Targeted Stimulation of an Orbitofrontal Network Disrupts Decisions Based on Inferred, Not Experienced Outcomes.

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 STATEMENT It 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.

Identity-Specific Reward Representations in Orbitofrontal Cortex Are Modulated by Selective Devaluation.

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 STATEMENT The 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.

Identity-specific coding of future rewards in the human orbitofrontal cortex.

Nervous systems must encode information about the identity of expected outcomes to make adaptive decisions. However, the neural mechanisms underlying identity-specific value signaling remain poorly understood. By manipulating the value and identity of appetizing food odors in a pattern-based imaging paradigm of human classical conditioning, we were able to identify dissociable predictive representations of identity-specific reward in orbitofrontal cortex (OFC) and identity-general reward in ventromedial prefrontal cortex (vmPFC). Reward-related functional coupling between OFC and olfactory (piriform) cortex and between vmPFC and amygdala revealed parallel pathways that support identity-specific and -general predictive signaling. The demonstration of identity-specific value representations in OFC highlights a role for this region in model-based behavior and reveals mechanisms by which appetitive behavior can go awry.

Distributed midbrain responses signal the content of positive identity prediction errors.

Recent work across species has shown that midbrain dopamine neurons signal not only errors in the prediction of reward value but also in the prediction of value-neutral sensory features. To support learning of associative structures in downstream areas, identity prediction errors (iPEs) should signal specific information about the mis-predicted outcome. Here, we used pattern-based analysis of functional magnetic resonance imaging (fMRI) data acquired during reversal learning to characterize the information content of iPE responses in the human midbrain. We find that fMRI responses to value-neutral identity errors contain information about the identity of the unexpectedly received reward (positive iPE+) but not about the identity of the omitted reward (negative iPE-). Exploratory analyses revealed representations of iPE- in the dorsomedial prefrontal cortex. These results demonstrate that ensemble midbrain responses to value-neutral identity errors convey information about the identity of unexpectedly received outcomes, which could shape the formation of novel stimulus-outcome associations that constitute cognitive maps.

Mental representations mediate aversive learning in humans.

Mental representations of stimuli that are not physically present are critical for a range of cognitive capacities, including perception, memory, and learning. Overly robust mental representations, however, can contribute to hallucinations in healthy individuals and those diagnosed with psychotic illness. Measuring the strength of mental representations can thus provide insight into how the contents of the mind influence both adaptive and maladaptive behaviors. In rodents, the robustness of mental representations has been tested using the representation-mediated learning (RML) task, in which animals respond less to a cue after a stimulus that has previously been associated with this cue has been paired with illness. This suggests that the mental representation of the cue enters into a negative association during aversive learning, even though the cue is not physically present. Here, we developed a human version of the RML task in which participants initially learned associations between two visual symbols and two different appetitive food odors. Preference for the food odors was then tested immediately before and after a session in which one symbol was paired with an aversive noise. We observed that mediated learning, in the form of selective decrease in preference for the odor previously paired with the noise-predicting symbol, was directly proportional to direct aversive learning for the symbols themselves. These findings suggest that a mental representation of the odor entered into a negative association with the sound and pave the way for future studies aimed at characterizing the neural circuits of mediated learning in the human brain. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer's disease.

Patients with early-stage Alzheimer's disease exhibit perceptual deficits in odour identification, often before the appearance of overt memory loss. This impairment coincides with the initial accumulation of pathological lesions in limbic olfactory brain regions. Although these data imply that odour stimuli may be effectively used as biological probes of limbic dysfunction, the precise neural mechanisms underlying the olfactory deficits in early Alzheimer's disease remain poorly understood. In the current study, we combined functional magnetic resonance imaging with an olfactory cross-adaptation paradigm to test the hypothesis that perceptual codes of odour quality in posterior piriform cortex are degraded in patients with Alzheimer's disease. In elderly control subjects, sequential presentation of qualitatively similar (versus qualitatively different) odourant pairs elicited cross-adapting responses in posterior piriform cortex, in accord with the pattern observed in healthy young adults. However, this profile was significantly blunted in patients with Alzheimer's disease, reflecting a functional disruption of odour quality coding in this olfactory brain area. These results highlight the potential of olfactory functional magnetic resonance imaging as a non-invasive bioassay of limbic functional integrity, and suggest that such an index could possibly aid in the early diagnosis of Alzheimer's disease. Furthermore, as a putative lesion model of odour quality processing in the human brain, our study suggests a causal role of posterior piriform cortex in differentiating olfactory objects.

Causal investigations into orbitofrontal control of human decision making.

Although it is widely accepted that the orbitofrontal cortex (OFC) is important for decision making, its precise contribution to behavior remains a topic of debate. While many loss of function experiments have been conducted in animals, causal studies of human OFC function are relatively scarce. This review discusses recent causal investigations into the human OFC, with an emphasis on advances in network-based brain stimulation approaches to indirectly perturb OFC function. Findings show that disruption of human OFC impairs decisions that require mental simulation of outcomes. Taken together, these results support the idea that human OFC contributes to decision making by representing a cognitive map of the task environment, facilitating inference of outcomes not yet experienced. Future work may utilize similar non-invasive approaches in clinical settings to mitigate decision making deficits in neuropsychiatric disorders.

To be specific: The role of orbitofrontal cortex in signaling reward identity.

The orbitofrontal cortex (OFC) plays a prominent role in signaling reward expectations. Two important features of rewards are their value (how good they are) and their specific identity (what they are). Whereas research on OFC has traditionally focused on reward value, recent findings point toward a pivotal role of reward identity in understanding OFC signaling and its contribution to behavior. Here, we review work in rodents, nonhuman primates, and humans on how the OFC represents expectations about the identity of rewards, and how these signals contribute to outcome-guided behavior. Moreover, we summarize recent findings suggesting that specific reward expectations in OFC are learned and updated by means of identity errors in the dopaminergic midbrain. We conclude by discussing how OFC encoding of specific rewards complements recent proposals that this region represents a cognitive map of relevant task states, which forms the basis for model-based behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Right orbitofrontal cortex mediates conscious olfactory perception.

Understanding how the human brain translates sensory impressions into conscious percepts is a key challenge of neuroscience research. Work in this area has overwhelmingly centered on the conscious experience of vision at the exclusion of the other senses--in particular, smell. We hypothesized that the orbitofrontal cortex (OFC) is a central substrate for olfactory conscious experience because of its privileged physiological role in odor processing. Combining functional magnetic resonance imaging, peripheral autonomic recordings, and olfactory psychophysics, we studied a case of complete anosmia (smell loss) in a patient with circumscribed traumatic brain injury to the right OFC. Despite a complete absence of conscious olfaction, the patient exhibited robust "blind smell," as indexed by reliable odor-evoked neural activity in the left OFC and normal autonomic responses to odor hedonics during presentation of stimuli to the left nostril. These data highlight the right OFC's critical role in subserving human olfactory consciousness.

Targeted Stimulation of Human Orbitofrontal Networks Disrupts Outcome-Guided Behavior.

Outcome-guided behavior requires knowledge about the current value of expected outcomes. Such behavior can be isolated in the reinforcer devaluation task, which assesses the ability to infer the current value of specific rewards after devaluation. Animal lesion studies demonstrate that orbitofrontal cortex (OFC) is necessary for normal behavior in this task, but a causal role for human OFC in outcome-guided behavior has not been established. Here, we used sham-controlled, non-invasive, continuous theta-burst stimulation (cTBS) to temporarily disrupt human OFC network activity by stimulating a site in the lateral prefrontal cortex that is strongly connected to OFC prior to devaluation of food odor rewards. Subjects in the sham group appropriately avoided Pavlovian cues associated with devalued food odors. However, subjects in the stimulation group persistently chose those cues, even though devaluation of food odors themselves was unaffected by cTBS. This behavioral impairment was mirrored in changes in resting-state functional magnetic resonance imaging (rs-fMRI) activity such that subjects in the stimulation group exhibited reduced OFC network connectivity after cTBS, and the magnitude of this reduction was correlated with choices after devaluation. These findings demonstrate the feasibility of indirectly targeting the human OFC with non-invasive cTBS and indicate that OFC is specifically required for inferring the value of expected outcomes.

Attention to odor modulates thalamocortical connectivity in the human brain.

It is widely assumed that the thalamus is functionally irrelevant for the sense of smell. Although animal studies suggest that the mediodorsal (MD) thalamus links primary olfactory (piriform) cortex to olfactory neocortical projection sites in orbitofrontal cortex (OFC), this transthalamic route is regarded to be inconsequential, particularly compared with a direct monosynaptic pathway linking piriform cortex and OFC. In this study, we combined functional magnetic resonance imaging with novel effective connectivity techniques to measure attention-dependent network coherence within direct (nonthalamic) and indirect (transthalamic) olfactory pathways. Human subjects were presented with (or without) an odor and with (or without) a tone, while selectively attending to either modality. Attention to odor significantly modulated neural coupling within the indirect pathway, strengthening MD thalamus-OFC connectivity. Critically, these effects were modality specific (odor > tone attention), directionally sensitive (forward > backward connections), and selective to route (indirect > direct pathway). Our findings support the idea that the human transthalamic pathway is an active modulatory target of olfactory attention. The results imply that olfaction, like all other sensory modalities, requires a thalamic relay, if only to consciously analyze a smell.

Sensory prediction errors in the human midbrain signal identity violations independent of perceptual distance.

The firing of dopaminergic midbrain neurons is thought to reflect prediction errors (PE) that depend on the difference between the value of expected and received rewards. However, recent work has demonstrated that unexpected changes in value-neutral outcome features, such as identity, can evoke similar responses. It remains unclear whether the magnitude of these identity PEs scales with the perceptual dissimilarity of expected and received rewards, or whether they are independent of perceptual similarity. We used a Pavlovian transreinforcer reversal task to elicit identity PEs for value-matched food odor rewards, drawn from two perceptual categories (sweet, savory). Replicating previous findings, identity PEs were correlated with fMRI activity in midbrain, OFC, piriform cortex, and amygdala. However, the magnitude of identity PE responses was independent of the perceptual distance between expected and received outcomes, suggesting that identity comparisons underlying sensory PEs may occur in an abstract state space independent of straightforward sensory percepts.

Olfactory connectivity mediates sleep-dependent food choices in humans.

Sleep deprivation has marked effects on food intake, shifting food choices toward energy-dense options. Here we test the hypothesis that neural processing in central olfactory circuits, in tandem with the endocannabinoid system (ECS), plays a key role in mediating this relationship. We combined a partial sleep-deprivation protocol, pattern-based olfactory neuroimaging, and ad libitum food intake to test how central olfactory mechanisms alter food intake after sleep deprivation. We found that sleep restriction increased levels of the ECS compound 2-oleoylglycerol (2-OG), enhanced encoding of food odors in piriform cortex, and shifted food choices toward energy-dense food items. Importantly, the relationship between changes in 2-OG and food choices was formally mediated by odor-evoked connectivity between the piriform cortex and insula, a region involved in integrating feeding-related signals. These findings describe a potential neurobiological pathway by which state-dependent changes in the ECS may modulate chemosensory processing to regulate food choices.

Dopamine neuron ensembles signal the content of sensory prediction errors.

Dopamine neurons respond to errors in predicting value-neutral sensory information. These data, combined with causal evidence that dopamine transients support sensory-based associative learning, suggest that the dopamine system signals a multidimensional prediction error. Yet such complexity is not evident in the activity of individual neurons or population averages. How then do downstream areas know what to learn in response to these signals? One possibility is that information about content is contained in the pattern of firing across many dopamine neurons. Consistent with this, here we show that the pattern of firing across a small group of dopamine neurons recorded in rats signals the identity of a mis-predicted sensory event. Further, this same information is reflected in the BOLD response elicited by sensory prediction errors in human midbrain. These data provide evidence that ensembles of dopamine neurons provide highly specific teaching signals, opening new possibilities for how this system might contribute to learning.

Grid-like Neural Representations Support Olfactory Navigation of a Two-Dimensional Odor Space.

Searching for food, friends, and mates often begins with an airborne scent. Importantly, odor concentration rises with physical proximity to an odorous source, suggesting a framework for orienting within olfactory landscapes to optimize behavior. Here, we created a two-dimensional odor space composed purely of odor stimuli to model how a navigator encounters smells in a natural environment. We show that human subjects can learn to navigate in olfactory space and form predictions of to-be-encountered smells. During navigation, fMRI responses in entorhinal cortex and ventromedial prefrontal cortex take the form of grid-like representations with hexagonal periodicity and entorhinal grid strength scaled with behavioral performance across subjects. The identification of olfactory grid-like codes with 6-fold symmetry highlights a unique neural mechanism by which odor information can be assembled into spatially navigable cognitive maps, optimizing orientation, and path finding toward an odor source.

Identity prediction errors in the human midbrain update reward-identity expectations in the orbitofrontal cortex.

There is general consensus that dopaminergic midbrain neurons signal reward prediction errors, computed as the difference between expected and received reward value. However, recent work in rodents shows that these neurons also respond to errors related to inferred value and sensory features, indicating an expanded role for dopamine beyond learning cached values. Here we utilize a transreinforcer reversal learning task and functional magnetic resonance imaging (fMRI) to test whether prediction error signals in the human midbrain are evoked when the expected identity of an appetitive food odor reward is violated, while leaving value matched. We found that midbrain fMRI responses to identity and value errors are correlated, suggesting a common neural origin for these error signals. Moreover, changes in reward-identity expectations, encoded in the orbitofrontal cortex (OFC), are directly related to midbrain activity, demonstrating that identity-based error signals in the midbrain support the formation of outcome identity expectations in OFC.

Converging prefrontal pathways support associative and perceptual features of conditioned stimuli.

Perceptually similar stimuli often predict vastly different outcomes, requiring the brain to maintain specific associations in the face of potential ambiguity. This could be achieved either through local changes in stimulus representations, or through modulation of functional connections between stimulus-coding and outcome-coding regions. Here we test these competing hypotheses using classical conditioning of perceptually similar odours in the context of human fMRI. Pattern-based analyses of odour-evoked fMRI activity reveal that odour category, identity and value are coded in piriform (PC), orbitofrontal (OFC) and ventromedial prefrontal (vmPFC) cortices, respectively. However, we observe no learning-related reorganization of category or identity representations. Instead, changes in connectivity between vmPFC and OFC are correlated with learning-related changes in value, whereas connectivity changes between vmPFC and PC predict changes in perceived odour similarity. These results demonstrate that dissociable neural pathways support associative and perceptual representations of sensory stimuli.

The role of piriform associative connections in odor categorization.

Distributed neural activity patterns are widely proposed to underlie object identification and categorization in the brain. In the olfactory domain, pattern-based representations of odor objects are encoded in piriform cortex. This region receives both afferent and associative inputs, though their relative contributions to odor perception are poorly understood. Here, we combined a placebo-controlled pharmacological fMRI paradigm with multivariate pattern analyses to test the role of associative connections in sustaining olfactory categorical representations. Administration of baclofen, a GABA(B) agonist known to attenuate piriform associative inputs, interfered with within-category pattern separation in piriform cortex, and the magnitude of this drug-induced change predicted perceptual alterations in fine-odor discrimination performance. Comparatively, baclofen reduced pattern separation between odor categories in orbitofrontal cortex, and impeded within-category generalization in hippocampus. Our findings suggest that odor categorization is a dynamic process concurrently engaging stimulus discrimination and generalization at different stages of olfactory information processing, and highlight the importance of associative networks in maintaining categorical boundaries.

Configural and elemental coding of natural odor mixture components in the human brain.

Most real-world odors are complex mixtures of distinct molecular components. Olfactory systems can adopt different strategies to contend with this stimulus complexity. In elemental processing, odor perception is derived from the sum of its parts; in configural processing, the parts are integrated into unique perceptual wholes. Here we used gas-chromatography/mass-spectrometry techniques to deconstruct a complex natural food smell and assess whether olfactory salience is confined to the whole odor or is also embodied in its parts. By implementing an fMRI sensory-specific satiety paradigm, we identified reward-based changes in orbitofrontal cortex (OFC) for the whole odor and for a small subset of components. Moreover, component-specific changes in OFC-amygdala connectivity correlated with perceived value. Our findings imply that the human brain has direct access to the elemental content of a natural food odor, and highlight the dynamic capacity of the olfactory system to engage both object-level and component-level mechanisms to subserve behavior.

Stimulus-specific enhancement of fear extinction during slow-wave sleep.

Sleep can strengthen memory for emotional information, but whether emotional memories can be specifically targeted and modified during sleep is unknown. In human subjects who underwent olfactory contextual fear conditioning, re-exposure to the odorant context in slow-wave sleep promoted stimulus-specific fear extinction, with parallel reductions of hippocampal activity and reorganization of amygdala ensemble patterns. Thus, fear extinction may be selectively enhanced during sleep, even without re-exposure to the feared stimulus itself.