Search

The human sense of smell plays an important role in appetite and food intake, detecting environmental threats, social interactions, and memory processing. However, little is known about the neural circuity supporting its function. The olfactory tracts project from the olfactory bulb along the base of the frontal cortex, branching into several striae to meet diverse cortical regions. Historically, using diffusion magnetic resonance imaging (dMRI) to reconstruct the human olfactory tracts has been prevented by susceptibility and motion artifacts. Here, we used a dMRI method with readout segmentation of long variable echo-trains (RESOLVE) to minimize image distortions and characterize the human olfactory tractsin vivo. We collected high-resolution dMRI data from 25 healthy human participants (12 male and 13 female) and performed probabilistic tractography using constrained spherical deconvolution (CSD). At the individual subject level, we identified the lateral, medial, and intermediate striae with their respective cortical connections to the piriform cortex and amygdala (AMY), olfactory tubercle (OT), and anterior olfactory nucleus (AON). We combined individual results across subjects to create a normalized, probabilistic atlas of the olfactory tracts. We then investigated the relationship between olfactory perceptual scores and measures of white matter integrity, including mean diffusivity (MD). Importantly, we found that olfactory tract MD negatively correlated with odor discrimination performance. In summary, our results provide a detailed characterization of the connectivity of the human olfactory tracts and demonstrate an association between their structural integrity and olfactory perceptual function.SIGNIFICANCE STATEMENTThis study provides the first detailedin vivodescription of the cortical connectivity of the three olfactory tract striae in the human brain, using diffusion magnetic resonance imaging (dMRI). Additionally, we show that tract microstructure correlates with performance on an odor discrimination task, suggesting a link between the structural integrity of the olfactory tracts and odor perception. Lastly, we generated a normalized probabilistic atlas of the olfactory tracts that may be used in future research to study its integrity in health and disease.

When direct experience is unavailable, animals and humans can imagine or infer the future to guide decisions. Behavior based on direct experience versus inference may recruit partially distinct brain circuits. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes, and OFC is necessary for behavior that requires inference but not for responding driven by direct experience. In humans, OFC activity is also correlated with inferred outcomes, but it is unclear whether OFC activity is required for inference-based behavior. To test this, we used noninvasive network-based continuous theta burst stimulation (cTBS) in human subjects (male and female) to target lateral OFC networks in the context of a sensory preconditioning task that was designed to isolate inference-based behavior from responding that can be based on direct experience alone. We show that, relative to sham, cTBS targeting this network impairs reward-related behavior in conditions in which outcome expectations have to be mentally inferred. In contrast, OFC-targeted stimulation does not impair behavior that can be based on previously experienced stimulus–outcome associations. These findings suggest that activity in the targeted OFC network supports decision-making when outcomes have to be mentally simulated, providing converging cross-species evidence for a critical role of OFC in model-based but not model-free control of behavior.SIGNIFICANCE STATEMENTIt is widely accepted that the orbitofrontal cortex (OFC) is important for decision-making. However, it is less clear how exactly this region contributes to behavior. Here we test the hypothesis that the human OFC is only required for decision-making when future outcomes have to be mentally simulated, but not when direct experience with stimulus–outcome associations is available. We show that targeting OFC network activity in humans using network-based continuous theta burst stimulation selectively impairs behavior that requires inference but does not affect responding that can be based solely on direct experience. These results are in line with previous findings in animals and suggest a critical role for human OFC in model-based but not model-free behavior.

Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology [D2receptor (D2R) antagonist amisulpride] in humans with resting-state functional magnetic resonance imaging and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the twofold clustering did not differ significantly between groups, blocking D2Rs significantly changed the composition of the sixfold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectivity patterns of individual OFC subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks.SIGNIFICANCE STATEMENTA key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the orbitofrontal cortex (OFC). We show that blockade of dopamine D2receptors has profound effects on the functional connectivity patterns of the OFC, yielding altered connectivity-based subdivisions of this region. Our results suggest that dopamine changes the connectional configuration of the OFC, possibly leading to transitions between different operating modes that favor either sensory input or recurrent processing in the prefrontal cortex. More generally, our findings support a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks and may have clinical implications for understanding the actions of antipsychotic agents.

The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors,post hocanalyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs.

Alterations in motivated behavior are a hallmark of attention-deficit/hyperactivity disorder (ADHD), one of the most common psychiatric disorders in children and adolescents. The orbitofrontal cortex (OFC) plays a key role in controlling goal-directed behavior, but the link between OFC dysfunction and behavioral deficits in ADHD, particularly in adolescence, remains poorly understood. Here we used advanced high-resolution functional magnetic resonance imaging (fMRI) of the human OFC in adolescents with ADHD and typically developing (TD) controls (N = 39, age 12–16, all male except for one female per group) to study reward-related OFC responses and how they relate to behavioral dysfunction in ADHD. During fMRI data acquisition, participants performed a simple decision-making task, allowing us to image expectation-related responses to small and large monetary outcomes. Across all participants, we observed significant signal increases to large versus small expected rewards in the OFC. These responses were significantly enhanced in ADHD relative to TD participants. Moreover, stronger reward-related activity was correlated with individual differences in hyperactive/impulsive symptoms in the ADHD group, whereas high cognitive ability was associated with normalized OFC responses. These results provide evidence for the importance of OFC dysfunctions in the neuropathology of ADHD, highlighting the role of OFC-dependent goal-directed control mechanisms in this disorder. SIGNIFICANCE STATEMENT Attention-deficit/hyperactivity disorder (ADHD) is characterized by alterations in motivated behavior which can be understood as diminished goal-directed control. The orbitofrontal cortex (OFC) plays a key role in controlling goal-directed behavior, but its potential contribution to ADHD symptomatology remains poorly understood. Using high-resolution fMRI, we show that adolescent ADHD patients display enhanced OFC signaling of future rewards and that these increased reward-related responses are correlated with the severity of hyperactivity/impulsivity. These findings suggest that an inability to adequately evaluate future outcomes may translate into maladaptive behavior in ADHD patients. They also challenge the idea that dysfunctions in dopaminergic brain areas are the sole contributor to reward-related symptoms in ADHD and point to a central contribution of goal-directed control circuits in hyperactivity.

Goal-directed behavior is sensitive to the current value of expected outcomes. This requires independent representations of specific rewards, which have been linked to orbitofrontal cortex (OFC) function. However, the mechanisms by which the human brain updates specific goals on the fly, and translates those updates into choices, have remained unknown. Here we implemented selective devaluation of appetizing food odors in combination with pattern-based neuroimaging and a decision-making task. We found that in a hungry state, participants chose to smell high-intensity versions of two value-matched food odor rewards. After eating a meal corresponding to one of the two odors, participants switched choices toward the low intensity of the sated odor but continued to choose the high intensity of the nonsated odor. This sensory-specific behavioral effect was mirrored by pattern-based changes in fMRI signal in lateral posterior OFC, where specific reward identity representations were altered after the meal for the sated food odor but retained for the nonsated counterpart. In addition, changes in functional connectivity between the OFC and general value coding in ventromedial prefrontal cortex (vmPFC) predicted individual differences in satiety-related choice behavior. These findings demonstrate how flexible representations of specific rewards in the OFC are updated by devaluation, and how functional connections to vmPFC reflect the current value of outcomes and guide goal-directed behavior.SIGNIFICANCE STATEMENTThe orbitofrontal cortex (OFC) is critical for goal-directed behavior. A recent proposal is that OFC fulfills this function by representing a variety of state and task variables (“cognitive maps”), including a conjunction of expected reward identity and value. Here we tested how identity-specific representations of food odor reward are updated by satiety. We found that fMRI pattern-based signatures of reward identity in lateral posterior OFC were modulated after selective devaluation, and that connectivity between this region and general value coding ventromedial prefrontal cortex (vmPFC) predicted choice behavior. These results provide evidence for a mechanism by which devaluation modulates a cognitive map of expected reward in OFC and thereby alters general value signals in vmPFC to guide goal-directed behavior.

Value-based decisions optimize the relation of costs and benefits. Costs and benefits confer not only value but also salience, which may influence decision making through attentional mechanisms. However, the computational and neurobiological role of salience in value-based decisions remains elusive. Here we develop and contrast two formal concepts of salience for value-based choices involving costs and benefits. Specifically, global salience (GS) first integrates costs and benefits and then determines salience based on this overall sum, whereas elemental salience (ES) first determines the salience of costs and benefits before integrating them. We dissociate the behavioral and neural effects of GS and ES from those of value using a value-based decision-making task and fMRI in humans. Specifically, we show that value guides choices and correlates with neural signals in the striatum. In contrast, only ES but not GS impacts decision making by speeding up reaction times. Moreover, activity in the right temporoparietal junction (RTPJ) reflects only ES and correlates with its response-accelerating behavioral effects. Finally, we report an ES-dependent change in functional connectivity between the RTPJ and the locus ceruleus, suggesting noradrenergic processes underlying the response-facilitating effects of ES on decision making. Together, these results support a novel concept of salience in value-based decision making and suggest a computational, anatomical, and neurochemical dissociation of value- and salience-based factors supporting value-based choices.

Rewards obtained from specific behaviors can and do change across time. To adapt to such conditions, humans need to represent and update associations between behaviors and their outcomes. Much previous work focused on how rewards affect the processing of specific tasks. However, abstract associations between multiple potential behaviors and multiple rewards are an important basis for adaptation as well. In this experiment, we directly investigated which brain areas represent associations between multiple tasks and rewards, using time-resolved multivariate pattern analysis of functional magnetic resonance imaging data. Importantly, we were able to dissociate neural signals reflecting task-reward associations from those related to task preparation and reward expectation processes, variables that were often correlated in previous research. We hypothesized that brain regions involved in processing tasks and/or rewards will be involved in processing associations between them. Candidate areas included the dorsal anterior cingulate cortex, which is involved in associating simple actions and rewards, and the parietal cortex, which has been shown to represent task rules and action values. Our results indicate that local spatial activation patterns in the inferior parietal cortex indeed represent task-reward associations. Interestingly, the parietal cortex flexibly changes its content of representation within trials. It first represents task-reward associations, later switching to process tasks and rewards directly. These findings highlight the importance of the inferior parietal cortex in associating behaviors with their outcomes and further show that it can flexibly reconfigure its function within single trials. Significance statement: Rewards obtained from specific behaviors rarely remain constant over time. To adapt to changing conditions, humans need to continuously update and represent the current association between behavior and its outcomes. However, little is known about the neural representation of behavior-outcome associations. Here, we used multivariate pattern analysis of functional magnetic resonance imaging data to investigate the neural correlates of such associations. Our results demonstrate that the parietal cortex plays a central role in representing associations between multiple behaviors and their outcomes. They further highlight the flexibility of the parietal cortex, because we find it to adapt its function to changing task demands within trials on relatively short timescales.

The primate orbitofrontal cortex (OFC) is involved in reward processing, learning, and decision making. Research in monkeys has shown that this region is densely connected with higher sensory, limbic, and subcortical regions. Moreover, a parcellation of the monkey OFC into two subdivisions has been suggested based on its intrinsic anatomical connections. However, in humans, little is known about any functional subdivisions of the OFC except for a rather coarse medial/lateral distinction. Here, we used resting-state fMRI in combination with unsupervised clustering techniques to investigate whether OFC subdivisions can be revealed based on their functional connectivity profiles with other brain regions. Examination of different cluster solutions provided support for a parcellation into two parts as observed in monkeys, but it also highlighted a much finer hierarchical clustering of the orbital surface. Specifically, we identified (1) a medial, (2) a posterior-central, (3) a central, and (4–6) three lateral clusters spanning the anterior–posterior gradient. Consistent with animal tracing studies, these OFC clusters were connected to other cortical regions such as prefrontal, temporal, and parietal cortices but also subcortical areas in the striatum and the midbrain. These connectivity patterns provide important implications for identifying specific functional roles of OFC subdivisions for reward processing, learning, and decision making. Moreover, this parcellation schema can provide guidance to report results in future studies.

The predicted reward of different behavioral options plays an important role in guiding decisions. Previous research has identified reward predictions in prefrontal and striatal brain regions. Moreover, it has been shown that the neural representation of a predicted reward is similar to the neural representation of the actual reward outcome. However, it has remained unknown how these representations emerge over the course of learning and how they relate to decision making. Here, we sought to investigate learning of predicted reward representations using functional magnetic resonance imaging and multivariate pattern classification. Using a pavlovian conditioning procedure, human subjects learned multiple novel cue–outcome associations in each scanning run. We demonstrate that across learning activity patterns in the orbitofrontal cortex, the dorsolateral prefrontal cortex (DLPFC), and the dorsal striatum, coding the value of predicted rewards become similar to the patterns coding the value of actual reward outcomes. Furthermore, we provide evidence that predicted reward representations in the striatum precede those in prefrontal regions and that representations in the DLPFC are linked to subsequent value-based choices. Our results show that different brain regions represent outcome predictions by eliciting the neural representation of the actual outcome. Furthermore, they suggest that reward predictions in the DLPFC are directly related to value-based choices.

Patients suffering from addiction persist in consuming substances of abuse, despite negative consequences or absence of positive consequences. One potential explanation is that these patients are impaired at flexibly adapting their behavior to changes in reward contingencies. A key aspect of adaptive decision-making involves updating the value of behavioral options. This is thought to be mediated via a teaching signal expressed as a reward prediction error (PE) in the striatum. However, to exert control over adaptive behavior, value signals need to be broadcast to higher executive regions, such as prefrontal cortex. Here we used functional MRI and a reinforcement learning task to investigate the neural mechanisms underlying maladaptive behavior in human male alcohol-dependent patients. We show that in alcohol-dependent patients the expression of striatal PEs is intact. However, abnormal functional connectivity between striatum and dorsolateral prefrontal cortex (dlPFC) predicted impairments in learning and the magnitude of alcohol craving. These results are in line with reports of dlPFC structural abnormalities in substance dependence and highlight the importance of frontostriatal connectivity in addiction, and its pivotal role in adaptive updating of action values and behavioral regulation. Furthermore, they extend the scope of neurobiological deficits underlying addiction beyond the focus on the striatum.

Everyday choice options have advantages (positive values) and disadvantages (negative values) that need to be integrated into an overall subjective value. For decades, economic models have assumed that when a person evaluates a choice option, different values contribute independently to the overall subjective value of the option. However, human choice behavior often violates this assumption, suggesting interactions between values. To investigate how qualitatively different advantages and disadvantages are integrated into an overall subjective value, we measured the brain activity of human subjects using fMRI while they were accepting or rejecting choice options that were combinations of monetary reward and physical pain. We compared different subjective value models on behavioral and neural data. These models all made similar predictions of choice behavior, suggesting that behavioral data alone are not sufficient to uncover the underlying integration mechanism. Strikingly, a direct model comparison on brain data decisively demonstrated that interactive value integration (where values interact and affect overall valuation) predicts neural activity in value-sensitive brain regions significantly better than the independent mechanism. Furthermore, effective connectivity analyses revealed that value-dependent changes in valuation are associated with modulations in subgenual anterior cingulate cortex-amygdala coupling. These results provide novel insights into the neurobiological underpinnings of human decision making involving the integration of different values.