A common currency for the computation of motivational values in the human striatum

Reward comparison in the brain is thought to be achieved through the use of a ‘common currency’, implying that reward value representations are computed on a unique scale in the same brain regions regardless of the reward type. Although such a mechanism has been identified in the ventro-medial prefrontal cortex and ventral striatum in the context of decision-making, it is less clear whether it similarly applies to non-choice situations. To answer this question, we scanned 38 participants with fMRI while they were presented with single cues predicting either monetary or erotic rewards, without the need to make a decision. The ventral striatum was the main brain structure to respond to both cues while showing increasing activity with increasing expected reward intensity. Most importantly, the relative response of the striatum to monetary vs erotic cues was correlated with the relative motivational value of these rewards as inferred from reaction times. Similar correlations were observed in a fronto-parietal network known to be involved in attentional focus and motor readiness. Together, our results suggest that striatal reward value signals not only obey to a common currency mechanism in the absence of choice but may also serve as an input to adjust motivated behaviour accordingly.     

Fast‐spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward

Although previous in vitro studies revealed inhibitory synaptic connections of fast‐spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast‐spiking neurons were distinguished from putative medium‐sized spiny neurons on the basis of their spike waveforms and rates. Cross‐correlograms of fast‐spiking and putative medium‐sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium‐sized spiny neuron spiking around fast‐spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast‐spiking unit firing. Many of these temporal relationships were dependent on the sleep–wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast‐spiking units and putative medium‐sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast‐spiking neurons in a reward‐searching task, they generally showed a pre‐reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed‐forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast‐spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward‐related changes in firing rate.     

Loss of striatal tyrosine‐hydroxylase interneurons impairs instrumental goal‐directed behavior

The striatum mediates a broad range of cognitive and motor functions. Within the striatum, recently discovered tyrosine hydroxylase expressing interneurons (THINs) provide a source of intrastriatal synaptic connectivity that is critical for regulating striatal activity, yet the role of THIN's in behavior remains unknown. Given the important role of the striatum in reward‐based behaviors, we investigated whether loss of striatal THINs would impact instrumental behavior in mice. We selectively ablated striatal THINs in TH‐Cre mice using chemogenetic techniques, and then tested THIN‐lesioned or control mice on three reward‐based striatal‐dependent instrumental tests: (a) progressive ratio test; (b) choice test following selective‐satiety induced outcome devaluation; (c) outcome reinstatement test. Both striatal‐THIN‐lesioned and control mice acquired an instrumental response for flavored food pellets, and their behavior did not differ in the progressive ratio test, suggesting intact effort to obtain rewards. However, striatal THIN lesions markedly impaired choice performance following selective‐satiety induced outcome devaluation. Unlike control mice, THIN‐lesioned mice did not adjust their choice of actions following a change in outcome value. In the outcome reinstatement test THIN‐lesioned and control mice showed response invigoration by outcome presentation, suggesting the incentive properties of outcomes were not disrupted by THIN lesions. Overall, we found that striatal THIN lesions selectively impaired goal‐directed behavior, while preserving motoric and appetitive behaviors. These findings are the first to describe a function of striatal THINs in reward‐based behavior, and further illustrate the important role for intrastriatal interneuronal connectivity in behavioral functions ascribed to the striatum more generally.     

Tonically active neurons in the striatum encode motivational contexts of action

In order to achieve a goal, one procures immediately available rewards, escape from aversive events or endures absence of rewards. The neuronal substrate for these goal-directed actions includes the limbic system and the basal ganglia. In the basal ganglia, classes of projection neurons in the striatum show activity with motivational as well as sensorimotor properties, such as expectation of reward and task schedule for obtaining reward. Tonically active neurons (TANs), presumed cholinergic interneurons in the striatum, respond to reward-associated stimuli, evolve their activity through learning and respond also to aversive event-associated stimuli such as airpuff on the face. A recent study showed that responses to visual cues are less selective to whether the cue instructs reward or no reward. To address this paradox, we asked macaque monkeys to perform a set of visual reaction time tasks while expecting the reward, aversive event or absence of reward. We found that TANs respond to instruction stimuli associated with motivational outcomes but not to unassociated ones, and that they mostly differentiate associated instructions. We also found that the higher percentage of TANs in the caudate nucleus respond to stimuli associated with motivational outcomes than in the putamen, whereas the higher percentage of TANs in the putamen respond to GO signals than in the caudate nucleus especially for an action anticipating a reward. These findings suggest a distinct, pivotal role played by TANs in the caudate nucleus and putamen in encoding instructed motivational contexts for goal-directed action selection and learning in the striatum.     

Mesolimbic recruitment by nondrug rewards in detoxified alcoholics: effort anticipation, reward anticipation, and reward delivery

Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol‐dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post‐response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two‐stage presentation of reward‐predictive information, subjects saw cues signaling opportunities to win Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol‐dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post‐response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two‐stage presentation of reward‐predictive information, subjects saw cues signaling opportunities to win Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol-dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post-response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two-stage presentation of reward-predictive information, subjects saw cues signaling opportunities to win $0, $1, or $10 for responding to a target. Following this response, subjects were notified whether their success would be indicated by a lexical notification (“Hit?”) or by delivery of a monetary reward (“Win?”). After a variable interval, subjects then viewed the trial outcome. We found no significant group differences in voxelwise activation by task contrasts, or in signal change extracted from VS. Both ADP and controls showed significant VS and other limbic recruitment by pre-response reward anticipation. In addition, controls also showed VS recruitment by post-response reward-anticipation, and ADP had appreciable subthreshold VS activation. Both groups also showed similar mesolimbic responses to reward deliveries. Across all subjects, a questionnaire measure of “hot” impulsivity correlated with VS recruitment by post-response anticipation of low rewards and with VS recruitment by delivery of low rewards. These findings indicate that incentive-motivational processing of nondrug rewards is substantially maintained in recovering alcoholics, and that reward-elicited VS recruitment correlates more with individual differences in trait impulsivity irrespective of addiction.     

Learning,memory and consolidation mechanisms for behavioral control in hierarchically organized cortico‐basal ganglia systems

This article aims to provide a synthesis on the question how brain structures cooperate to accomplish hierarchically organized behaviors, characterized by low‐level, habitual routines nested in larger sequences of planned, goal‐directed behavior. The functioning of a connected set of brain structures—prefrontal cortex, hippocampus, striatum, and dopaminergic mesencephalon—is reviewed in relation to two important distinctions: (a) goal‐directed as opposed to habitual behavior and (b) model‐based and model‐free learning. Recent evidence indicates that the orbitomedial prefrontal cortices not only subserve goal‐directed behavior and model‐based learning, but also code the “landscape” (task space) of behaviorally relevant variables. While the hippocampus stands out for its role in coding and memorizing world state representations, it is argued to function in model‐based learning but is not required for coding of action–outcome contingencies, illustrating that goal‐directed behavior is not congruent with model‐based learning. While the dorsolateral and dorsomedial striatum largely conform to the dichotomy between habitual versus goal‐directed behavior, ventral striatal functions go beyond this distinction. Next, we contextualize findings on coding of reward‐prediction errors by ventral tegmental dopamine neurons to suggest a broader role of mesencephalic dopamine cells, viz. in behavioral reactivity and signaling unexpected sensory changes. We hypothesize that goal‐directed behavior is hierarchically organized in interconnected cortico‐basal ganglia loops, where a limbic‐affective prefrontal‐ventral striatal loop controls action selection in a dorsomedial prefrontal–striatal loop, which in turn regulates activity in sensorimotor‐dorsolateral striatal circuits. This structure for behavioral organization requires alignment with mechanisms for memory formation and consolidation. We propose that frontal corticothalamic circuits form a high‐level loop for memory processing that initiates and temporally organizes nested activities in lower‐level loops, including the hippocampus and the ripple‐associated replay it generates. The evidence on hierarchically organized behavior converges with that on consolidation mechanisms in suggesting a frontal‐to‐caudal directionality in processing control.     

The corticostriatal input to giant aspiny interneurons in the rat: a candidate pathway for synchronising the response to reward-related cues

Tonically active neurons (TANs) in the mammalian striatum show a pause in their ongoing firing activity in response to an auditory cue that is paired with a reward. This response to reward-related cues develops through learning and becomes expressed synchronously by TANs located throughout the striatum. The pause response is abolished by inactivating the thalamic inputs to the striatum but a short-latency excitatory response to reward-related cues remains, which may originate in the cortex. We investigated the cortical inputs to striatal neurons to determine the electrophysiological properties of their cortical projections. We made in vivo intracellular recordings from 14 giant aspiny interneurons (which correspond to the TANs) and from a control group of spiny projection neurons (n=18) in urethane-anaesthetised rats. All giant aspiny interneurons were tonically active (firing rate: 3.0+/-1.5 Hz) and displayed small-amplitude subthreshold fluctuations in membrane potential. These fluctuations in membrane potential were correlated with the cortical electroencephalogram (EEG). Test stimulation of the contralateral cortex induced postsynaptic potentials (PSPs) in giant aspiny interneurons. These PSPs were significantly shorter in latency (5.1+/-1.6 ms) than those measured in spiny projection neurons (9.3+/-2.8 ms; p<0.01), whereas the latencies of ipsilaterally evoked PSPs did not differ. Taken together, these observations suggest that giant aspiny interneurons are under the significant influence of spontaneous excitatory inputs and receive specialised input from either faster conducting or less branching cortical fibres than spiny projection neurons. These inputs may be involved in the synchronised convergence of reward-related cues from spatially distinct cortical areas onto giant aspiny interneurons.     

Long‐lasting contribution of dopamine in the nucleus accumbens core,but not dorsal lateral striatum,to sign‐tracking

The attribution of incentive salience to reward‐paired cues is dependent on dopamine release in the nucleus accumbens core (NAcC). These dopamine signals conform to traditional reward‐prediction error signals and have been shown to diminish with time. Here we examined whether the diminishing dopamine signal in the NAcC has functional implications for the expression of sign‐tracking, a Pavlovian conditioned response indicative of the attribution of incentive salience to reward‐paired cues. Food‐restricted male Sprague Dawley rats were trained in a Pavlovian paradigm in which an insertable lever predicted delivery of food reward in a nearby food cup. After 7 or 14 training sessions, rats received infusions of saline, the dopamine antagonist flupenthixol, or the GABA agonists baclofen and muscimol into the NAcC or the dorsal lateral striatum (DLS). Dopamine antagonism within the NAcC attenuated sign‐tracking, whereas reversible inactivation did not affect sign‐tracking but increased non‐specific food cup checking behaviors. Neither drug in the DLS affected sign‐tracking behavior. Critically, extended training did not alter these effects. Although extended experience with an incentive stimulus may reduce cue‐evoked dopamine in the NAcC, this does not remove the dependence on dopamine in this region to promote Pavlovian cue approach nor result in the recruitment of dorsal lateral striatal systems for this behavior. These data support the notion that dopamine within the mesoaccumbal system, but not the nigrostriatal system, contributes critically to incentive motivational processes independent of the length of training.     

Attentional modulation of reward processing in the human brain

Although neural signals of reward anticipation have been studied extensively, the functional relationship between reward and attention has remained unclear: Neural signals implicated in reward processing could either reflect attentional biases towards motivationally salient stimuli, or proceed independently of attentional processes. Here, we sought to disentangle reward and attention‐related neural processes by independently modulating reward value and attentional task demands in a functional magnetic resonance imaging study in healthy human participants. During presentation of a visual reward cue that indicated whether monetary reward could be obtained in a subsequent reaction time task, participants either attended to the reward cue or performed an unrelated attention‐demanding task at two different levels of difficulty. In ventral striatum and ventral tegmental area, neural responses were modulated by reward anticipation irrespective of attentional demands, thus indicating attention‐independent processing of reward cues. By contrast, additive effects of reward and attention were observed in visual cortex. Critically, reward‐related activations in right anterior insula strongly depended on attention to the reward cue. Dynamic causal modelling revealed that the attentional modulation of reward processing in insular cortex was mediated by enhanced effective connectivity from ventral striatum to anterior insula. Our results provide evidence for distinct functional roles of the brain regions involved in the processing of reward‐indicating information: While subcortical structures signal the motivational salience of reward cues even when attention is fully engaged elsewhere, reward‐related responses in anterior insula depend on available attentional resources, likely reflecting the conscious evaluation of sensory information with respect to motivational value. Hum Brain Mapp 35:3036–3051, 2014. © 2013 Wiley Periodicals, Inc.     

Neuronal activity in monkey ventral striatum related to the expectation of reward.

Projections from cortical and subcortical limbic structures to the basal ganglia are predominantly directed to the ventral striatum. The present study investigated how the expectation of external events with behavioral significance is reflected in the activity of ventral striatal neurons. A total of 420 neurons were studied in macaque monkeys performing in a delayed go-no-go task. Lights of different colors instructed the animal to do an arm-reaching movement or refrain from moving, respectively, when a trigger light was illuminated a few seconds later. Task performance was reinforced by liquid reward in both situations. A total of 60 ventral striatal neurons showed sustained increases of activity before the occurrence of individual task events. In 43 of these neurons, activations specifically preceded the delivery of reward, independent of the movement or no-movement reaction. In a series of additional tests, these activations were time locked to the subsequent reward, disappeared within a few trials when reward was omitted, and were temporally unrelated to mouth movements. Changes in the appetitive value of the reward liquid modified the magnitude of activations, suggesting a possible relationship to the hedonic properties of the expected event. Activations also occurred when reward was delivered in a predictable manner outside of any behavioral task. These data suggest that neurons in the ventral striatum are activated during states of expectation of individual environmental events that are predictable to the subject through its past experience. The prevalence of activations related to the expectation of reward suggests that ventral striatal neurons have access to central representations of reward and thereby participate in the processing of information underlying the motivational control of goal-directed behavior.     

Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum

Phasic changes in dopamine activity play a critical role in learning and goal-directed behavior. Unpredicted reward and reward-predictive cues evoke phasic increases in the firing rate of the majority of midbrain dopamine neurons--results that predict uniformly broadcast increases in dopamine concentration throughout the striatum. However, measurement of dopamine concentration changes during reward has cast doubt on this prediction. We systematically measured phasic changes in dopamine in four striatal subregions [nucleus accumbens shell and core (Core), dorsomedial (DMS) and dorsolateral striatum] in response to stimuli known to activate a majority of dopamine neurons. We used fast-scan cyclic voltammetry in awake and behaving rats, which measures changes in dopamine on a similar timescale to the electrophysiological recordings that established a relationship between phasic dopamine activity and reward. Unlike the responses of midbrain dopamine neurons, unpredicted food reward and reward-predictive cues evoked a phasic increase in dopamine that was subregion specific. In rats with limited experience, unpredicted food reward evoked an increase exclusively in the Core. In rats trained on a discriminative stimulus paradigm, both unpredicted reward and reward-predictive cues evoked robust phasic dopamine in the Core and DMS. Thus, phasic dopamine release in select target structures is dynamic and dependent on context and experience. Because the four subregions assayed receive different inputs and have differential projection targets, the regional selectivity of phasic changes in dopamine has important implications for information flow through the striatum and plasticity that underlies learning and goal-directed behavior.     

Striatal Dopamine and Reward Prediction Error Signaling in Unmedicated Schizophrenia Patients

Increased striatal dopamine synthesis capacity has consistently been reported in patients with schizophrenia. However, the mechanism translating this into behavior and symptoms remains unclear. It has been proposed that heightened striatal dopamine may blunt dopaminergic reward prediction error signaling during reinforcement learning. In this study, we investigated striatal dopamine synthesis capacity, reward prediction errors, and their association in unmedicated schizophrenia patients (n = 19) and healthy controls (n = 23). They took part in FDOPA-PET and underwent functional magnetic resonance imaging (fMRI) scanning, where they performed a reversal-learning paradigm. The groups were compared regarding dopamine synthesis capacity (Ki^cer), fMRI neural prediction error signals, and the correlation of both. Patients did not differ from controls with respect to striatal Ki^cer. Taking into account, comorbid alcohol abuse revealed that patients without such abuse showed elevated Ki^cer in the associative striatum, while those with abuse did not differ from controls. Comparing all patients to controls, patients performed worse during reversal learning and displayed reduced prediction error signaling in the ventral striatum. In controls, Ki^cer in the limbic striatum correlated with higher reward prediction error signaling, while there was no significant association in patients. Ki^cer in the associative striatum correlated with higher positive symptoms and blunted reward prediction error signaling was associated with negative symptoms. Our results suggest a dissociation between striatal subregions and symptom domains, with elevated dopamine synthesis capacity in the associative striatum contributing to positive symptoms while blunted prediction error signaling in the ventral striatum related to negative symptoms.     

Maladaptive striatal plasticity and abnormal reward‐learning in cervical dystonia

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients.     

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.     

Connectivity-based segmentation of the striatum in Huntington's disease: vulnerability of motor pathways

The striatum, the primary site of degeneration in Huntington's disease (HD), connects to the cerebral cortex via topographically organized circuits subserving unique motor, associative and limbic functions. Currently, it is not known whether all cortico-striatal circuits are equally affected in HD. We aimed to study the selective vulnerability of individual cortico-striatal circuits within the striatum in HD, and hypothesized that motor cortico-striatal pathways would be most affected, consistent with HD being a primarily motor disorder. Diffusion Tensor Imaging (DTI) tractography was used to identify connections between the striatum and seven major cortical regions in 12 HD patients and 14 matched controls. The striatum of both groups was parcellated into subregions based on connectivity with the cerebral cortex. Volumetric and DTI microstructural measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) were obtained within each subregion and compared statistically between groups. Tractography demonstrated the topographic organization of cortical connections in the striatum of both controls and HD patients. In HD patients, the greatest difference from controls in volume, FA and MD was observed in M1 and S1 subregions of the caudate and putamen. Motor symptoms correlated with volume and MD in sensorimotor striatal subregions, suggesting that sensorimotor striatal degeneration is closely related to motor dysfunction. DTI tractography provides a novel approach to sensitively examine circuit-specific abnormalities in HD and has identified that the motor cortico-striatal circuit is selectively vulnerable in HD.     

Meta‐analytic evidence for altered mesolimbic responses to reward in schizophrenia

Dysfunction of reward‐related neural circuitry in schizophrenia (SCZ) has been widely reported, and may provide insight into the motivational and cognitive disturbances that characterize the disorder. Although previous meta‐analyses of reward learning paradigms in SCZ have been performed, a meta‐analysis of whole‐brain coordinate maps in SCZ alone has not been conducted. In this study, we performed an activation likelihood estimate (ALE) meta‐analysis, and performed a follow‐up analysis of functional connectivity and functional decoding of identified regions. We report several salient findings that extend prior work in this area. First, an alteration in reward‐related activation was observed in the right ventral striatum, but this was not solely driven by hypoactivation in the SCZ group compared to healthy controls. Second, the region was characterized by functional connectivity primarily with the lateral prefrontal cortex and pre‐supplementary motor area (preSMA), as well as subcortical regions such as the thalamus which show structural deficits in SCZ. Finally, although the meta‐analysis showed no regions outside the ventral striatum to be significantly altered, regions with higher functional connectivity with the ventral striatum showed a greater number of subthreshold foci. Together, these findings confirm the alteration of ventral striatal function in SCZ, but suggest that a network‐based approach may assist future analysis of the functional underpinnings of the disorder.     

Effects of ventral striatal lesions on first‐ and second‐order appetitive conditioning

Rats with bilateral lesions of the ventral striatal nucleus accumbens failed to acquire Pavlovian second‐order conditioning to auditory stimuli paired with visual stimuli that had previously received first‐order pairings with food. This deficit in second‐order conditioning was specific to learning driven by incentive properties of the first‐order cues, and was observed whether the first‐order training had occurred prior to or after lesion surgery. Lesions also produced deficits in the display of conditioned responses to the first‐order conditioned stimulus, but only when they were made after first‐order training. These results suggest a specific role for the ventral striatum in acquiring and expressing incentive properties of conditioned stimuli through second‐order conditioning, as well as a more general role in expressing previously acquired Pavlovian conditioned responses.     

Neurons in the orbitofrontal cortex code both visual shapes and reward types

It has been reported that neurons in the orbitofrontal cortex respond to visual cues that predict reward; however, few studies have focused on the neuronal correlates with the predicted reward type and the cue stimulus. In this study, we used a paired association task and introduced a reversal condition, in which cue stimuli that usually predict water were switched to predict juice, and vice versa. Of 111 cue-responsive neurons, 60 neurons (54.1%) depended on both the cue stimulus and the predicted reward type. The results suggest that neurons in the orbitofrontal cortex can code both visual and reward information, and contribute to the association between these two pieces of information according to the current combination of a cue stimulus and a reward type.     

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.Key words: ventral striatum, orbitofrontal cortex, ventromedial prefrontal cortex, monetary incentive delay task, genetic vulnerability, cue processing     

fMRI study of neural sensitization to hedonic stimuli in long‐term,daily cannabis users

Although there is emergent evidence illustrating neural sensitivity to cannabis cues in cannabis users, the specificity of this effect to cannabis cues as opposed to a generalized hyper‐sensitivity to hedonic stimuli has not yet been directly tested. Using fMRI, we presented 53 daily, long‐term cannabis users and 68 non‐using controls visual and tactile cues for cannabis, a natural reward, and, a sensory‐perceptual control object to evaluate brain response to hedonic stimuli in cannabis users. The results showed an interaction between group and reward type such that the users had greater response during cannabis cues relative to natural reward cues (i.e., fruit) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area compared to non‐users (cluster‐threshold z = 2.3, P < 0.05). In the users, there were positive brain‐behavior correlations between neural response to cannabis cues in fronto‐striatal‐temporal regions and subjective craving, marijuana‐related problems, withdrawal symptoms, and levels of THC metabolites (cluster‐threshold z = 2.3, P < 0.05). These findings demonstrate hyper‐responsivity, and, specificity of brain response to cannabis cues in long‐term cannabis users that are above that of response to natural reward cues. These observations are concordant with incentive sensitization models suggesting sensitization of mesocorticolimbic regions and disruption of natural reward processes following drug use. Although the cross‐sectional nature of this study does not provide information on causality, the positive correlations between neural response and indicators of cannabis use (i.e., THC levels) suggest that alterations in the reward system are, in part, related to cannabis use. Hum Brain Mapp 37:3431–3443, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.