Structural Connectivity between Olfactory Tubercle and Ventrolateral Periaqueductal Gray Implicated in Human Feeding Behavior.

The olfactory tubercle (TUB), also called the tubular striatum, receives direct input from the olfactory bulb and, along with the nucleus accumbens, is one of the two principal components of the ventral striatum. As a key component of the reward system, the ventral striatum is involved in feeding behavior, but the vast majority of research on this structure has focused on the nucleus accumbens, leaving the TUB's role in feeding behavior understudied. Given the importance of olfaction in food seeking and consumption, olfactory input to the striatum should be an important contributor to motivated feeding behavior. Yet the TUB is vastly understudied in humans, with very little understanding of its structural organization and connectivity. In this study, we analyzed macrostructural variations between the TUB and the whole brain and explored the relationship between TUB structural pathways and feeding behavior, using body mass index (BMI) as a proxy in females and males. We identified a unique structural covariance between the TUB and the periaqueductal gray (PAG), which has recently been implicated in the suppression of feeding. We further show that the integrity of the white matter tract between the two regions is negatively correlated with BMI. Our findings highlight a potential role for the TUB-PAG pathway in the regulation of feeding behavior in humans.

Midbrain signaling of identity prediction errors depends on orbitofrontal cortex networks.

Outcome-guided behavior requires knowledge about the identity of future rewards. Previous work across species has shown that the dopaminergic midbrain responds to violations in expected reward identity and that the lateral orbitofrontal cortex (OFC) represents reward identity expectations. Here we used network-targeted transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) during a trans-reinforcer reversal learning task to test the hypothesis that outcome expectations in the lateral OFC contribute to the computation of identity prediction errors (iPE) in the midbrain. Network-targeted TMS aiming at lateral OFC reduced the global connectedness of the lateral OFC and impaired reward identity learning in the first block of trials. Critically, TMS disrupted neural representations of expected reward identity in the OFC and modulated iPE responses in the midbrain. These results support the idea that iPE signals in the dopaminergic midbrain are computed based on outcome expectations represented in the lateral OFC.

Evaluation of the NIH Toolbox Odor Identification Test across normal cognition, amnestic mild cognitive impairment, and dementia due to Alzheimer's disease.

INTRODUCTION: Olfactory decline is associated with cognitive decline in aging, amnestic mild cognitive impairment (aMCI), and amnestic dementia associated with Alzheimer's disease neuropathology (ADd). The National Institutes of Health Toolbox Odor Identification Test (NIHTB-OIT) may distinguish between these clinical categories. METHODS: We compared NIHTB-OIT scores across normal cognition (NC), aMCI, and ADd participants (N = 389, ≥65 years) and between participants positive versus negative for AD biomarkers and the APOE ε4 allele. RESULTS: NIHTB-OIT scores decreased with age (p < 0.001) and were lower for aMCI (p < 0.001) and ADd (p < 0.001) compared to NC participants, correcting for age and sex. The NIHTB-OIT detects aMCI (ADd) versus NC participants with 49.4% (56.5%) sensitivity and 88.8% (89.5%) specificity. NIHTB-OIT scores were lower for participants with positive AD biomarkers (p < 0.005), but did not differ based on the APOE ε4 allele (p > 0.05). DISCUSSION: The NIHTB-OIT distinguishes clinically aMCI and ADd participants from NC participants. HIGHLIGHTS: National Institutes of Health Toolbox Odor Identification Test (NIHTB-OIT) discriminated normal controls from mild cognitive impairment. NIHTB-OIT discriminated normal controls from Alzheimer's disease dementia. Rate of olfactory decline with age was similar across all diagnostic categories. NIHTB-OIT scores were lower in participants with positive Alzheimer's biomarker tests. NIHTB-OIT scores did not differ based on APOE genotype.

Expectancy-related changes in firing of dopamine neurons depend on hippocampus.

The orbitofrontal cortex (OFC) and hippocampus (HC) are both implicated in forming the cognitive or task maps that support flexible behavior. Previously, we used the dopamine neurons as a sensor or tool to measure the functional effects of OFC lesions (Takahashi et al., 2011). We recorded midbrain dopamine neurons as rats performed an odor-based choice task, in which errors in the prediction of reward were induced by manipulating the number or timing of the expected rewards across blocks of trials. We found that OFC lesions ipsilateral to the recording electrodes caused prediction errors to be degraded consistent with a loss in the resolution of the task states, particularly under conditions where hidden information was critical to sharpening the predictions. Here we have repeated this experiment, along with computational modeling of the results, in rats with ipsilateral HC lesions. The results show HC also shapes the map of our task, however unlike OFC, which provides information local to the trial, the HC appears to be necessary for estimating the upper-level hidden states based on the information that is discontinuous or separated by longer timescales. The results contrast the respective roles of the OFC and HC in cognitive mapping and add to evidence that the dopamine neurons access a rich information set from distributed regions regarding the predictive structure of the environment, potentially enabling this powerful teaching signal to support complex learning and behavior.

Appetite-regulating hormones modulate odor perception and odor-evoked activity in hypothalamus and olfactory cortices.

Odors guide food seeking, and food intake modulates olfactory function. This interaction is mediated by appetite-regulating hormones like ghrelin, insulin, and leptin, which alter activity in the rodent olfactory bulb, but their effects on downstream olfactory cortices have not yet been established in humans. The olfactory tract connects the olfactory bulb to the cortex through 3 main striae, terminating in the piriform cortex (PirC), amygdala (AMY), olfactory tubercule (OT), and anterior olfactory nucleus (AON). Here, we test the hypothesis that appetite-regulating hormones modulate olfactory processing in the endpoints of the olfactory tract and the hypothalamus. We collected odor-evoked functional magnetic resonance imaging (fMRI) responses and plasma levels of ghrelin, insulin, and leptin from human subjects (n = 25) after a standardized meal. We found that a hormonal composite measure, capturing variance relating positively to insulin and negatively to ghrelin, correlated inversely with odor intensity ratings and fMRI responses to odorized vs. clean air in the hypothalamus, OT, and AON. No significant correlations were found with activity in PirC or AMY, the endpoints of the lateral stria. Exploratory whole-brain analyses revealed significant correlations near the diagonal band of Broca and parahippocampal gyrus. These results demonstrate that high (low) blood plasma concentrations of insulin (ghrelin) decrease perceived odor intensity and odor-evoked activity in the cortical targets of the medial and intermediate striae of the olfactory tract, as well as the hypothalamus. These findings expand our understanding of the cortical mechanisms by which metabolic hormones in humans modulate olfactory processing after a meal.

Lateral orbitofrontal cortex integrates predictive information across multiple cues to guide behavior.

Individuals are often faced with multiple cues that concurrently predict the same outcome, and combining these predictions may benefit behavior. Previous work has studied the neural basis of decision-making, predominantly using isolated sensory stimuli, and so the mechanisms that allow us to leverage multiple cues remain unclear. In two experiments, we used neuroimaging and network-targeted brain stimulation to probe how the brain integrates outcome predictions to guide adaptive behavior. We identified neural signatures of outcome integration in the lateral orbitofrontal cortex (OFC), where concurrently presented cues evoke stronger pattern-based representations of expected outcomes. Moreover, perturbing lateral OFC network activity impairs subjects' ability to leverage predictions from multiple cues to facilitate responding. Intriguingly, we found similar behavioral and brain mechanisms for reward-predicting cues and for cues predicting the absence of reward. These findings highlight a causal role for the lateral OFC in utilizing outcome predictions from multiple cues to guide behavior.

High-precision mapping reveals the structure of odor coding in the human brain.

Odor perception is inherently subjective. Previous work has shown that odorous molecules evoke distributed activity patterns in olfactory cortices, but how these patterns map on to subjective odor percepts remains unclear. In the present study, we collected neuroimaging responses to 160 odors from 3 individual subjects (18 h per subject) to probe the neural coding scheme underlying idiosyncratic odor perception. We found that activity in the orbitofrontal cortex (OFC) represents the fine-grained perceptual identity of odors over and above coarsely defined percepts, whereas this difference is less pronounced in the piriform cortex (PirC) and amygdala. Furthermore, the implementation of perceptual encoding models enabled us to predict olfactory functional magnetic resonance imaging responses to new odors, revealing that the dimensionality of the encoded perceptual spaces increases from the PirC to the OFC. Whereas encoding of lower-order dimensions generalizes across subjects, encoding of higher-order dimensions is idiosyncratic. These results provide new insights into cortical mechanisms of odor coding and suggest that subjective olfactory percepts reside in the OFC.

Recruitment of grid-like responses in human entorhinal and piriform cortices by odor landmark-based navigation.

Olfactory navigation is universal across the animal kingdom. Humans, however, have rarely been considered in this context. Here, we combined olfactometry techniques, virtual reality (VR) software, and neuroimaging methods to investigate whether humans can navigate an olfactory landscape by learning the spatial relationships among discrete odor cues and integrating this knowledge into a spatial map. Our data show that over time, participants improved their performance on the odor navigation task by taking more direct paths toward targets and completing more trials within a given time period. This suggests that humans can successfully navigate a complex odorous environment, reinforcing the notion of human olfactory navigation. fMRI data collected during the olfactory navigation task revealed the emergence of grid-like responses in entorhinal and piriform cortices that were attuned to the same grid orientation. This result implies the existence of a specialized olfactory grid network tasked with guiding spatial navigation based on odor landmarks.

Computationally Informed Interventions for Targeting Compulsive Behaviors.

Compulsive behaviors are central to addiction and obsessive-compulsive disorder and can be understood as a failure of adaptive decision making. Particularly, they can be conceptualized as an imbalance in behavioral control, such that behavior is guided predominantly by learned rather than inferred outcome expectations. Inference is a computational process required for adaptive behavior, and recent work across species has identified the neural circuitry that supports inference-based decision making. This includes the orbitofrontal cortex, which has long been implicated in disorders of compulsive behavior. Inspired by evidence that modulating orbitofrontal cortex activity can alter inference-based behaviors, here we discuss noninvasive approaches to target these circuits in humans. Specifically, we discuss the potential of network-targeted transcranial magnetic stimulation and real-time neurofeedback to modulate the neural underpinnings of inference. Both interventions leverage recent advances in our understanding of the neurocomputational mechanisms of inference-based behavior and may be used to complement current treatment approaches for behavioral disorders.

Calcium activity is a degraded estimate of spikes.

Recording action potentials extracellularly during behavior has led to fundamental discoveries regarding neural function-hippocampal neurons respond to locations in space,1 motor cortex neurons encode movement direction,2 and dopamine neurons signal reward prediction errors3-observations undergirding current theories of cognition,4 movement,5 and learning.6 Recently it has become possible to measure calcium flux, an internal cellular signal related to spiking. The ability to image calcium flux in anatomically7,8 or genetically9 identified neurons can extend our knowledge of neural circuit function by allowing activity to be monitored in specific cell types or projections, or in the same neurons across many days. However, while initial studies were grounded in prior unit recording work, it has become fashionable to assume that calcium is identical to spiking, even though the spike-to-fluorescence transformation is nonlinear, noisy, and unpredictable under real-world conditions.10 It remains an open question whether calcium provides a high-fidelity representation of single-unit activity in awake, behaving subjects. Here, we have addressed this question by recording both signals in the lateral orbitofrontal cortex (OFC) of rats during olfactory discrimination learning. Activity in the OFC during olfactory learning has been well-studied in humans,11,12,13,14 nonhuman primates,15,16 and rats,17,18,19,20,21 where it has been shown to signal information about both the sensory properties of odor cues and the rewards they predict. Our single-unit results replicated prior findings, whereas the calcium signal provided only a degraded estimate of the information available in the single-unit spiking, reflecting primarily reward value.

On the state-dependent nature of odor perception.

The olfactory system-and odor perception by extension-is susceptible to state-dependent influences. This review delves into human behavioral research in this area, and also touches on mechanistic evidence and examples from animal work. The review summarizes studies on the impact of satiety state on olfaction, highlighting the robust effects of food intake on the perceived pleasantness of food odors and olfactory decision-making. The impacts of other behavioral states on olfaction are also discussed. While research in this area is more limited, preliminary evidence suggests that odor perception is altered by circadian state, sleep deprivation, and mood. The flexibility in olfactory function described here can be considered adaptive, as it serves to direct behavior toward stimuli with high state-dependent value.

Mapping the Microstructure and Striae of the Human Olfactory Tract with Diffusion MRI.

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 tracts in 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 STATEMENT This study provides the first detailed in vivo description 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.

Components of Behavioral Activation Therapy for Depression Engage Specific Reinforcement Learning Mechanisms in a Pilot Study.

Background: Behavioral activation is an evidence-based treatment for depression. Theoretical considerations suggest that treatment response depends on reinforcement learning mechanisms. However, which reinforcement learning mechanisms are engaged by and mediate the therapeutic effect of behavioral activation remains only partially understood, and there are no procedures to measure such mechanisms. Objective: To perform a pilot study to examine whether reinforcement learning processes measured through tasks or self-report are related to treatment response to behavioral activation. Method: The pilot study enrolled 13 outpatients (12 completers) with major depressive disorder, from July of 2018 through February of 2019, into a nine-week trial with BA. Psychiatric evaluations, decision-making tests and self-reported reward experience and anticipations were acquired before, during and after the treatment. Task and self-report data were analysed by using reinforcement-learning models. Inferred parameters were related to measures of depression severity through linear mixed effects models. Results: Treatment effects during different phases of the therapy were captured by specific decision-making processes in the task. During the weeks focusing on the active pursuit of reward, treatment effects were more pronounced amongst those individuals who showed an increase in Pavlovian appetitive influence. During the weeks focusing on the avoidance of punishments, treatment responses were more pronounced in those individuals who showed an increase in Pavlovian avoidance. Self-reported anticipation of reinforcement changed according to formal RL rules. Individual differences in the extent to which learning followed RL rules related to changes in anhedonia. Conclusions: In this pilot study both task- and self-report-derived measures of reinforcement learning captured individual differences in treatment response to behavioral activation. Appetitive and aversive Pavlovian reflexive processes appeared to be modulated by separate psychotherapeutic interventions, and the modulation strength covaried with response to specific interventions. Self-reported changes in reinforcement expectations are also related to treatment response. Trial Registry Name: Set Your Goal: Engaging in GO/No-Go Active Learning, #NCT03538535, http://www.clinicaltrials.gov.

Opioid antagonism modulates wanting-related frontostriatal connectivity.

Theoretical accounts distinguish between motivational ('wanting') and hedonic ('liking') dimensions of rewards. Previous animal and human research linked wanting and liking to anatomically and neurochemically distinct brain mechanisms, but it remains unknown how the different brain regions and neurotransmitter systems interact in processing distinct reward dimensions. Here, we assessed how pharmacological manipulations of opioid and dopamine receptor activation modulate the neural processing of wanting and liking in humans in a randomized, placebo-controlled, double-blind clinical trial. Reducing opioid receptor activation with naltrexone selectively reduced wanting of rewards, which on a neural level was reflected by stronger coupling between dorsolateral prefrontal cortex and the striatum under naltrexone compared with placebo. In contrast, reducing dopaminergic neurotransmission with amisulpride revealed no robust effects on behavior or neural activity. Our findings thus provide insights into how opioid receptors mediate neural connectivity related to specifically motivational, not hedonic, aspects of rewards.

Olfactory perceptual decision-making is biased by motivational state.

Growing evidence suggests that internal factors influence how we perceive the world. However, it remains unclear whether and how motivational states, such as hunger and satiety, regulate perceptual decision-making in the olfactory domain. Here, we developed a novel behavioral task involving mixtures of food and nonfood odors (i.e., cinnamon bun and cedar; pizza and pine) to assess olfactory perceptual decision-making in humans. Participants completed the task before and after eating a meal that matched one of the food odors, allowing us to compare perception of meal-matched and non-matched odors across fasted and sated states. We found that participants were less likely to perceive meal-matched, but not non-matched, odors as food dominant in the sated state. Moreover, functional magnetic resonance imaging (fMRI) data revealed neural changes that paralleled these behavioral effects. Namely, odor-evoked fMRI responses in olfactory/limbic brain regions were altered after the meal, such that neural patterns for meal-matched odor pairs were less discriminable and less food-like than their non-matched counterparts. Our findings demonstrate that olfactory perceptual decision-making is biased by motivational state in an odor-specific manner and highlight a potential brain mechanism underlying this adaptive behavior.

Aversive outcomes impact human olfactory discrimination learning and generalization.

Learning associations between sensory stimuli and outcomes, and generalizing these associations to novel stimuli, are a fundamental feature of adaptive behavior. Given a noisy olfactory world, stimulus generalization holds unique relevance for the olfactory system. Recent studies suggest that aversive outcomes induce wider generalization curves by modulating discrimination thresholds, but evidence for similar processes in olfaction does not exist. Here, we use a novel olfactory discrimination learning paradigm to address the question of how outcome valence impacts associative learning and generalization in humans. Subjects underwent discrimination learning, where they learned to associate odor mixtures with either aversive (shock) or neutral (air puff) outcomes. We find better olfactory learning for odors associated with aversive compared to neutral outcomes. We further show that generalization gradients are also modulated by outcome valence, with the shock group exhibiting a steeper gradient. Computational modeling revealed that differences in generalization are driven by a narrower excitatory gradient in the shock group, indicating more discriminatory responses. These findings provide novel evidence that olfactory learning and generalization are strongly affected by the valence of outcomes. This adaptive mechanism allows for behavioral flexibility in novel situations with related stimuli and with outcomes of different valences. Because odor stimuli differ considerably from one encounter to the next, adaptive generalization may be especially important in the olfactory system. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cross-species studies on orbitofrontal control of inference-based behavior.

Many decisions are guided by expectations about their outcomes. These expectations can arise from two fundamentally different sources: from direct experience with outcomes and the events and actions that precede them or from mental simulations and inferences when direct experience is missing. Here we discuss four elegant tasks from animal learning theory (devaluation, sensory preconditioning, Pavlovian-to-instrumental transfer, and Pavlovian overexpectation) and how they can be used to isolate behavior that is based on such mental simulations from behavior that can be based solely on experience. We then review findings from studies in rodents, nonhuman primates, and humans that use these tasks in combination with neural recording and loss-of-function experiments to understand the role of the orbitofrontal cortex (OFC) in outcome inference. The results of these studies show that activity in the OFC is correlated with inferred outcome expectations and that an intact OFC is necessary for inference-based behavior and learning. In summary, these findings provide converging cross-species support for the idea that the OFC is critical for behavior that is based on inferred outcomes, whereas it is not required when expectations can be based on direct experience alone. This conclusion may have important implications for our understanding of the role of OFC in psychiatric disorders and how we may be able to treat them. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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).

Neural circuits for inference-based decision-making.

In novel situations, where direct experience is lacking or outdated, humans must rely on mental simulations to predict future outcomes. This review discusses recent work on the neural circuits that support such inference-based behavior. We focus on two specific examples: 1) using knowledge about the associative structure of the world to infer outcomes when direct experience is lacking; 2) inferring the current value of options when the desirability of the associated outcome has changed since the original learning experience. These two examples can be studied in the sensory preconditioning and devaluation tasks, respectively. We review results from studies in animals and humans suggesting that the orbitofrontal cortex (OFC), together with the hippocampus and amygdala, is necessary for inference in both of these tasks. Together, these findings suggest that the OFC is a critical hub in the brain network that supports inference-based decision-making.