinence minus satiety) in: right OFC, right dorsolateral prefrontal cortex (DLPFC), occipital cortex, ACC, ventral striatum/nucleus accumbens, thalamus, amygdala, bilateral hippocampus, left caudate, and right insula. These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse.
doi:10.1523/JNEUROSCI.2966-07.2007
PMCID: PMC2153440  PMID: 18094242
Addiction; Cerebral Blood Flow; Cortex; Mesolimbic; Nicotine; Neuroimaging
16.  A biased activation theory of the cognitive and attentional modulation of emotion 
Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex (OFC). The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex (ACC). Similar effects are found for selective attention, to for example the pleasantness vs. the intensity of stimuli, which modulates representations of reward value and affect in the orbitofrontal and anterior cingulate cortices. The mechanisms for the effects of cognition and attention on emotion are top-down biased competition and top-down biased activation. Affective and mood states can in turn influence memory and perception, by backprojected biasing influences. Emotion-related decision systems operate to choose between gene-specified rewards such as taste, touch, and beauty. Reasoning processes capable of planning ahead with multiple steps held in working memory in the explicit system can allow the gene-specified rewards not to be selected, or to be deferred. The stochastic, noisy, dynamics of decision-making systems in the brain may influence whether decisions are made by the selfish-gene-specified reward emotion system, or by the cognitive reasoning system that explicitly calculates reward values that are in the interests of the individual, the phenotype.
doi:10.3389/fnhum.2013.00074
PMCID: PMC3600537  PMID: 23508210
cognition; emotion; orbitofrontal cortex; decision-making; the noisy brain; planning
17.  Neuronal reference frames for social decisions in primate frontal cortex 
Nature neuroscience  2012;16(2):243-250.
Social decisions play a crucial role in the success of individuals and the groups they compose. Group members respond vicariously to benefits obtained by others, and impairments in this capacity contribute to neuropsychiatric disorders like autism and sociopathy. We studied how neurons in three frontal cortical areas encode the outcomes of social decisions as monkeys performed a reward-allocation task. Neurons in the orbitofrontal cortex (OFC) predominantly encoded rewards delivered to oneself. Neurons in the anterior cingulate gyrus (ACCg) encoded reward allocations to the other monkey, reward allocations to oneself, or both. Neurons in the anterior cingulate sulcus (ACCs) signaled reward allocations to the other monkey or no one. Within this network of received (OFC) and foregone (ACCs) reward signaling, ACCg emerges as a key nexus for the computation of shared experience and social reward. Individual and species-specific variations in social decision-making might result from the relative activation and influence of these areas.
doi:10.1038/nn.3287
PMCID: PMC3557617  PMID: 23263442
18.  Dorsolateral Prefrontal Cortex Drives Mesolimbic Dopaminergic Regions to Initiate Motivated Behavior 
How does the brain translate information signaling potential rewards into motivation to get them? Motivation to obtain reward is thought to depend on the midbrain, (particularly the ventral tegmental area, VTA), the nucleus accumbens (NAcc), and the dorsolateral prefrontal cortex (dlPFC), but it is not clear how the interactions amongst these regions relate to reward-motivated behavior. To study the influence of motivation on these reward-responsive regions and on their interactions, we used Dynamic Causal Modeling (DCM) to analyze functional magnetic resonance imaging (fMRI) data from humans performing a simple task designed to isolate reward anticipation. The use of fMRI permitted the simultaneous measurement of multiple brain regions while human participants anticipated and prepared for opportunities to obtain reward, thus allowing characterization of how information about reward changes physiology underlying motivational drive. Further, we modeled the impact of external reward cues on causal relationships within this network, thus elaborating a link between physiology, connectivity, and motivation. Specifically, our results indicated that dlPFC was the exclusive entry point of information about reward in this network, and that anticipated reward availability caused VTA activation only via its effect on the dlPFC. Anticipated reward thus increased dlPFC activation directly, whereas it influenced VTA and NAcc only indirectly, by enhancing intrinsically weak or inactive pathways from the dlPFC. Our findings of a directional prefrontal influence on dopaminergic regions during reward anticipation suggest a model in which the dlPFC integrates and transmits representations of reward to the mesolimbic and mesocortical dopamine systems, thereby initiating motivated behavior.
doi:10.1523/JNEUROSCI.0895-11.2011
PMCID: PMC3182466  PMID: 21753011
19.  The social evaluation of faces: a meta-analysis of functional neuroimaging studies 
Neuroscience research on the social evaluation of faces has accumulated over the last decade, yielding divergent results. We used a meta-analytic technique, multi-level kernel density analysis (MKDA), to analyze 29 neuroimaging studies on face evaluation. Across negative face evaluations, we observed the most consistent activations in bilateral amygdala. Across positive face evaluations, we observed the most consistent activations in medial prefrontal cortex, pregenual anterior cingulate cortex (pgACC), medial orbitofrontal cortex (mOFC), left caudate and nucleus accumbens (NAcc). Based on additional analyses comparing linear and non-linear responses, we propose a ventral/dorsal dissociation within the amygdala, wherein separate populations of neurons code for face valence and intensity, respectively. Finally, we argue that some of the differences between studies are attributable to differences in the typicality of face stimuli. Specifically, extremely attractive faces are more likely to elicit responses in NAcc/caudate and mOFC.
doi:10.1093/scan/nsr090
PMCID: PMC3594716  PMID: 22287188
meta-analysis; fMRI; social cognition; face perception; face evaluation; trait judgments; trustworthiness; attractiveness
20.  Attentional Bias to Food Images Associated With Elevated Weight and Future Weight Gain: An fMRI Study 
Obesity (Silver Spring, Md.)  2011;19(9):1775-1783.
Behavioral studies reveal that obese vs. lean individuals show attentional bias to food stimuli. Yet research has not investigated this relation using objective brain imaging or tested whether attentional bias to food stimuli predicts future weight gain, which are important aims given the prominence of food cues in the environment. We used functional magnetic resonance imaging (fMRI) to examine attentional bias in 35 adolescent girls ranging from lean to obese using an attention network task involving food and neutral stimuli. BMI correlated positively with speed of behavioral response to both appetizing food stimuli and unappetizing food stimuli, but not to neutral stimuli. BMI correlated positively with activation in brain regions related to attention and food reward, including the anterior insula/frontal operculum, lateral orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and superior parietal lobe, during initial orientation to food cues. BMI also correlated with greater activation in the anterior insula/frontal operculum during reallocation of attention to appetizing food images and with weaker activation in the medial OFC and ventral pallidum during reallocation of attention to unappetizing food images. Greater lateral OFC activation during initial orientation to appetizing food cues predicted future increases in BMI. Results indicate that overweight is related to greater attentional bias to food cues and that youth who show elevated reward circuitry responsivity during food cue exposure are at increased risk for weight gain.
doi:10.1038/oby.2011.168
PMCID: PMC4007087  PMID: 21681221
21.  Affective and cognitive prefrontal cortex projections to the lateral habenula in humans 
Anterior insula (AI) and dorsal ACC (dACC) are known to process information about pain, loss, adversities, bad, harmful or suboptimal choices and consequences that threaten survival or well-being. Also pregenual ACC (pgACC) is linked to loss and pain, being activated by sad thoughts and regrets. Lateral habenula (LHb) is stimulated by predicted and received pain, discomfort, aversive outcome, loss. Its chronic stimulation makes us feel worse/low and gradually stops us choosing and moving for the suboptimal or punished choices, by direct and indirect (via rostromedial tegmental nucleus, RMTg) inhibition of dorsal raphe nucleus (DRN) and VTA/SNc. The response selectivity of LHb neurons suggests their cortical input from affective and cognitive evaluative regions that make expectations about bad, unpleasant or suboptimal outcomes. Based on these facts I predicted direct dACC, pgACC and AI projections to LHb, which form part of an adversity processing circuit that learns to avoid bad outcomes by suppressing dopamine and serotonin signal. To test this connectivity I used Diffusion Tensor Imaging (DTI). I found dACC, pgACC, AI and caudolateral OFC (clOFC) projections to LHb. I predicted no corticohabenular projections from the reward processing regions: medial OFC (mOFC) and ventral ACC (vACC) because both respond most strongly to good, high valued stimuli and outcomes, inducing dopamine and serotonin release. This lack of LHb projections was confirmed for vACC and likely for mOFC. The surprising findings were the corticohabenular projections from the cognitive prefrontal cortex regions, known for flexible reasoning, planning and combining whatever information are relevant for reaching current goals. I propose that the prefrontohabenular projections provide a teaching signal for value-based choice behavior, to learn to deselect, avoid or inhibit the potentially harmful, low valued or wrong choices, goals, strategies, predictions and ways of doing things, to prevent bad or suboptimal consequences.
doi:10.3389/fnhum.2014.00819
PMCID: PMC4209891  PMID: 25386128
prefrontal cortex; lateral habenula; inhibitory self-control; adversity processing circuit; value-based choice behavior; dopamine signaling
22.  Effects of motivation on reward and attentional networks: an fMRI study 
Brain and Behavior  2012;2(6):741-753.
Existing evidence suggests that reward and attentional networks function in concert and that activation in one system influences the other in a reciprocal fashion; however, the nature of these influences remains poorly understood. We therefore developed a three-component task to assess the interaction effects of reward anticipation and conflict resolution on the behavioral performance and the activation of brain reward and attentional systems. Sixteen healthy adult volunteers aged 21–45 years were scanned with functional magnetic resonance imaging (fMRI) while performing the task. A two-way repeated measures analysis of variance (ANOVA) with cue (reward vs. non-reward) and target (congruent vs. incongruent) as within-subjects factors was used to test for main and interaction effects. Neural responses to anticipation, conflict, and reward outcomes were tested. Behaviorally there were main effects of both reward cue and target congruency on reaction time. Neuroimaging results showed that reward anticipation and expected reward outcomes activated components of the attentional networks, including the inferior parietal and occipital cortices, whereas surprising non-rewards activated the frontoinsular cortex bilaterally and deactivated the ventral striatum. In turn, conflict activated a broad network associated with cognitive control and motor functions. Interaction effects showed decreased activity in the thalamus, anterior cingulated gyrus, and middle frontal gyrus bilaterally when difficult conflict trials (e.g., incongruent targets) were preceded by reward cues; in contrast, the ventral striatum and orbitofrontal cortex showed greater activation during congruent targets preceded by reward cues. These results suggest that reward anticipation is associated with lower activation in attentional networks, possibly due to increased processing efficiency, whereas more difficult, conflict trials are associated with lower activity in regions of the reward system, possibly because such trials are experienced as less rewarding.
doi:10.1002/brb3.80
PMCID: PMC3500461  PMID: 23170237
Attention; brain reward system; fMRI; motivation; neuroimaging; neuroscience
23.  Sex Differences in Neural Responses to Stress and Alcohol Context Cues 
Human brain mapping  2010;32(11):1998-2013.
Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. The present study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (p<.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the right dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala and hippocampus than women, whereas women showed greater alcohol-cue related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion modulation regions, including the medial OFC, ventromedial PFC, left superior-medial PFC and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal and ventral) in men, supporting its involvement in alcohol ‘urge’ in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences, and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.
doi:10.1002/hbm.21165
PMCID: PMC3236497  PMID: 21162046
Sex differences; Stress; Alcohol cue; Reward; Brain fMRI; Prefrontal Cortex
24.  Adolescents’ risky decision-making activates neural networks related to social cognition and cognitive control processes 
This study examines by means of functional magnetic resonance imaging the neural mechanisms underlying adolescents’ risk decision-making in social contexts. We hypothesize that the social context could engage brain regions associated with social cognition processes and developmental changes are also expected. Sixty participants (adolescents: 17–18, and young adults: 21–22 years old) read narratives describing typical situations of decision-making in the presence of peers. They were asked to make choices in risky situations (e.g., taking or refusing a drug) or ambiguous situations (e.g., eating a hamburger or a hotdog). Risky as compared to ambiguous scenarios activated bilateral temporoparietal junction (TPJ), bilateral middle temporal gyrus (MTG), right medial prefrontal cortex, and the precuneus bilaterally; i.e., brain regions related to social cognition processes, such as self-reflection and theory of mind (ToM). In addition, brain structures related to cognitive control were active [right anterior cingulate cortex (ACC), bilateral dorsolateral prefrontal cortex (DLPFC), bilateral orbitofrontal cortex], whereas no significant clusters were obtained in the reward system (ventral striatum). Choosing the dangerous option involved a further activation of control areas (ACC) and emotional and social cognition areas (temporal pole). Adolescents employed more neural resources than young adults in the right DLPFC and the right TPJ in risk situations. When choosing the dangerous option, young adults showed a further engagement in ToM related regions (bilateral MTG) and in motor control regions related to the planning of actions (pre-supplementary motor area). Finally, the right insula and the right superior temporal gyrus were more activated in women than in men, suggesting more emotional involvement and more intensive modeling of the others’ perspective in the risky conditions. These findings call for more comprehensive developmental accounts of decision-making in social contexts that incorporate the role of emotional and social cognition processes.
doi:10.3389/fnhum.2014.00060
PMCID: PMC3924553  PMID: 24592227
adolescent risk and ambiguous decision-making; dangerous and safe choices; fMRI; decision-making in social context; emotional and social cognitive processing; age and gender differences
25.  Policy Adjustment in a Dynamic Economic Game 
PLoS ONE  2006;1(1):e103.
Making sequential decisions to harvest rewards is a notoriously difficult problem. One difficulty is that the real world is not stationary and the reward expected from a contemplated action may depend in complex ways on the history of an animal's choices. Previous functional neuroimaging work combined with principled models has detected brain responses that correlate with computations thought to guide simple learning and action choice. Those works generally employed instrumental conditioning tasks with fixed action-reward contingencies. For real-world learning problems, the history of reward-harvesting choices can change the likelihood of rewards collected by the same choices in the near-term future. We used functional MRI to probe brain and behavioral responses in a continuous decision-making task where reward contingency is a function of both a subject's immediate choice and his choice history. In these more complex tasks, we demonstrated that a simple actor-critic model can account for both the subjects' behavioral and brain responses, and identified a reward prediction error signal in ventral striatal structures active during these non-stationary decision tasks. However, a sudden introduction of new reward structures engages more complex control circuitry in the prefrontal cortex (inferior frontal gyrus and anterior insula) and is not captured by a simple actor-critic model. Taken together, these results extend our knowledge of reward-learning signals into more complex, history-dependent choice tasks. They also highlight the important interplay between striatum and prefrontal cortex as decision-makers respond to the strategic demands imposed by non-stationary reward environments more reminiscent of real-world tasks.
doi:10.1371/journal.pone.0000103
PMCID: PMC1762366  PMID: 17183636

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