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Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD., (© 2022. The Author(s).)

In an uncertain world, the ability to predict and update the relationships between environmental cues and outcomes is a fundamental element of adaptive behaviour. This type of learning is typically thought to depend on prediction error, the difference between expected and experienced events and in the reward domain that has been closely linked to mesolimbic dopamine. There is also increasing behavioural and neuroimaging evidence that disruption to this process may be a cross-diagnostic feature of several neuropsychiatric and neurological disorders in which dopamine is dysregulated. However, the precise relationship between haemodynamic measures, dopamine and reward-guided learning remains unclear. To help address this issue, we used a translational technique, oxygen amperometry, to record haemodynamic signals in the nucleus accumbens (NAc) and orbitofrontal cortex (OFC), while freely moving rats performed a probabilistic Pavlovian learning task. Using a model-based analysis approach to account for individual variations in learning, we found that the oxygen signal in the NAc correlated with a reward prediction error, whereas in the OFC it correlated with an unsigned prediction error or salience signal. Furthermore, an acute dose of amphetamine, creating a hyperdopaminergic state, disrupted rats' ability to discriminate between cues associated with either a high or a low probability of reward and concomitantly corrupted prediction error signalling. These results demonstrate parallel but distinct prediction error signals in NAc and OFC during learning, both of which are affected by psychostimulant administration. Furthermore, they establish the viability of tracking and manipulating haemodynamic signatures of reward-guided learning observed in human fMRI studies by using a proxy signal for BOLD in a freely behaving rodent.

Background: Substance use at an early age conveys substantial risk for later substance-related problems. A better understanding of early risk factors could result in more timely and effective intervention. This study investigated the predictive utility of the brain's response to reward anticipation as a risk factor for early substance use initiation., Methods: Participants were 34 children (25 male) at high risk for alcohol and other substance use disorders from a longitudinal functional magnetic resonance imaging study, scanned at a mean age of 10.5 years (SD = 1.2) when participants were substance-naïve. We used a monetary incentive delay task to examine the hemodynamic response of the nucleus accumbens to gain and loss anticipation. Logistic regression was used to test the hypothesis that these brain response patterns would have predictive utility over and above early externalizing behaviors and family history of substance use disorder, two key risk factors for substance use problems, in differentiating those who initiated substance use before age 16 (n = 18) and those who did not (n = 16)., Results: Greater nucleus accumbens activation during monetary gain anticipation in childhood increased the likelihood of initiating substance use during early adolescence (p = .023). The model that comprised neural data in addition to early externalizing behaviors and family history showed significantly better fit than the model without neural data (χ 2 2  = 7.38, p = .025)., Conclusions: Heightened gain anticipation activation in the nucleus accumbens may predispose individuals to early substance use, beyond the risk conveyed by other known factors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

As an essential part of sympathetic activation that prepares the organism for "fight or flight," peripheral norepinephrine (NE) plays an important role in regulating cardiac activity and the tone of blood vessels, increasing blood flow to the heart and the brain and decreasing blood flow to the organs not as necessary for immediate survival. To assess whether this effect is applicable to the brain, we used high-speed amperometry to measure the changes in nucleus accumbens (NAc) levels of oxygen and glucose induced by intravenous injections of NE in awake freely moving rats. We found that NE at low doses (2-18 μg/kg) induces correlative increases in NAc oxygen and glucose, suggesting local vasodilation and enhanced entry of these substances in brain tissue from the arterial blood. By using temperature recordings from the NAc, temporal muscle, and skin, we show that this central effect is associated with strong skin vasoconstriction and phasic increases in intrabrain heat production, indicative of metabolic neural activation. A tight direct correlation between NE-induced changes in metabolic activity and NAc levels of oxygen and glucose levels suggests that local cerebral vasodilation is triggered via a neurovascular coupling mechanism. Our data suggest that NE, by changing vascular tone and cardiac activity, triggers a visceral sensory signal that rapidly reaches the central nervous system via sensory nerves and induces neural activation. This neural activation leads to a chain of neurovascular events that promote entry of oxygen and glucose in brain tissue, thus preventing any possible metabolic deficit during functional activation. NEW & NOTEWORTHY Using high-speed amperometry and thermorecording in freely moving rats, we demonstrate that intravenous norepinephrine at physiological doses induces rapid correlative increases in nucleus accumbens oxygen and glucose levels coupled with increased intrabrain heat production. Although norepinephrine cannot cross the blood-brain barrier, by changing cardiac activity and vascular tone, it creates a sensory signal that reaches the central nervous system via sensory nerves, induces neural activation, and triggers a chain of neurovascular events that promotes intrabrain entry of oxygen and glucose.

Activation of the ventral tegmental area (VTA) and mesolimbic networks is essential to motivation, performance, and learning. Humans routinely attempt to motivate themselves, with unclear efficacy or impact on VTA networks. Using fMRI, we found untrained participants' motivational strategies failed to consistently activate VTA. After real-time VTA neurofeedback training, however, participants volitionally induced VTA activation without external aids, relative to baseline, Pre-test, and control groups. VTA self-activation was accompanied by increased mesolimbic network connectivity. Among two comparison groups (no neurofeedback, false neurofeedback) and an alternate neurofeedback group (nucleus accumbens), none sustained activation in target regions of interest nor increased VTA functional connectivity. The results comprise two novel demonstrations: learning and generalization after VTA neurofeedback training and the ability to sustain VTA activation without external reward or reward cues. These findings suggest theoretical alignment of ideas about motivation and midbrain physiology and the potential for generalizable interventions to improve performance and learning., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Reactive changes of astrocytes were studied in forebrain nucleus accumbens in rats (n = 12) after global cerebral ischemia induced by bilateral occlusion of both common carotid arteries, which is a frequently used model to assess the effectiveness of pharmacological agents that have anti-ischemic and neuroprotective properties. Under these conditions, the nucleus accumbens was in the area of partial ischemia. Morphometric study of nucleus accumbens was performed in three groups of rats (4 animals in each group) after ligation of both common carotid arteries, after a sham operation and in healthy animals. Astrocytes were demonstrated in serial sections using the reaction to glial fibrillary acidic protein counterstained with hematoxylin. 7 days after the surgery, in each animal the number of astrocytes was counted in the sections in 7 successiive squares of 0.01 mm2 each, the distance between their bodies and the capillary wall was measured within the circle of 20 μm radius, the cell body area and the length of their main processes were determined. It is found that astrocytes in the nucleus accumbens in the model of bilateral occlusion of the common carotid arteries for 7 days experienced a partial state of ischemia. Their reactive changes were manifested by the signs of the cytotoxic edema, damaging intermediate filament proteins in their bodies, processes and in the perivascular glial membranes. The concentration of the astrocyte cell bodies near blood capillaries is the adaptation mechanism and is a condition for the survival of cells under the restriction of blood flow in the brain.

Experiments in financial decision-making point to two complementary processes that encode prospective gain and loss preceding the choice to purchase consumer goods. These processes involve the nucleus accumbens (NAcc) and the right anterior insula, respectively. The current experiment used functional MRI to investigate whether these regions served a similar function during an analogous social decision-making task without the influence of monetary outcomes. In this task, subjects chose partners based on face stimuli of varying attractiveness (operationalizing value) and ratings of compatibility with the participant (operationalizing likelihood of rejection). The NAcc responded to anticipated gain; the right anterior insula responded to compatibility, but not in a manner that suggests an analogy to anticipated cost. Logistic regression modeling demonstrated that both regions predicted subsequent choice above and beyond the influence of group attractiveness ratings or compatibility alone. Although the function of the insula may differ between tasks, these results suggest that financial and social decision-making recruit a similar network of brain regions., (© The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

This study examines the cognitive and neural determinants of honesty and dishonesty. Human subjects undergoing fMRI completed a monetary incentive delay task eliciting responses to anticipated reward in the nucleus accumbens. Subjects next performed an incentivized prediction task, giving them real and repeated opportunities for dishonest gain. Subjects attempted to predict the outcomes of random computerized coin-flips and were financially rewarded for accuracy. In some trials, subjects were rewarded based on self-reported accuracy, allowing them to gain money dishonestly by lying. Dishonest behavior was indexed by improbably high levels of self-reported accuracy. Nucleus accumbens response in the first task, involving only honest rewards, accounted for ∼25% of the variance in dishonest behavior in the prediction task. Individuals showing relatively strong nucleus accumbens responses to anticipated reward also exhibited increased dorsolateral prefrontal activity (bilateral) in response to opportunities for dishonest gain. These results address two hypotheses concerning (dis)honesty. According to the "Will" hypothesis, honesty results from the active deployment of self-control. According to the "Grace" hypothesis, honesty flows more automatically. The present results suggest a reconciliation between these two hypotheses while explaining (dis)honesty in terms of more basic neural mechanisms: relatively weak responses to anticipated rewards make people morally "Graceful," but individuals who respond more strongly may resist temptation by force of Will., (Copyright © 2014 the authors 0270-6474/14/3410564-09$15.00/0.)

We examined a rapid-cycling bipolar disorder patient who demonstrated manic episode regularly at around day 7 of the menstrual cycle. We hypothesize that gonadal hormones may induce a state-dependent change in cerebral microstructure and function. Following this hypothesis, the serum levels of estradiol and progesterone were analyzed and diffusion tensor imaging data were examined between the manic and euthymic states of the patient. Estradiol levels increased in the late follicular phase at manic state when compared to the luteal or early follicular phase at euthymic state. DTI results showed that the patient had increased fractional anisotropy values at manic state in the bilateral nucleus accumbens (NAc) and its connected areas, which is a major projection field of the mesolimbic dopamine (DA) system, perhaps reflecting microstructural changes due to neuronal activation related to manic episodes. According to these results, we consider that the mesolimbic DA system of this patient has hypersensitivity to estradiol, and elevation of the estradiol level increases the activity of the dopaminergic system, which in turn may contribute to recurrent manic episodes. Our findings provide a clue for understanding how fluctuations in gonadal hormone may amplify or ameliorate the symptomatology of psychiatric disorders related to the menstrual cycle., (© 2013 Published by Elsevier Ireland Ltd.)

Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.

Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.

The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson's disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning.

Failures of self-regulation are common, leading to many of the most vexing problems facing contemporary society, from overeating and obesity to impulsive sexual behavior and STDs. One reason that people may be prone to engaging in unwanted behaviors is heightened sensitivity to cues related to those behaviors; people may overeat because of hyperresponsiveness to food cues, addicts may relapse following exposure to their drug of choice, and some people might engage in impulsive sexual activity because they are easily aroused by erotic stimuli. An open question is the extent to which individual differences in neural cue reactivity relate to actual behavioral outcomes. Here we show that individual differences in human reward-related brain activity in the nucleus accumbens to food and sexual images predict subsequent weight gain and sexual activity 6 months later. These findings suggest that heightened reward responsivity in the brain to food and sexual cues is associated with indulgence in overeating and sexual activity, respectively, and provide evidence for a common neural mechanism associated with appetitive behaviors.

Neuropathic pain is the most difficult type of pain to control, and patients lose their motivation for the purposive pursuit with a decrease in their quality of life. Using a functional magnetic resonance imaging analysis, we demonstrated that blood oxygenation level-dependent signal intensity was increased in the ipsilateral nucleus accumbens (N.Acc.) following peripheral nerve injury. microRNAs are small, noncoding RNA molecules that direct the post-transcriptional suppression of gene expression, and play an important role in regulating synaptic plasticity. In this study, we found that sciatic nerve ligation induced a drastic decrease in the expression of miR200b and miR429 in N.Acc. neurons. The expression of DNA methyltransferase 3a (DNMT3a), which is the one of the predicted targets of miR200b/429, was significantly increased in the limbic forebrain including N.Acc. at 7 d after sciatic nerve ligation. Double-immunolabeling with antibodies specific to DNMT3a and NR1 showed that DNMT3a-immunoreactivity in the N.Acc. was located in NR1-labeled neurons, indicating that increased DNMT3a proteins were dominantly expressed in postsynaptic neurons in the N.Acc. area under a neuropathic pain-like state. The results of these analyses provide new insight into an epigenetic modification that is accompanied by a dramatic decrease in miR200b and miR429 along with the dysfunction of "mesolimbic motivation/valuation circuitry" under a neuropathic pain-like state. These phenomena may result in an increase in DNMT3a in neurons of the N.Acc. under neuropathic pain, which leads to the long-term transcription-silencing of several genes.

This article investigates the functional connectivity patterns of the nucleus accumbens (NAcc) in 18 healthy participants using a resting state functional connectivity (rsFC) protocol. Also, a meta-analytic connectivity modeling (MACM) was used to characterize patterns of functional coactivations involving NAcc: The results of a structure-based meta-analyses of 57 fMRI and PET studies were submitted to activation likelihood estimation analysis to estimate consistent activation patterns across the different imaging studies. The results of the combined rsFC and MACM analyses show that spontaneous activity in NAcc predicts activity in regions implicated in reward circuitries, including orbitomedial prefrontal cortex, globus pallidus, thalamus, midbrain, amygdala, and insula. This confirms the key role of NAcc in the mesocorticolimbic system, which integrates inputs from limbic and cortical regions. We also detected activity in brain regions having few or no direct anatomical connections with NAcc, such as sensorimotor cortex, cerebellum, medial and posterior parietal cortex, and medial/inferior temporal cortex, supporting the view that not all functional connections can be explained by anatomical connections but can also result from connections mediated by third areas. Our rsFC findings are in line with the results of the structure-based meta-analysis: MACM maps are superimposable with NAcc rsFC results, and the reward paradigm class is the one that most frequently generates activation in NAcc. Our results overlap considerably with recently proposed schemata of the main neuron systems in the limbic forebrain and in the anterior part of the limbic midbrain in rodents and nonhuman primates.

Numerous studies have demonstrated that consuming high-calorie food leads to subsequent overeating by chronic dieters. The present study investigates the neural correlates of such self-regulatory failures using fMRI. Chronic dieters (n = 50) and non-dieters (n = 50) consumed either a 15-oz glass of cold water or a 15-oz milkshake and were subsequently imaged while viewing pictures of animals, environmental scenes, people, and appetizing food items. Results revealed a functional dissociation in nucleus accumbens and amygdala activity that paralleled well-established behavioral patterns of eating observed in dieters and non-dieters. Whereas non-dieters showed the greatest nucleus accumbens activity in response to food items after water consumption, dieters showed the greatest activity after consuming the milkshake. Activity in the left amygdala demonstrated the reverse interaction. Considered together with previously reported behavioral findings, the present results offer a suggested neural substrate for diet failure.

Background: Substance-abusing individuals tend to display abnormal reward processing and a vulnerability to being impulsive. Detoxified alcoholics show differences in regional brain activation during a monetary incentive delay task. However, there is limited information on whether this uncharacteristic behavior represents a biological predisposition toward alcohol abuse, a consequence of chronic alcohol use, or both., Methods: We investigated proposed neural correlates of substance disorder risk by examining reward system activity during a monetary incentive delay task with separate reward prospect, reward anticipation, and reward outcome phases in 30 individuals with and 19 without family histories of alcoholism. All subjects were healthy, lacked DSM-IV past or current alcohol or substance abuse histories, and were free of illegal substances as verified by a urine toxicology screening at the time of scanning. Additionally, we explored specific correlations between task-related nucleus accumbens (NAcc) activation and distinct factor analysis-derived domains of behavioral impulsivity., Results: During reward anticipation, functional magnetic resonance imaging data confirmed blunted NAcc activation in family history positive subjects. In addition, we found atypical activation in additional reward-associated brain regions during additional task phases. We further found a significant negative correlation between NAcc activation during reward anticipation and an impulsivity construct., Conclusions: Overall, results demonstrate that sensitivity of the reward circuit, including NAcc, is functionally different in alcoholism family history positive individuals in multiple regards., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A reward or punishment can seem better or worse depending on what else might have happened. Little is known, however, about how neural representations of an anticipated incentive might be influenced by the available alternatives. We used event-related FMRI to investigate the activation in the nucleus accumbens (NAcc), while we varied the available alternative incentives in a monetary incentive delay task. Some task blocks included only uncertain gains and losses; others included the same uncertain gains and losses intermixed with certain gains and losses. The availability of certain gains and losses increased NAcc activation for uncertain losses and decreased the difference between uncertain gains and losses. We suggest that this pattern of activation can result from reference point changes across blocks, and that the worst available loss may serve as an important anchor for NAcc activation. These findings imply that NAcc activation represents anticipated incentive value relative to the current context of available alternative gains and losses.

Rationale: Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, 'paradoxical' responses to psychostimulants have been reported at this age., Objectives: Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague-Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min., Results: Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters., Conclusions: The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy.

A great deal of behavioral and economic research suggests that the value attached to a reward stands in inverse relation to the amount of effort required to obtain it, a principle known as effort discounting. In the present article, we present the first direct evidence for a neural analogue of effort discounting. We used fMRI to measure neural responses to monetary rewards in the human nucleus accumbens (NAcc), a structure previously demonstrated to encode reference-dependent reward information. The magnitude of accumbens activation was found to vary with both reward outcome and the degree of mental effort demanded to obtain individual rewards. For a fixed level of reward, the NAcc was less strongly activated following a high-demand for effort than following a low demand. The magnitude of this effect was noted to correlate with preceding activation in the dorsal anterior cingulate cortex, a region that has been proposed to monitor information-processing demands and to mediate in the subjective experience of effort.

Background: The long-standing observation that the novelty-seeking personality trait is a predictor of drug use and other reinforcable risky behaviors raises the question as to how novelty and reward processing functionally interact in mesolimbic dopaminergic circuitry and how this interaction is modulated by the novelty-seeking personality trait., Methods: Functional magnetic resonance imaging (fMRI) hemodynamic responses to novelty and reward (monetary incentive) from the substantia nigra/ventral tegmental area (SN/VTA), the nucleus accumbens (NAcc), and the hippocampus of 29 subjects were correlated with novelty-seeking scores. These correlations were compared with those obtained for scores of reward-dependence. The fMRI data were taken from two experiments in which the interaction of novelty and reward was manipulated as a within-subject variable, and long-term memory for the critical stimuli was assessed after 24 hours., Results: Novelty-seeking was positively correlated with SN/VTA activation elicited by novel cues that did not predict reward, whereas reward-dependence was related to activations elicited by novel cues that predicted reward. The positive correlation between SN/VTA responses to novelty and novelty-seeking scores was accompanied by a negative correlation with reward-related SN/VTA activation and memory enhancement., Conclusions: SN/VTA responses to novelty and reward are differentially affected by personality traits of novelty-seeking and reward-dependence. Importantly, novelty-seekers were more responsive to novel cues in the absence of reward and needed less reward to boost their memory for novel cues. These observations strongly suggest that for novelty-seekers, the motivational value of novelty is not necessarily based on actual reward-predicting stimulus properties.

Posttraumatic stress disorder (PTSD) is known to be associated with altered medial prefrontal activation in response to threatening stimuli and with behavioural deficits in prefrontal functions such as working memory and attention. Given the importance of these areas and processes for decision-making, this functional magnetic resonance imaging study investigated whether decision-making is altered in patients with PTSD. In particular, the neural response to gain and loss feedback was evaluated in a decision-making task in which subjects could maximise their number of points total by learning a particular response pattern. Behaviourally, controls learned the correct response pattern faster than patients. Functionally, patients and controls differed in their neural response to gains, but not in their response to losses. During the processing of gains in the late phase of learning, PTSD patients as compared to controls showed lower activation in the nucleus accumbens and the mesial PFC, critical structures in the reward pathway. This reduced activation was not due to different rates of learning, since it was similarly present in patients with unimpaired learning performance. These findings suggest that positive outcome information lost its salience for patients with PTSD. This may reflect decreasing motivation as the task progressed.

The shy-bold continuum is a fundamental behavioral trait conserved across human and nonhuman animals. Individual differences along the shy-bold continuum are presumed to arise from, and are maintained by, differences in the excitability of forebrain limbic areas involved in the evaluation of stimulus saliency. To test this hypothesis, the authors conducted an event-related functional MRI (fMRI) study in which brain scans were acquired on shy and bold adults during the presentation of neutral stranger and personally familiar faces. Shy adults exhibited greater bilateral amygdala activation during the presentation of stranger faces and greater left amygdala activation during personally familiar faces than their bold counterparts. Bold adults exhibited greater bilateral nucleus accumbens activation in response to stranger and personally familiar faces than shy adults. Findings suggest that there are distinct neural substrates underlying and maintaining individual differences along a shy-bold continuum in humans., ((Copyright) 2008 APA, all rights reserved.)

In functional magnetic resonance imaging research, nucleus accumbens (NAcc) activation spontaneously increases before financial risk taking. As anticipation of diverse rewards can increase NAcc activation, even incidental reward cues may influence financial risk taking. Using event-related functional magnetic resonance imaging, we predicted and found that anticipation of viewing rewarding stimuli (erotic pictures for 15 heterosexual men) increased financial risk taking, and that this effect was partially mediated by increases in NAcc activation. These results are consistent with the notion that incidental reward cues influence financial risk taking by altering anticipatory affect, and so identify a neuropsychological mechanism that may underlie effective emotional appeals in financial, marketing, and political domains.

Rationale: Animal research suggests that anticipation of reward can elicit dopamine release in the nucleus accumbens (NAcc). Human functional magnetic resonance imaging (FMRI) research further suggests that reward anticipation can increase local blood oxygen level dependent (BOLD) signal in the NAcc. However, the physiological relationship between dopamine release and BOLD signal increases in the NAcc has not yet been established., Objectives: This review considers pharmacological MRI (phMRI) evidence for a directional relationship between NAcc dopamine release and BOLD signal, as well as implications for human psychopathological symptoms., Results: Accumulating phMRI evidence supports a simple model in which NAcc dopamine release activates postsynaptic D1 receptors, which changes postsynaptic membrane potential, eventually increasing local BOLD signal. This continuing influence can change on a second-to-second basis., Conclusions: Dopamine release in the NAcc appears to increase local BOLD signal via agonism of postsynaptic D1 receptors. Such a physiological mechanism implies that FMRI may be used to track symptoms related to NAcc dopaminergic dysregulation in psychiatric disorders including schizophrenia and attention deficit/hyperactivity disorder.

Evidence indicates that dopaminergic medication in Parkinson's disease may impair certain aspects of cognitive function, such as reversal learning. We used functional magnetic resonance imaging in patients with mild Parkinson's disease to investigate the neural site at which L-DOPA acts during reversal learning. Patients were scanned both ON and OFF their normal dopamine-enhancing L-DOPA medication during the performance of a probabilistic reversal learning task. We demonstrate that L-DOPA modulated reversal-related activity in the nucleus accumbens, but not in the dorsal striatum or the prefrontal cortex. These data concur with evidence from studies with experimental animals and indicate an important role for the human nucleus accumbens in the dopaminergic modulation of reversal learning.

Adolescence has been characterized by risk-taking behaviors that can lead to fatal outcomes. This study examined the neurobiological development of neural systems implicated in reward-seeking behaviors. Thirty-seven participants (7-29 years of age) were scanned using event-related functional magnetic resonance imaging and a paradigm that parametrically manipulated reward values. The results show exaggerated accumbens activity, relative to prefrontal activity in adolescents, compared with children and adults, which appeared to be driven by different time courses of development for these regions. Accumbens activity in adolescents looked like that of adults in both extent of activity and sensitivity to reward values, although the magnitude of activity was exaggerated. In contrast, the extent of orbital frontal cortex activity in adolescents looked more like that of children than adults, with less focal patterns of activity. These findings suggest that maturing subcortical systems become disproportionately activated relative to later maturing top-down control systems, biasing the adolescent's action toward immediate over long-term gains.

The precise role of the anterior cingulate cortex in monitoring, evaluating, and correcting behavior remains unclear despite numerous theories and much empirical data implicating it in cognitive control. The present event-related functional magnetic resonance imaging study was able to separate monitoring from error-specific functions by allowing subjects to reject a trial so as to avoid errors. Cingulate and left dorsolateral prefrontal activity was greatest on rejection trials but comparable for correct and error trials, whereas an error-specific response was observed in bilateral insula. A dissociation was also observed between the cingulate and the nucleus accumbens with the latter more active for error than reject trials. These results reveal that the functional role of the cingulate is not particular to errors but instead is related to an evaluative function concerned with on-line behavioral adjustment in the service of avoiding losses.

Cannabinoid receptors have been implicated in the regulation of blood flow in the cerebral vasculature. Because the nucleus accumbens (NAc) shows high levels of central cannabinoid receptor 1 (CB1) expression we examined the effects of cannabinoids on the local transient alkaline shifts and increases in extracellular oxygen induced by electrical stimulation of the medial forebrain bundle (MFB) in conscious animals. These changes result from increases in cerebral blood flow (CBF) and metabolism in the NAc that are evoked by the stimulation. Oxygen and pH changes were monitored using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in the NAc of freely moving rats. Administration of the cannabinoid receptor agonist WIN55,212-2 potently inhibited extracellular oxygen and pH changes, an effect that was reversed and prevented by pre-treatment with the CB1 receptor antagonists SR141716A and AM251. The effects on pH following WIN55,212-2 were similar to those following nimodipine, a recognized vasodilator. When AM251 was injected alone, the amplitude of electrically evoked pH shifts was unaffected. Administration of AM404 and VDM11, endocannabinoid transport inhibitors, partially inhibited pH transients in a CB1 receptor-dependent manner. The present findings suggest that CB1 receptor activation modulates changes in two well-established indices of local blood flow and metabolism resulting from electrically evoked activation of ascending fibers. Although endogenous cannabinoid tone alone is not sufficient to modify these responses, uptake blockade demonstrates that the system has the potential to exert CB1-specific effects similar to those of full agonists.

Using functional magnetic resonance imaging (fMRI) we found that a noxious thermal stimulus (46 degrees C) to the hand activates the nucleus accumbens (NAc) in humans, while a non-noxious warm stimulus (41 degrees C) does not. Following the noxious stimulus, two distinct foci of decreased activation were observed showing distinct time course profiles. One focus was anterior, superior, and lateral and the second that was more posterior, inferior, and medial. The anatomical segregation may correlate with the functional components of the NAc, i.e., shell and core. The results support heterogeneity of function within the NAc and have implications for the understanding the contribution of NAc function to processing of pain and analgesia.

Background: Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity., Methods: Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues., Results: Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls., Conclusions: This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.

Anticipated reward magnitude and probability comprise dual components of expected value (EV), a cornerstone of economic and psychological theory. However, the neural mechanisms that compute EV have not been characterized. Using event-related functional magnetic resonance imaging, we examined neural activation as subjects anticipated monetary gains and losses that varied in magnitude and probability. Group analyses indicated that, although the subcortical nucleus accumbens (NAcc) activated proportional to anticipated gain magnitude, the cortical mesial prefrontal cortex (MPFC) additionally activated according to anticipated gain probability. Individual difference analyses indicated that, although NAcc activation correlated with self-reported positive arousal, MPFC activation correlated with probability estimates. These findings suggest that mesolimbic brain regions support the computation of EV in an ascending and distributed manner: whereas subcortical regions represent an affective component, cortical regions also represent a probabilistic component, and, furthermore, may integrate the two.

We investigated the effect of estrogen on cocaine-induced brain activity using blood oxygen level-dependent (BOLD) magnetic resonance imaging. Ovariectomized (Ovx) rats without estrogen and Ovx rats with estrogen (Ovx+E) were given a single saline or cocaine injection (15 mg/kg, i.p.) for 5 d. After 7 d of withdrawal from injections, rats were challenged with cocaine during functional imaging. Acute cocaine administration produced positive BOLD activation in the prefrontal cortex, nucleus accumbens, striatum, ventral tegmental area, and hippocampus, among other brain regions. Positive BOLD signal changes were lower in Ovx+E than in Ovx rats. With repeated cocaine administration, Ovx+E rats showed enhanced BOLD signal changes in the nucleus accumbens, ventral tegmental area, and hippocampus compared with acutely treated animals. Our results indicate that estrogen influences the effects of acute and repeated cocaine administration on BOLD signal changes. The data suggest that in females with estrogen, cocaine-induced neuronal activity is enhanced after repeated cocaine administration. It is possible that the actions of estrogen within the aforementioned brain regions potentiate the behavioral response to cocaine observed in female rats.

Although considerable progress has been made towards understanding the neural systems mediating conditioned fear, little is known about the neural mechanisms underlying conditioned inhibitors of fear (or safety signals). The present series of experiments examined the involvement of the nucleus accumbens (NAC) in mediating the effects of safety signals on behavior using a conditioned inhibition of fear-potentiated startle paradigm. Neither increasing dopaminergic nor decreasing glutamatergic function in the NAC altered the magnitude of conditioned fear or conditioned inhibition of fear in rats. Furthermore, large pre- or post-training electrolytic lesions of the NAC did not affect acquisition or expression of fear-potentiated startle or conditioned inhibition of fear-potentiated startle. Taken together, these data suggest that the NAC is not critically involved in the acquisition or expression of fear-potentiated startle or conditioned inhibition of fear-potentiated startle. Previous research has implicated the NAC in 'reward-attenuated startle' in which presentation of a stimulus paired with food decreased startle responding. The present results, therefore, indicate important neural dissociations between the processing of appetitive and safety signals, even though behavioral studies and learning theories have suggested that these two forms of learning share some commonalities.

This study implemented a risk-taking task during fMRI to probe the brain circuitry involved in risk-taking decision-making in 12 healthy control subjects. Partially supporting the initial hypotheses, deliberation prior to selection of safe relative to risky responses generated greater activation in the inferior frontal cortex, superior temporal gyrus, and middle temporal gyrus; and deliberation prior to selection of risky relative to safe responses generated greater activation in medial frontal cortex, occipital cortex, nucleus accumbens and caudate. Additionally, accumbens activation correlated positively with the harm avoidance subscale of the Temperament and Character Inventory (TCI) 125. These findings may provide target neural systems to study in subjects who exhibit problematic risk-taking behaviors and may partially explain why certain risky behaviors occur.

Thirty male Sprague-Dawley rats were divided into two groups and trained to self-administer either saline (n = 14) or heroin (0.1 mg/kg per injection, n = 16) for 10-12 days until a stable self-administration (SA) behavior was achieved. After 8-9 days of withdrawal, each group was divided into two subgroups for reinstatement tests and functional magnetic resonance image (fMRI) scanning, respectively, to determine the neural correlates of the reinstatement of heroin-seeking behavior. For reinstatement testing, heroin-SA rats (n = 10) displayed robust reinstatement of drug-seeking behavior triggered by an acute heroin priming injection, whereas saline control rats (n = 8) did not show such a behavioral response. Regional positive or negative blood oxygen level-dependent (BOLD) signals, induced by heroin priming injection, were observed in both groups of rats during fMRI scanning. However, such heroin-induced positive BOLD signal primarily in the prefrontal cortex and parietal cortex was significantly attenuated in heroin-SA rats (n = 6) when compared to saline control rats (n = 6). Similarly, the heroin-induced negative BOLD signal in the subcortical regions, such as in the nucleus accumbens and hippocampus, was also significantly attenuated in both signal intensity and number of brain voxels activated in heroin-SA rats. These data demonstrate that heroin-induced reinstatement of drug-seeking behavior coincides with a significant, enduring reduction in opiate-induced brain activity in heroin-SA rats, suggesting a possible role of opiate tolerance in mediating reinstatement of drug-seeking behavior., (Copyright 2004 Elsevier Inc.)

Studies on white rats showed that intraperitoneal administration of small doses of fentanyl (0.005 mg/kg) and morphine (1 mg/kg) decreased local blood flow and increased partial pressure of oxygen (pO2) in the frontoparietal area of the cerebral cortex but had the opposite effects in the nucleus accumbens--where there was a significant increase in local blood flow and just as significant a decrease in pO2. Analysis of the data led to the conclusion that these changes must result from significant changes in functional-metabolic activity in these structures, induced by intraperitoneal administration of fentanyl or morphine.

Objective: We wanted to assess possible alterations in brain activation in PTSD patients with severe hyperarousal symptoms and impulsive aggressiveness., Method: 25 Croatian War (1991-1995) veterans with combat-related PTSD with severe hyperarousal symptoms and impulsive aggressiveness were assessed for possible alterations in cerebral blood flow in single photon emission computed tomography brain scans., Results: Increased regional cerebral blood flow in projection area of nucleus accumbens was found in 13 of 25 subjects, and for all in the dominant brain hemisphere., Discussion: We believe that at least some of PTSD symptoms, and especially the impulsive aggression, can be associated with increased regional cerebral blood flow in the projection area of nucleus accumbens.

The aim of this study was to examine effects of i.p. injected Fentanyl (0.005 mg/kg) and Morphine (1 mg/kg) on local cerebral blood flow (ICBF) and tissue pO2 level in frontal-parietal area of the cortex and nucleus accumbens of the rat's brain. Either fentanyl or morphine injection resulted in significant increase of local blood flow in the n.accumbens and its decrease in frontal-parietal area of cortex. Measurement of oxygen partial pressure revealed the opposite (to ICBF) changes: a decrease in n.accumbens and its increase in cortical area of the brain. Analysis of this data and electrical activity recorded from both said structures allow to conclude that they are conditioned by respective changes in functional-metabolic activity induced by intraperitoneal injection either fentanyl or morphine: its suppression in frontal-parietal area of the cortex and development of seizure-like activity in the n.accumbens.

Comparative studies have implicated the nucleus accumbens (NAcc) in the anticipation of incentives, but the relative responsiveness of this neural substrate during anticipation of rewards versus punishments remains unclear. Using event-related functional magnetic resonance imaging, we investigated whether the anticipation of increasing monetary rewards and punishments would increase NAcc blood oxygen level-dependent contrast (hereafter, "activation") in eight healthy volunteers. Whereas anticipation of increasing rewards elicited both increasing self-reported happiness and NAcc activation, anticipation of increasing punishment elicited neither. However, anticipation of both rewards and punishments activated a different striatal region (the medial caudate). At the highest reward level ($5.00), NAcc activation was correlated with individual differences in self-reported happiness elicited by the reward cues. These findings suggest that whereas other striatal areas may code for expected incentive magnitude, a region in the NAcc codes for expected positive incentive value.

Functional brain mapping based on changes in local cerebral blood flow (lCBF) or glucose utilization (lCMR(glc)) induced by functional activation is generally carried out in animals under anesthesia, usually alpha-chloralose because of its lesser effects on cardiovascular, respiratory, and reflex functions. Results of studies on the role of nitric oxide (NO) in the mechanism of functional activation of lCBF have differed in unanesthetized and anesthetized animals. NO synthase inhibition markedly attenuates or eliminates the lCBF responses in anesthetized animals but not in unanesthetized animals. The present study examines in conscious rats and rats anesthetized with alpha-chloralose the effects of vibrissal stimulation on lCMR(glc) and lCBF in the whisker-to-barrel cortex pathway and on the effects of NO synthase inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) on the magnitude of the responses. Anesthesia markedly reduced the lCBF and lCMR(glc) responses in the ventral posteromedial thalamic nucleus and barrel cortex but not in the spinal and principal trigeminal nuclei. L-NAME did not alter the lCBF responses in any of the structures of the pathway in the unanesthetized rats and also not in the trigeminal nuclei of the anesthetized rats. In the thalamus and sensory cortex of the anesthetized rats, where the lCBF responses to stimulation had already been drastically diminished by the anesthesia, L-NAME treatment resulted in loss of statistically significant activation of lCBF by vibrissal stimulation. These results indicate that NO does not mediate functional activation of lCBF under physiological conditions.

We used PET to study differences in cerebral blood flow (CBF) in smooth pursuit, predictive saccades and fixation. Eye movements were monitored in the scanner. Compared with fixation, pursuit and predictive saccades activated a network of highly similar areas, including frontal eye fields, supplementary eye fields, V5 and medial cuneus. Our findings are consistent with non-human primate studies that suggest that pursuit and saccades are controlled by similar and adjacent neural areas. Pursuit was associated with greater activation of caudate than saccades, suggesting a role for basal ganglia in pursuit that is consistent with studies of neurological populations. Saccades were associated with greater activation of cerebellum and frontal eye fields. A frontal-cerebellar loop may be important in coordinating the preparation and timing of saccades in predictive tracking.

Objective: To assist in the development of a model for the psychopathology of emotions, the present study sought to identify the neural circuits associated with the evaluation of visual stimuli for emotional valence., Method: Seventeen healthy individuals were shown three sets of emotionally laden pictures carrying pleasant, unpleasant, and neutral content. While subjects evaluated the picture set for emotional valence, regional cerebral blood flow was measured with the use of [15O] water positron emission tomography. Subjective ratings of the emotional valence of the picture sets were recorded. Data were analyzed by comparing the images acquired during the neutral condition with the unpleasant and pleasant image sets and the unpleasant and pleasant conditions with each other., Results: Processing of pleasant stimuli was associated with increased blood flow in the dorsal-lateral, orbital, and medial frontal cortex relative to the unpleasant condition and in the cingulate, precuneus, and visual cortex relative to the neutral condition. Evaluation of unpleasant stimuli activated the amygdala, visual cortex, and cerebellum relative to the pleasant condition and the nucleus accumbens, precuneus, and visual cortex relative to the neutral condition., Conclusions: Observing and assigning emotional value to unpleasant stimuli produced activations in subcortical limbic regions, whereas evaluation of pleasant stimuli produced activations in cortical limbic areas. These findings are consistent with the notion of a subcortical and archaic danger recognition system and a system detecting pleasantness in events and situations that is phylogenetically younger, involving primarily the prefrontal cortex.

Immuno-electron-microscopic investigations of cerebrospinal fluid (CSF)-contacting neurons immunoreactive to vasoactive intestinal peptide in the duck lateral septum have revealed that this cell type gives rise to an adventricular dendrite terminating with a bulbous swelling in the lateral ventricle. The swelling bears a cilium and contains mitochondria and immunolabeled dense-core vesicles. Two types of processes emerge from the basal part of the perikaryon. The first has a large diameter, contains diffusely distributed immunoreaction, and receives synaptic input, indicating that this process is a basal dendrite. The other type is of a beaded appearance, displays immunolabeled dense-core vesicles, and represents the axon of the CSF-contacting neuron. VIP-immunoreactive terminal formations are located within the neuropil of the lateral septum and the nucleus accumbens. Some of them form synaptic contacts with immunonegative profiles. No VIP-immunoreactive terminal formations are seen in the perivascular spaces of the lateral septum. Tracer experiments with horseradish peroxidase have revealed that the blood-brain barrier is lacking in the lateral septal organ and nucleus accumbens of the duck. Capillaries, arterioles, and venoles of this region are coated by nonfenestrated endothelial cells connected by "leaky" junctions, allowing the tracer to penetrate from the lumen into the perivascular space and further into the intercellular clefts of the neuropil. Our immuno-electron-microscopic investigations show that VIP-immunoreactive CSF-contacting neurons of the lateral septum closely resemble CSF-contacting neurons occurring in other brain regions, e.g., the hypothalamus. The arrangement of VIP-immunoreactive terminal formations suggests that, in the lateral septum, the VIP-like neuropeptide serves as a neurotransmitter (-modulator). The lack of a blood-brain barrier in the lateral septal organ and the nucleus accumbens raises the possibility that this region is a window in the avian brain allowing exchange of information between the central nervous system and the bloodstream; it thus resembles a circumventricular organ.