Neural Systems for Memory-based Value Judgment and Decision-making.

Real-life choices often require that we draw inferences about the value of options based on structured, schematic knowledge about their utility for our current goals. Other times, value information may be retrieved directly from a specific prior experience with an option. In an fMRI experiment, we investigated the neural systems involved in retrieving and assessing information from different memory sources to support value-based choice. Participants completed a task in which items could be conferred positive or negative value based on schematic associations (i.e., schema value) or learned directly from experience via deterministic feedback (i.e., experienced value). We found that ventromedial pFC (vmPFC) activity correlated with the influence of both experience- and schema-based values on participants' decisions. Connectivity between the vmPFC and middle temporal cortex also tracked the inferred value of items based on schematic associations on the first presentation of ingredients, before any feedback. In contrast, the striatum responded to participants' willingness to bet on ingredients as a function of the unsigned strength of their memory for those options' values. These results argue that the striatum and vmPFC play distinct roles in memory-based value judgment and decision-making. Specifically, the vmPFC assesses the value of options based on information inferred from schematic knowledge and retrieved from prior direct experience, whereas the striatum controls a decision to act on options based on memory strength.

Ventromedial Frontal Lobe Damage Alters how Specific Attributes are Weighed in Subjective Valuation.

The concept of subjective value is central to current neurobiological views of economic decision-making. Much of this work has focused on signals in the ventromedial frontal lobe (VMF) that correlate with the subjective value of a variety of stimuli (e.g., food, monetary gambles), and are thought to support decision-making. However, the neural processes involved in assessing and integrating value information from the attributes of such complex options remain to be defined. Here, we tested the necessary role of VMF in weighting attributes of naturalistic stimuli during value judgments. We asked how distinct attributes of visual artworks influenced the subjective value ratings of subjects with VMF damage, compared to healthy participants and a frontal lobe damaged control group. Subjects with VMF damage were less influenced by the energy (emotion, complexity) and color radiance (warmth, saturation) of the artwork, while they were similar to control groups in considering saliency, balance and concreteness. These dissociations argue that VMF is critical for allowing certain affective content to influence subjective value, while sparing the influence of perceptual or representational information. These distinctions are important for better defining the often-underspecified concept of subjective value and developing more detailed models of the brain mechanisms underlying decision behavior.

Necessary Contributions of Human Frontal Lobe Subregions to Reward Learning in a Dynamic, Multidimensional Environment.

UNLABELLED: Real-world decisions are typically made between options that vary along multiple dimensions, requiring prioritization of the important dimensions to support optimal choice. Learning in this setting depends on attributing decision outcomes to the dimensions with predictive relevance rather than to dimensions that are irrelevant and nonpredictive. This attribution problem is computationally challenging, and likely requires an interplay between selective attention and reward learning. Both these processes have been separately linked to the prefrontal cortex, but little is known about how they combine to support learning the reward value of multidimensional stimuli. Here, we examined the necessary contributions of frontal lobe subregions in attributing feedback to relevant and irrelevant dimensions on a trial-by-trial basis in humans. Patients with focal frontal lobe damage completed a demanding reward learning task where options varied on three dimensions, only one of which predicted reward. Participants with left lateral frontal lobe damage attributed rewards to irrelevant dimensions, rather than the relevant dimension. Damage to the ventromedial frontal lobe also impaired learning about the relevant dimension, but did not increase reward attribution to irrelevant dimensions. The results argue for distinct roles for these two regions in learning the value of multidimensional decision options under dynamic conditions, with the lateral frontal lobe required for selecting the relevant dimension to associate with reward, and the ventromedial frontal lobe required to learn the reward association itself. SIGNIFICANCE STATEMENT: The real world is complex and multidimensional; how do we attribute rewards to predictive features when surrounded by competing cues? Here, we tested the critical involvement of human frontal lobe subregions in a probabilistic, multidimensional learning environment, asking whether focal lesions affected trial-by-trial attribution of feedback to relevant and irrelevant dimensions. The left lateral frontal lobe was required for filtering option dimensions to allow appropriate feedback attribution, while the ventromedial frontal lobe was necessary for learning the value of features in the relevant dimension. These findings argue that selective attention and associative learning processes mediated by anatomically distinct frontal lobe subregions are both critical for adaptive choice in more complex, ecologically valid settings.

Ventromedial Frontal Cortex Is Critical for Guiding Attention to Reward-Predictive Visual Features in Humans.

Adaptively interacting with our environment requires extracting information that will allow us to successfully predict reward. This can be a challenge, particularly when there are many candidate cues, and when rewards are probabilistic. Recent work has demonstrated that visual attention is allocated to stimulus features that have been associated with reward on previous trials. The ventromedial frontal lobe (VMF) has been implicated in learning in dynamic environments of this kind, but the mechanism by which this region influences this process is not clear. Here, we hypothesized that the VMF plays a critical role in guiding attention to reward-predictive stimulus features based on feedback. We tested the effects of VMF damage in human subjects on a visual search task in which subjects were primed to attend to task-irrelevant colors associated with different levels of reward, incidental to the search task. Consistent with previous work, we found that distractors had a greater influence on reaction time when they appeared in colors associated with high reward in the previous trial compared with colors associated with low reward in healthy control subjects and patients with prefrontal damage sparing the VMF. However, this reward modulation of attentional priming was absent in patients with VMF damage. Thus, an intact VMF is necessary for directing attention based on experience with cue-reward associations. We suggest that this region plays a role in selecting reward-predictive cues to facilitate future learning. SIGNIFICANCE STATEMENT: There has been a swell of interest recently in the ventromedial frontal cortex (VMF), a brain region critical to associative learning. However, the underlying mechanism by which this region guides learning is not well understood. Here, we tested the effects of damage to this region in humans on a task in which rewards were linked incidentally to visual features, resulting in trial-by-trial attentional priming. Controls and subjects with prefrontal damage sparing the VMF showed normal reward priming, but VMF-damaged patients did not. This work sheds light on a potential mechanism through which this region influences behavior. We suggest that the VMF is necessary for directing attention to reward-predictive visual features based on feedback, facilitating future learning and decision-making.

Lesions to different regions of frontal cortex have dissociable effects on voluntary persistence.

Deciding how long to keep waiting for uncertain future rewards is a complex problem. Previous research has shown that choosing to stop waiting results from an evaluative process that weighs the subjective value of the awaited reward against the opportunity cost of waiting. In functional neuroimaging data, activity in ventromedial prefrontal cortex (vmPFC) tracks the dynamics of this evaluation, while activation in the dorsomedial prefrontal cortex (dmPFC) and anterior insula (AI) ramps up before a decision to quit is made. Here, we provide causal evidence of the necessity of these brain regions for successful performance in a willingness-to-wait task. 28 participants with frontal lobe lesions were tested on their ability to adaptively calibrate how long they waited for monetary rewards. We grouped the participants based on the location of their lesions, which were primarily in ventromedial, dorsomedial, or lateral parts of their prefrontal cortex (vmPFC, dmPFC, and lPFC, respectively), or in the anterior insula. We compared the performance of each subset of lesion participants to behavior in a control group without lesions (n=18). Finally, we fit a newly developed computational model to the data to glean a more mechanistic understanding of how lesions affect the cognitive processes underlying choice. We found that participants with lesions to the vmPFC waited less overall, while participants with lesions to the dmPFC and anterior insula were specifically impaired at calibrating their level of persistence to the environment. These behavioral effects were accounted for by systematic differences in parameter estimates from a computational model of task performance: while the vmPFC group showed reduced initial willingness to wait, lesions to the dmPFC/anterior insula were associated with slower learning from negative feedback. These findings corroborate the notion that failures of persistence can be driven by sophisticated cost-benefit analyses rather than lapses in self-control. They also support the functional specialization of different parts of the prefrontal cortex in service of voluntary persistence.

Abstract task representations for inference and control.

Behavioral flexibility depends on our capacity to build and leverage abstract knowledge about tasks. Recently, two separate lines of research have implicated distinct brain networks in representing abstract task information: a frontoparietal cortical network, and a network involving the medial temporal lobe (MTL), medial prefrontal, and orbitofrontal cortex (OMPFC). These observations have mostly been made in parallel, with little attempt to understand their relationship. Here, we hypothesize that abstract task representations in these networks differ primarily in format, not content. Namely, that the MTL-OMPFC network maintains task knowledge in a flexible cognitive map, while the frontoparietal network formats this knowledge as productions that facilitate action selection. We discuss novel implications and predictions for behavioral flexibility arising from this hypothesis.

Differential assessment of frontally-mediated behaviors between self- and informant-report in patients with obsessive-compulsive disorder following gamma ventral capsulotomy.

Obsessive-Compulsive Disorder (OCD) is a debilitating disorder causing marked distress and functional impairment. While advances in behavioral and pharmacotherapies have been effective for a majority of patients with OCD, 10-30% remain treatment refractory and severely impaired. For a subset of treatment-resistant individuals with the most severe and disabling (intractable) illness, gamma ventral capsulotomy (GVC) appears effective in reducing OCD symptoms and functional impairment. However, the effects of the ventral internal capsule lesion via GVC surgery on executive function in everyday life have been minimally investigated. Examining behavioral outcomes of GVC also provides a rare opportunity to probe the functional importance of the ventral prefrontal-subcortical connections of the internal capsule white matter tract in a relatively homogenous sample of patients with comparable white matter lesions. The present study investigated changes in frontally-mediated behaviors, measured by the Frontal Systems Behavior Scale (FrSBe), following GVC in 45 individuals with severe and otherwise intractable OCD, as rated by patients themselves and family members. Linear mixed effects models revealed a significant improvement in patient self-ratings on the FrSBe after surgery, while family ratings did not significantly change. Interestingly, improvement on the FrSBe for both self and family raters was significantly correlated with improvement in OCD symptomatology post-surgery, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). At the group level, we found no evidence of decline in frontally-mediated behaviors assessed by the FrSBe as a result of focal white matter disconnection via GVC. However, we cannot rule out the possibility that placebo effects or compromised patient self-awareness or insight contributed to the significant improvement in self ratings. Our measures may also have limited sensitivity to more selective impairments that could result from a small lesion to the ventral internal capsule. The present study demonstrates the need for detailed investigation of cognitive and behavioral changes as important factors when considering GVC as a viable treatment option for patients with refractory OCD.

Neural representation of abstract task structure during generalization.

Cognitive models in psychology and neuroscience widely assume that the human brain maintains an abstract representation of tasks. This assumption is fundamental to theories explaining how we learn quickly, think creatively, and act flexibly. However, neural evidence for a verifiably generative abstract task representation has been lacking. Here, we report an experimental paradigm that requires forming such a representation to act adaptively in novel conditions without feedback. Using functional magnetic resonance imaging, we observed that abstract task structure was represented within left mid-lateral prefrontal cortex, bilateral precuneus, and inferior parietal cortex. These results provide support for the neural instantiation of the long-supposed abstract task representation in a setting where we can verify its influence. Such a representation can afford massive expansions of behavioral flexibility without additional experience, a vital characteristic of human cognition.

Under construction: ventral and lateral frontal lobe contributions to value-based decision-making and learning.

Even apparently simple choices, like selecting a dessert in a pastry shop, involve options characterized by multiple motivationally relevant attributes. Neuroeconomic research suggests that the human brain may track the subjective value of such options, allowing disparate reward-predictive information to be compared in a common currency. However, the brain mechanisms involved in identifying value-predictive features and combining these to assess the value of each decision option remain unclear. Here, we review recent evidence from studies of multi-attribute decision-making in people with focal frontal lobe damage and in healthy people undergoing functional magnetic resonance imaging. This work suggests that ventromedial and lateral prefrontal cortex and orbitofrontal cortex are important for forming value judgments under conditions of complexity. We discuss studies supporting the involvement of these regions in selecting among and evaluating option attributes during value judgment and decision-making and when learning from reward feedback. These findings are consistent with roles for these regions in guiding value construction. They argue for a more nuanced understanding of how ventral and lateral prefrontal cortex contribute to discovering and recognizing value, processes that are required under the complex conditions typical of many everyday decisions.

Ventromedial frontal lobe damage affects interpretation, not exploration, of emotional facial expressions.

Recognizing and distinguishing the emotional states of those around us is crucial for adaptive social behavior. Previous work has shown that damage to the ventromedial frontal lobe (VMF) impairs recognition of subtle emotional facial expressions and affects fixation patterns to face stimuli. However, whether this relates to deficits in acquiring or interpreting facial expression information remains unclear. We tested 37 patients with frontal lobe damage, including 17 subjects with VMF lesions, in a series of emotion recognition tasks with different gaze manipulations. Subjects were asked to rate neutral, subtle and extreme emotional expressions while freely examining faces, while instructed to look only at the eyes, and in a gaze-contingent condition that required top-down direction of eye movements to reveal the stimulus. People with VMF damage were worse at detecting subtle disgust during free viewing and confused extreme emotional expressions more than healthy controls. However, fixation patterns did not differ systematically between groups during free or gaze-contingent viewing conditions. Moreover, instruction to fixate only the eyes did not improve the performance of VMF damaged subjects. These data argue that VMF is not necessary for normal fixations to emotional face stimuli, and that impairments in emotion recognition after VMF damage do not stem from impaired information gathering, as indexed by patterns of fixation.

Lesion Studies in Contemporary Neuroscience.

Studies of humans with focal brain damage and non-human animals with experimentally induced brain lesions have provided pivotal insights into the neural basis of behavior. As the repertoire of neural manipulation and recording techniques expands, the utility of studying permanent brain lesions bears re-examination. Studies on the effects of permanent lesions provide vital data about brain function that are distinct from those of reversible manipulations. Focusing on work carried out in humans and nonhuman primates, we address the inferential strengths and limitations of lesion studies, recent methodological developments, the integration of this approach with other methods, and the clinical and ecological relevance of this research. We argue that lesion studies are essential to the rigorous assessment of neuroscience theories.

Testing necessary regional frontal contributions to value assessment and fixation-based updating.

Value-based decisions are biased by the time people spend viewing each option: Options fixated longer are chosen more often, even when previously rated as less appealing. This bias is thought to reflect 'value updating' as new evidence is accumulated. Prior work has shown that ventromedial prefrontal cortex (PFC) carries a fixation-dependent value comparison signal, while other studies implicate dorsomedial PFC in representing the value of alternative options. Here, we test whether these regions are necessary for fixation-related value updating in 33 people with frontal lobe damage and 27 healthy controls performing a simple choice task. We show that damage to dorsomedial PFC leads to an exaggerated influence of fixations on choice, while damage to ventromedial or lateral PFC has no effect on this bias. These findings suggest a critical role for dorsomedial, and not ventromedial PFC, in mediating the relative influence of current fixations and a priori value on choice.

Eye spy: the predictive value of fixation patterns in detecting subtle and extreme emotions from faces.

Successful social interaction requires recognizing subtle changes in the mental states of others. Deficits in emotion recognition are found in several neurological and psychiatric illnesses, and are often marked by disturbances in gaze patterns to faces, typically interpreted as a failure to fixate on emotionally informative facial features. However, there has been very little research on how fixations inform emotion recognition in healthy people. Here, we asked whether fixations predicted detection of subtle and extreme emotions in faces. We used a simple model to predict emotion detection scores from participants' fixation patterns. The best fit of this model heavily weighted fixations to the eyes in detecting subtle fear, disgust and surprise, with less weight, or zero weight, given to mouth and nose fixations. However, this model could not successfully predict detection of subtle happiness, or extreme emotional expressions, with the exception of fear. These findings argue that detection of most subtle emotions is best served by fixations to the eyes, with some contribution from nose and mouth fixations. In contrast, detection of extreme emotions and subtle happiness appeared to be less dependent on fixation patterns. The results offer a new perspective on some puzzling dissociations in the neuropsychological literature, and a novel analytic approach for the study of eye gaze in social or emotional settings.

Technical report: exploring the basis of congenital myasthenic syndromes in an undergraduate course, using the model organism, Caenorhabditis elegans.

Mutations affecting acetylcholine receptors have been causally linked to the development of congenital myasthenic syndromes (CMS) in humans resulting from neuromuscular transmission defects. In an undergraduate Molecular Neurobiology course, the molecular basis of CMS was explored through study of a Caenorhabditis elegans model of the disease. The nicotinic acetylcholine receptor (nAChR), located on the postsynaptic muscle cell membrane, contains a pentameric ring structure comprised of five homologous subunits. In the nematode C. elegans, unc-63 encodes an α subunit of nAChR. UNC-63 is required for the function of nAChR at the neuromuscular junction. Mutations in unc-63 result in defects in locomotion and egg-laying and may be used as models for CMS. Here, we describe the responses of four unc-63 mutants to the cholinesterase inhibitor pyridostigmine bromide (range 0.9-15.6 mM in this study), a treatment for CMS that mitigates deficiencies in cholinergic transmission by elevating synaptic ACh levels. Our results show that 15.6 mM pyridostigmine bromide enhanced mobility in two alleles, depressed mobility in one allele and in N2, while having no effect on the fourth allele. This indicates that while pyridostigmine bromide may be effective at ameliorating symptoms of CMS in certain cases, it may not be a suitable treatment for all individuals due to the diverse etiology of this disease. Students in the Molecular Neurobiology course enhanced their experience in scientific research by conducting an experiment designed to increase understanding of genetic defects of neurological function.