Effective connectivity of a reward network in obese women

Exaggerated reactivity to food cues in obese women appears to be mediated in part by a hyperactive reward system that includes the nucleus accumbens, amygdala, and orbitofrontal cortex. The present study used functional magnetic resonance imaging (fMRI) to investigate whether differences between 12 obese and 12 normal-weight women in reward-related brain activation in response to food images can be explained by changes in the functional interactions between key reward network regions. A two-step path analysis/General Linear Model approach was used to test whether there were group differences in network connections between nucleus accumbens, amygdala, and orbitofrontal cortex in response to high- and low-calorie food images. There was abnormal connectivity in the obese group in response to both high- and low-calorie food cues compared to normal-weight controls. Compared to controls, the obese group had a relative deficiency in the amygdala's modulation of activation in both orbitofrontal cortex and nucleus accumbens, but excessive influence of orbitofrontal cortex's modulation of activation in nucleus accumbens. The deficient projections from the amygdala might relate to suboptimal modulation of the affective/emotional aspects of a food's reward value or an associated cue's motivational salience, whereas increased orbitofrontal cortex to nucleus accumbens connectivity might contribute to a heightened drive to eat in response to a food cue. Thus, it is possible that not only greater activation of the reward system, but also differences in the interaction of regions in this network may contribute to the relatively increased motivational value of foods in obese individuals.     

Common and distinct networks underlying reward valence and processing stages: a meta-analysis of functional neuroimaging studies

To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC), as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore take distributed and interrelated representations of reward valuation and valence assessment into account.     

Mapping adolescent reward anticipation,receipt, and prediction error during the monetary incentive delay task

The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental period's association with altered reward sensitivity. Here, a large sample (n = 1,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward‐related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.     

An fMRI study of reward circuitry in patients with minimal or extensive history of major depression

Functional abnormalities in regions associated with reward processing are apparent in people with depression, but the extent to which disease burden impacts on the processing of reward is unknown. This research examined the neural correlates of reward processing in patients with major depressive disorder and varying degrees of past illness burden. Twenty-nine depressed patients and twenty-five healthy subjects with no lifetime history of psychiatric illness completed the study. Subsets of fourteen patients were presenting for first lifetime treatment of a depressive episode, and fifteen patients had at least three treated episodes of depression. We used functional magnetic resonance imaging to study blood oxygen level-dependent signals during the performance of a contingency reversal reward paradigm. The results identified group differences in the response to punishers bilaterally in the orbitofrontal and medial prefrontal regions. In addition, areas such as the nucleus accumbens, anterior cingulate and ventral prefrontal cortices were activated greatest by controls during reward processing, less by patients early in the course of illness and least by patients with highly recurrent illness—suggesting that these areas are sensitive to the impact of disease burden and repeated episodes of depression. Reward processing in people with depression may be associated with diminished signaling of incentive salience, a reduction in the formation of reward-related associations and heightened sensitivities for negatively valenced stimuli, all of which could contribute to symptoms of depression.     

Dissociation of BOLD responses to reward prediction errors and reward receipt by a model comparison

The representation of reward anticipation and reward prediction errors is the basis for reward-associated learning. The representation of whether or not a reward occurred (reward receipt) is important for decision making. Recent studies suggest that, while reward anticipation and reward prediction errors are encoded in the midbrain and the ventral striatum, reward receipts are encoded in the medial orbitofrontal cortex. In order to substantiate this functional specialization we analyzed data from an fMRI study in which 59 subjects completed two simple monetary reward paradigms. Because reward receipts and reward prediction errors were correlated, a statistical model comparison was applied separating the effects of the two. Reward prediction error fitted BOLD responses significantly better than reward receipt in the midbrain and the ventral striatum. Conversely, reward receipt fitted BOLD responses better in the orbitofrontal cortex. Activation related to reward anticipation was found in the orbitofrontal cortex. The results confirm a functional specialization of behaviorally important aspects of reward processing within the mesolimbic dopaminergic system.     

Emotional imagery: Assessing pleasure and arousal in the brain's reward circuitry

Research on emotional perception and learning indicates appetitive cues engage nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), whereas amygdala activity is modulated by the emotional intensity of appetitive and aversive cues. This study sought to determine patterns of functional activation and connectivity among these regions during narrative emotional imagery. Using event‐related fMRI, we investigate activation of these structures when participants vividly imagine pleasant, neutral, and unpleasant scenes. Results indicate that pleasant imagery selectively activates NAc and mPFC, whereas amygdala activation was enhanced during both pleasant and unpleasant imagery. NAc and mPFC activity were each correlated with the rated pleasure of the imagined scenes, while amygdala activity was correlated with rated emotional arousal. Functional connectivity of NAc and mPFC was evident throughout imagery, regardless of hedonic content, while correlated activation of the amygdala with NAc and mPFC was specific to imagining pleasant scenes. These findings provide strong evidence that pleasurable text‐driven imagery engages a core appetitive circuit, including NAc, mPFC, and the amygdala. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Neural correlates of substance abuse: Reduced functional connectivity between areas underlying reward and cognitive control

Substance use disorders (SUD) have been associated with dysfunction in reward processing, habit formation, and cognitive‐behavioral control. Accordingly, neurocircuitry models of addiction highlight roles for nucleus accumbens, dorsal striatum, and prefrontal/anterior cingulate cortex. However, the precise nature of the disrupted interactions between these brain regions in SUD, and the psychological correlates thereof, remain unclear. Here we used magnetic resonance imaging to measure rest‐state functional connectivity of three key striatal nuclei (nucleus accumbens, dorsal caudate, and dorsal putamen) in a sample of 40 adult male prison inmates (n = 22 diagnosed with SUD; n = 18 without SUD). Relative to the non‐SUD group, the SUD group exhibited significantly lower functional connectivity between the nucleus accumbens and a network of frontal cortical regions involved in cognitive control (dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and frontal operculum). There were no group differences in functional connectivity for the dorsal caudate or dorsal putamen. Moreover, the SUD group exhibited impairments in laboratory measures of cognitive‐behavioral control, and individual differences in functional connectivity between nucleus accumbens and the frontal cortical regions were related to individual differences in measures of cognitive‐behavioral control across groups. The strength of the relationship between functional connectivity and cognitive control did not differ between groups. These results indicate that SUD is associated with abnormal interactions between subcortical areas that process reward (nucleus accumbens) and cortical areas that govern cognitive‐behavioral control. Hum Brain Mapp 35:4282–4292, 2014. © 2014 Wiley Periodicals, Inc .     

Activation of neurones in the prefrontal cortex by brain-stimulation reward in the rat

To investigate reward pathways in the brain, recording were made from neurones while electrical stimulation was applied to brain-stimulation reward sites in the rat. Single units in most areas of the neocortex were not activated by the stimulation. In the sulcal prefrontal cortex (which forms the dorsal bank of the rhinal sulcus) and in the medial prefrontal cortex (which forms the medial pregenual wall of the hemisphere) single units were activated by the stimulation. This indication that prefrontal neurones are involved in brain-stimulation reward received support from the observation that the neurones were activated in self-stimulation of many different sites — the lateral hypothalamus, the midbrain tegmentum ventrolateral to the central grey, the nucleus accumbens, and the medial prefrontal cortex. Many of the prefrontal units were directly (probably antidromically) excited, with short latencies (1–10 msec), by stimulus pulses applied to self-stimulation sites other than the nucleus accumbens. Many prefrontal units were trans-synaptically activated with longer latencies (2–30 msec) by stimulus pulses applied to the self-stimulation sites. Further evidence that the prefrontal neurones are involved in brain-stimulation reward is that units in the prefrontal cortex were in general not activated from non-reward sites in the midbrain tegmentum. Also neurones in many other areas of the neocortex did not appear to be activated by the brain-stimulation reward.     

Structure-function coupling within the reward network in preschool children predicts executive functioning in later childhood

Early differences in reward behavior have been linked to executive functioning development. The nucleus accumbens (NAc) and orbitofrontal cortex (OFC) are activated by reward-related tasks and identified as key nodes of the brain circuit that underlie reward processing. We aimed to investigate the relation between NAc-OFC structural and functional connectivity in preschool children, as well as associations with future reward sensitivity and executive function. We showed that NAc-OFC structural and functional connectivity were not significantly associated in preschool children, but both independently predicted sensitivity to reward in males in a left-lateralized manner. Moreover, significant NAc-OFC structure-function coupling was only found in individuals who performed poorly on executive function tasks in later childhood, but not in the middle- and high-performing groups. As structure-function coupling is proposed to measure functional specialization, this finding suggests premature functional specialization within the reward network, which may impede dynamic communication with other regions, affects executive function development. Our study also highlights the utility of multimodal imaging data integration when studying the effects of reward network functional flexibility in the preschool age, a critical period in brain and executive function development.     

Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia

Theories of schizophrenia propose that abnormal functioning of the neural reward system is linked to negative and psychotic symptoms, by disruption of reward processing and promotion of context-independent false associations. Recently, it has been argued that an insula–anterior cingulate cortex (ACC) salience network system enables switching of brain states from the default mode to a task-related activity mode. Abnormal interaction between the insula–ACC system and reward processing regions may help explain abnormal reinforcer processing and symptoms. Here we use functional magnetic resonance imaging to assess the neural correlates of reward processing in schizophrenia. Furthermore, we investigated functional connectivity between the dopaminergic midbrain, a key region for the processing of reinforcers, and other brain regions. In response to rewards, controls activated task related regions (striatum, amygdala/hippocampus and midbrain) and the insula–ACC salience network. Patients similarly activated the insula–ACC salience network system but failed to activate task related regions. Reduced functional connectivity between the midbrain and the insula was found in schizophrenia, with the extent of this abnormality correlating with increased psychotic symptoms. The findings support the notion that reward processing is abnormal in schizophrenia and highlight the potential role of abnormal interactions between the insula–ACC salience network and reward regions.     

Role of oxytocin in the control of stress and food intake

Oxytocin neurones in the hypothalamus are activated by stressful stimuli and food intake. The oxytocin receptor is located in various brain regions, including the sensory information‐processing cerebral cortex; the cognitive information‐processing prefrontal cortex; reward‐related regions such as the ventral tegmental areas, nucleus accumbens and raphe nucleus; stress‐related areas such as the amygdala, hippocampus, ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray; homeostasis‐controlling hypothalamus; and the dorsal motor complex controlling intestinal functions. Oxytocin affects behavioural and neuroendocrine stress responses and terminates food intake by acting on the metabolic or nutritional homeostasis system, modulating emotional processing, reducing reward values of food intake, and facilitating sensory and cognitive processing via multiple brain regions. Oxytocin also plays a role in interactive actions between stress and food intake and contributes to adaptive active coping behaviours.     

Brain stimulation reward and dopamine terminal fields. I. Caudate-putamen, nucleus accumbens and amygdala

The boundaries and relative sensitivity of brain stimulation reward were mapped in relation to the dopamine (DA) terminal fields of the striatum and adjacent limbic structures. Brain stimulation was rewarding throughout the caudate and nucleus accumbens and in portions of the amygdala and olfactory tubercle. The best striatal sites were anterior, ventral and medial; this correlated with an anterior-posterior gradient but not with a dorsal-ventral or a medial-lateral gradient of DA terminal density. No close correspondence was seen between the boundaries of the reward system and those of the DA terminal fields as revealed by glyoxylic acid-induced DA fluorescence. Reward sites in the olfactory tubercle and amygdala were found in DA-free as well as DA-rich regions of these structures; stimulation in DA-rich regions did not always support self-stimulation. These data go against the view that direct activation of dopamine terminals or their efferent targets accounts for the rewarding quality of stimulation in these regions.     

No laughing matter: intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter

Infant laughter is a rewarding experience. It activates neural reward circuits and promotes parental proximity and care, thus facilitating parent-infant attachment. The neuropeptide oxytocin might enhance the incentive salience of infant laughter by modulating neural circuits related to the perception of infant cues. In a randomized controlled trial with functional magnetic resonance imaging we investigated the influence of intranasally administered oxytocin on functional brain connectivity in response to infant laughter. Blood oxygenation level-dependent responses to infant laughter were measured in 22 nulliparous women who were administered oxytocin and 20 nulliparous women who were administered a placebo. Elevated oxytocin levels reduced activation in the amygdala during infant laughter and enhanced functional connectivity between the amygdala and the orbitofrontal cortex, the anterior cingulate, the hippocampus, the precuneus, the supramarginal gyri, and the middle temporal gyrus. Increased functional connectivity between the amygdala and regions involved in emotion regulation may reduce negative emotional arousal while enhancing the incentive salience of the infant laughter.     

Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation

The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep-brain-stimulation treatment for obsessive-compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate "top-down" (cortex → nucleus accumbens)- from "bottom-up" (nucleus accumbens → cortex)-directed synchronization (functional connectivity). "Top-down"-directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward-related processing and may be relevant to understanding the mechanisms of deep-brain stimulation and its beneficial effects on psychiatric conditions.     

Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue‐triggered ‘wanting’ for reward: entire core and medial shell mapped as substrates for PIT enhancement

Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience (‘wanting’) that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d‐Ala, nMe‐Phe, Glyol‐enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue‐triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian‐Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue‐triggered ‘wanting’ in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far‐rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of ‘wanting’ to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS ‘wanting’ peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before.     

Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward‐driven behaviors, which can result in life‐altering morbidity. The mesocorticolimbic dopamine network guides reward‐motivated behavior; however, its role in this treatment‐related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward‐learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD‐fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex‐matched PD patients with (n = 19) or without (n = 18) ICB. An incentive‐based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole‐brain voxelwise analyses and region‐of‐interest‐based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala‐to‐midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum‐to‐subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment‐avoidance learning. These data indicate that PD‐ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward‐based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509–521, 2018. © 2017 Wiley Periodicals, Inc.     

Neurophysiological analysis of brain-stimulation reward in the monkey

Neuronal activity related to brain-stimulation reward and to feeding was analyzed in rhesus monkeys and squirrel monkeys as follows. First, self-stimulation of the lateral hypothalamus, orbitofrontal cortex, amygdala and nucleus accumbens was found. Second, a population of single neurones in the lateral hypothalamus was found to be trans-synaptically activated from one or several self-stimulation sites. It was also found that populations of neurones in the orbitofrontal cortex and amygdala were activated from at least some of the self-stimulation sites. Thus, in the monkey, there is evidence for an interconnected set of self-stimulation sites, stimulation in any one of which may activate neurones in the other regions. These sites include the lateral hypothalamus, amygdala, and orbitofrontal cortex. Third, in one sample of 764 neurones in the lateral hypothalamis and substantia innominata which were activated from brain-stimulation reward sites, 13.6% were also activated during feeding, by the sight and/or taste of food. The responses of the neurones with activity associated with taste occurred only while some substances (e.g. sweet substances such as glucose) were in the mouth, depended on the concentration of the substances being tasted, and were independent of mouth movements made by the monkeys. Fourth, the responses of these neutrones occurre to food when the monkeys were hungry, but not when they were satiated. Fifth, self-stimulation occurred in the region of these neurones in the lateral hypothalamus and substantia innominata, and was attenuated by satiety. These results suggest that self-stimulation of some brain sites occurs because of activation of neurones in the lateral hypothalamus and substantia innominata activated by the sight and/or taste of food in the hungry animal, and that these neurones are involved in responses to food reward.     

A three‐wave longitudinal study of subcortical–cortical resting‐state connectivity in adolescence: Testing age‐ and puberty‐related changes

Adolescence is the transitional period between childhood and adulthood, characterized by substantial changes in reward‐driven behavior. Although reward‐driven behavior is supported by subcortical‐medial prefrontal cortex (PFC) connectivity, the development of these circuits is not well understood. Particularly, while puberty has been hypothesized to accelerate organization and activation of functional neural circuits, the relationship between age, sex, pubertal change, and functional connectivity has hardly been studied. Here, we present an analysis of resting‐state functional connectivity between subcortical structures and the medial PFC, in 661 scans of 273 participants between 8 and 29 years, using a three‐wave longitudinal design. Generalized additive mixed model procedures were used to assess the effects of age, sex, and self‐reported pubertal status on connectivity between subcortical structures (nucleus accumbens, caudate, putamen, hippocampus, and amygdala) and cortical medial structures (dorsal anterior cingulate, ventral anterior cingulate, subcallosal cortex, frontal medial cortex). We observed an age‐related strengthening of subcortico‐subcortical and cortico‐cortical connectivity. Subcortical–cortical connectivity, such as, between the nucleus accumbens—frontal medial cortex, and the caudate—dorsal anterior cingulate cortex, however, weakened across age. Model‐based comparisons revealed that for specific connections pubertal development described developmental change better than chronological age. This was particularly the case for changes in subcortical–cortical connectivity and distinctively for boys and girls. Together, these findings indicate changes in functional network strengthening with pubertal development. These changes in functional connectivity may maximize the neural efficiency of interregional communication and set the stage for further inquiry of biological factors driving adolescent functional connectivity changes.     

Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients

CONTEXT In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. OBJECTIVE To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. DESIGN A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. SETTING Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. PARTICIPANTS A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects MAIN OUTCOME MEASURES Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. RESULTS Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. CONCLUSIONS Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.     

Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways

Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia. We found that trait anhedonia was negatively correlated with pleasantness ratings of music stimuli and with activation of key brain structures involved in reward processing, including nucleus accumbens (NAc), basal forebrain and hypothalamus which are linked by the medial forebrain bundle to the ventral tegmental area (VTA). Brain regions important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with trait anhedonia. Furthermore, effective connectivity between NAc, VTA and paralimbic areas, that regulate emotional reactivity to hedonic stimuli, was negatively correlated with trait anhedonia. Our results indicate that trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and related limbic and paralimbic systems involved in reward processing. Critically, this association can be detected even in individuals without psychiatric illness. Our findings have important implications both for understanding the neurobiological basis of anhedonia and for the treatment of anhedonia in psychiatric disorders.