Prefrontal Mechanisms Research Articles

Transformations in prefrontal ensemble activity underlying rapid threat avoidance learning.

The capacity to learn cues that predict aversive outcomes, and understand how to avoid those outcomes, is critical for adaptive behavior. Naturalistic avoidance often means accessing a safe location, but whether a location is safe depends on the nature of the impending threat. These relationships must be rapidly learned if animals are to survive. The prelimbic subregion (PL) of the medial prefrontal cortex (mPFC) integrates learned associations to influence these threat avoidance strategies. Prior work has focused on the role of PL activity in avoidance behaviors that are fully established, leaving the prefrontal mechanisms that drive rapid avoidance learning poorly understood. To determine when and how these learning-related changes emerge, we recorded PL neural activity using miniscope calcium imaging as mice rapidly learned to avoid a threatening cue by accessing a safe location. Over the course of learning, we observed enhanced modulation of PL activity representing intersections of a threatening cue with safe or risky locations and movements between them. We observed rapid changes in PL population dynamics that preceded changes observable in the encoding of individual neurons. Successful avoidance could be predicted from cue-related population dynamics during early learning. Population dynamics during specific epochs of the conditioned tone period correlated with the modeled learning rates of individual animals. In contrast, changes in single-neuron encoding occurred later, once an avoidance strategy had stabilized. Together, our findings reveal the sequence of PL changes that characterize rapid threat avoidance learning.

Healthy dietary choices involve prefrontal mechanisms associated with long-term reward maximization but not working memory.

Taste and health are critical factors to be considered when choosing foods. Prioritizing healthiness over tastiness requires self-control. It has also been suggested that self-control is guided by cognitive control. We then hypothesized that neural mechanisms underlying healthy food choice are associated with both self-control and cognitive control. Human participants performed a food choice task and a working memory task during functional MRI scanning. Their degree of self-control was assessed behaviorally by the value discount of delayed monetary rewards in intertemporal choice. Prioritizing healthiness in food choice was associated with greater activity in the superior, dorsolateral, and medial prefrontal cortices. Importantly, the prefrontal activity was greater in individuals with smaller delay discounting (i.e. high self-control) who preferred a delayed larger reward to an immediate smaller reward in intertemporal choice. On the other hand, working memory activity did not show a correlation with delay discounting or food choice activity, which was further supported by supplementary results that analyzed data from the Human Connectome Project. Our results suggest that the prefrontal cortex plays a critical role in healthy food choice, which requires self-control, but not working memory, for maximization of reward attainments in a remote future.

Anhedonia is associated with overgeneralization of conditioned fear during late adolescence and early adulthood

BackgroundPavlovian fear paradigms involve learning to associate cues with threat or safety. Aberrances in Pavlovian fear learning correlate with psychopathology, especially anxiety disorders. This study evaluated symptom dimensions of anxiety and depression in relation to Pavlovian fear acquisition and generalization. Methods256 participants (70.31 % female) completed a Pavlovian fear acquisition and generalization paradigm at ages 18–19 and 21–22 years. Analyses focused on indices of learning (self-reported US expectancy, skin conductance). Multilevel models tested associations with orthogonal symptom dimensions (Anhedonia-Apprehension, Fears, General Distress) at each timepoint. ResultsAll dimensions were associated with weaker acquisition of US expectancies at each timepoint. Fears was associated with overgeneralization only at age 21–22. General Distress was associated with overgeneralization only at age 18–19. Anhedonia-Apprehension was associated with overgeneralization at ages 18–19 and 21–22. ConclusionsAnhedonia-Apprehension disrupts Pavlovian fear acquisition and increases overgeneralization of fear. These effects may emerge during adolescence and remain into young adulthood. General Distress and Fears also contribute to overgeneralization of fear, but these effects may vary as prefrontal mechanisms of fear inhibition continue to develop during late adolescence. Targeting specific symptom dimensions, particularly Anhedonia-Apprehension, may decrease fear generalization and augment interventions built on Pavlovian principles, such as exposure therapy.

Asymmetric Prefrontal Cortex Activation Associated with Mutual Gaze of Mothers and Children during Shared Play

Mother–child shared play provides rich opportunities for mutual symmetrical interactions that serve to foster bond formation in dyads. Mutual gaze, a symmetrical behaviour that occurs during direct eye contact between two partners, conveys important cues of social engagement, affect and attention. However, it is not known whether the prefrontal cortical areas responsible for higher-order social cognition of mothers and children likewise exhibit neural symmetry; that is, similarity in direction of neural activation in mothers and children. This study used functional Near-infrared Spectroscopy (fNIRS) hyperscanning on 22 pairs of mothers and their preschool-aged children as they engaged in a 10-min free-play session together. The play interaction was video recorded and instances of mutual gaze were coded for after the experiment. Multivariate linear regression analyses revealed that neural asymmetry occurred during mother–child mutual gaze, where mothers showed a deactivation of prefrontal activity whereas children showed an activation instead. Findings suggest that mothers and children may employ divergent prefrontal mechanisms when engaged in symmetrical behaviours such as mutual gaze. Future studies could ascertain whether the asymmetric nature of a parent–child relationship, or potential neurodevelopmental differences in social processing between adults and children, significantly contribute to this observation.

Frontal Alpha Asymmetry in Posttraumatic Stress Disorder: Group Differences Among Individuals With and Without PTSD During an Inhibitory Control Task.

The current study examined frontal alpha asymmetry (FAA) as a marker of approach- and avoidance-related prefrontal activity in participants with and without trauma exposure and posttraumatic stress disorder (PTSD). We investigated FAA in an inhibitory control paradigm (threatening vs nonthreatening cues) under 2 levels of cognitive demand (baseline: images constant within a block of trials; vs filtering: images varied randomly within a block) in 3 groups of participants: individuals with PTSD (n = 16), exposed to trauma but without PTSD (n = 14), and a control group without PTSD or trauma exposure (n = 15). Under low demand (baseline), both PTSD and trauma-exposed participants exhibited significantly greater relative left than right frontal brain activity (approach) to threatening than to nonthreatening images. Under high demand (filtering), no FAA differences were found between threatening and nonthreatening images, but PTSD participants revealed more relative left than right FAA, whereas trauma-exposed participants showed reduced left relative right FAA. In all conditions, healthy controls exhibited reduced left relative to right FAA and no differences between threatening and nonthreatening images. Study findings suggest dysfunctional prefrontal mechanisms of emotion regulation in PTSD, but adaptive prefrontal regulation in trauma-exposed individuals without PTSD.

Cross-Hemispheric Complementary Prefrontal Mechanisms during Task Switching under Perceptual Uncertainty.

Flexible adaptation to changing environments is a representative executive control function implicated in the frontoparietal network that requires appropriate extraction of goal-relevant information through perception of the external environment. It remains unclear, however, how the flexibility is achieved under situations where goal-relevant information is uncertain. To address this issue, the current study examined neural mechanisms for task switching in which task-relevant information involved perceptual uncertainty. Twenty-eight human participants of both sexes alternated behavioral tasks in which they judged motion direction or color of visually presented colored dot stimuli that moved randomly. Task switching was associated with frontoparietal regions in the left hemisphere, and perception of ambiguous stimuli involved contralateral homologous frontoparietal regions. On the other hand, in stimulus-modality-dependent occipitotemporal regions, task coding information was increased during task switching. Effective connectivity analysis revealed that the frontal regions signaled toward the modality-dependent occipitotemporal regions when a relevant stimulus was more ambiguous, whereas the occipitotemporal regions signaled toward the frontal regions when the stimulus was more distinctive. These results suggest that complementary prefrontal mechanisms in the left and right hemispheres help to achieve a behavioral goal when the external environment involves perceptual uncertainty.SIGNIFICANCE STATEMENT In our daily life, environmental information to achieve a goal is not always certain, but we make judgments in such situations, and change our behavior accordingly. This study examined how the flexibility of behavior is achieved in a situation where goal-relevant information involves perceptual uncertainty. fMRI revealed that the lateral prefrontal cortex (PFC) in the left hemisphere is associated with behavioral flexibility, and the perception of ambiguous stimuli involves the PFC in the right hemisphere. These bilateral PFC signaled to stimulus-modality-dependent occipitotemporal regions, depending on perceptual uncertainty and the task to be performed. These top-down signals supplement task coding in the occipitotemporal regions, and highlight interhemispheric prefrontal mechanisms involved in executive control and perceptual decision-making.

Amplified engagement of prefrontal cortex during control of voluntary action in Tourette syndrome.

Tourette syndrome is characterized by ‘unvoluntary’ tics, which are compulsive, yet often temporarily suppressible. The inferior frontal gyrus is implicated in motor control, including inhibition of pre-potent actions through influences on downstream subcortical and motor regions. Although tic suppression in Tourette syndrome also engages the inferior frontal gyrus, it is unclear whether such prefrontal control of action is also dysfunctional: Tic suppression studies do not permit comparison with control groups, and neuroimaging studies of motor inhibition can be confounded by the concurrent expression or suppression of tics. Here, patients with Tourette syndrome were directly compared to control participants when performing an intentional inhibition task during functional MRI. Tic expression was recorded throughout for removal from statistical models. Participants were instructed to make a button press in response to Go cues, withhold responses to NoGo cues, and decide whether to press or withhold to ‘Choose’ cues. Overall performance was similar between groups, for both intentional inhibition rates (% Choose-Go) and reactive NoGo inhibition commission errors. A subliminal face prime elicited no additional effects on intentional or reactive inhibition. Across participants, the task activated prefrontal and motor cortices and subcortical nuclei, including pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus, thalamus and primary motor cortex. In Tourette syndrome, activity was elevated in the inferior frontal gyrus, insula and basal ganglia, most notably within the right inferior frontal gyrus during voluntary action and inhibition (Choose-Go and Choose-NoGo), and reactive inhibition (NoGo-correct). Anatomically, the locus of this inferior frontal gyrus hyperactivation during control of voluntary action matched that previously reported for tic suppression. In Tourette syndrome, activity within the caudate nucleus was also enhanced during both intentional (Choose-NoGo) and reactive (NoGo-correct) inhibition. Strikingly, despite the absence of overt motor behaviour, primary motor cortex activity increased in patients with Tourette syndrome but decreased in controls during both reactive and intentional inhibition. Additionally, severity of premonitory sensations scaled with functional connectivity of the pre-supplementary motor area to the caudate nucleus, globus pallidus and thalamus when choosing to respond (Choose-Go). Together, these results suggest that patients with Tourette syndrome use equivalent prefrontal mechanisms to suppress tics and withhold non-tic actions, but require greater inferior frontal gyrus engagement than controls to overcome motor drive from hyperactive downstream regions, notably primary motor cortex. Moreover, premonitory sensations may cue midline motor regions to generate tics through interactions with the basal ganglia.

Selective extinction through cognitive evaluation: Linking emotion regulation and extinction

The extinction of a previously conditioned response can be modulated through cognitive processes, including feature-based information, and explicit instruction. Here, we introduce a selective extinction through cognitive evaluation (SECE) task in which information is cognitively evaluated on a trial-by-trial basis to ascertain the extinction contingencies. Participants were conditioned to expect an electric shock during the presentation of one of two letters (CS+/CS-). During the SECE task, the letters were presented within words belonging to two categories, one of which indicated safety (COG-_CS+ trials), while risk of shock was maintained for the other category (COG+_CS+ trials). Skin conductance responses indicated that participants reduced their response to COG-_CS+ trials compared to COG+_CS+ trials. Clusters in bilateral insula and anterior cingulate cortex showed activation for COG+_CS+ trials that was reduced for COG-_CS+ trials. A network of brain regions, including left inferior frontal gyrus, and bilateral temporal and parietal cortices showed greater activation for COG-_CS+ versus COG+_CS+ trials. This is consistent with the semantic processing and decision-making necessary to evaluate the trial contingencies. We compared activation in the SECE task to activation in a cognitive reappraisal task in which participants were asked to attend to, or regulate their emotional reactions to affective IAPS images. This task replicated prefrontal activation seen in previous reappraisal studies. A voxelwise conjunction analysis found no overlap between the cognitive reappraisal and the SECE task, but we did find evidence for common activation in follow-up ROI analyses, supporting the idea of common lateral prefrontal mechanisms involved in both processes.

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.

Does Media Violence Cause Violence? Can exposure to Violent TV Shows, Movies and Video Games turn people Aggressive and Desensitized to Violence?

The existing literature is indicative of the fact that violence has been rooted in the mass media like never before and with the growing advancement technological advancement children and adolescents spend considerable amount of time exposed to such violence through various sources of media. In order to address this growing concern, this paper analyses the impact of media violence exposure on the development of aggressive feelings, thoughts and behaviour in children and youth. The content analysis of TV shows, movies and video games as most commonly used sources of media have been analysed along with the studies that show rapid increase in violent behaviour after being exposed to virtual violence. It also explores the neurophysiological perspectives by analysing the consequences of exposure to violent media on adolescents’ brain through neuroimaging. Although limited research has been conducted in this field, but the empirical evidence demonstrates an alteration in the prefrontal mechanisms after exposure to violent media, that are responsible for controlling emotion and behaviour leading to aggression. Based on the current longitudinal research, it is also observed that excessive exposure to media violence makes the youth less emotional and desensitized towards real life violence which ultimately leads to aggressive behaviour and have negative long-term effects on the brain. Future research should integrate other risk factors and research paradigms in order to have a more comprehensive picture with continuous development in next generations’ media technology and changing horizons of violence.

Economic Decisions through Circuit Inhibition.

Economic choices between goods are thought to rely on the orbitofrontal cortex (OFC), but the decision mechanisms remain poorly understood. To shed light on this fundamental issue, we recorded from the OFC of monkeys choosing between two juices offered sequentially. An analysis of firing rates across time windows revealed the presence of different groups of neurons similar to those previously identified under simultaneous offers. This observation suggested that economic decisions in the two modalities are formed in the same neural circuit. We then examined several hypotheses on the decision mechanisms. OFC neurons encoded good identities and values in a juice-based representation (labeled lines). Contrary to previous assessments, our data argued against the idea that decisions rely on mutual inhibition at the level of offer values. In fact, we showed that previous arguments for mutual inhibition were confounded by differences in value ranges. Instead, decisions seemed to involve mechanisms of circuit inhibition, whereby each offer value indirectly inhibited neurons encoding the opposite choice outcome. Our results reconcile a variety of previous findings and provide a general account for the neuronal underpinnings of economic choices.

Eye-gaze processing in the broader bipolar phenotype revealed by electrical neuroimaging

Previous studies have documented atypical brain responses to faces in individuals with bipolar disorder (BD) and in their relatives. In view of previous findings of atypical face processing in youths at risk for BD, the aim of this study was to examine whether BD patients and offspring would show differential activation in networks of the social brain when processing eye-gaze.Data from 18 euthymic BD patients and 18 offspring, as well as 36 age-matched healthy controls, were collected using a delayed face-matching paradigm, event related potentials and electrical neuroimaging methods.The P200 component, which is implicated in facial cues decoding, differentiated the BD groups from their age-matched controls. P200 source reconstruction indicates impairments conveyed by eye-contact in a network involved in experiencing others’ social intentions in BD patients (supplementary motor cortex, precentral gyrus, inferior parietal lobe), and the engagement of compensatory prefrontal mechanisms for modulating these functions in BD offspring. When viewing faces that had an averted gaze, BD patients and offspring showed a hypo-activation, compared to controls, particularly in regions involved in experiencing others’ feelings (post-central gyrus in BD patients / ventral premotor cortex in offspring). Therefore, the neural mechanism for decoding shifts in eye-gaze may be a familial characteristic of BD.

Prefrontal circuit mechanisms accounting for the modulation of active and passive coping stress responses

Prefrontal circuit mechanisms accounting for the modulation of active and passive coping stress responses

Prefrontal mechanisms combining rewards and beliefs in human decision-making

In uncertain and changing environments, optimal decision-making requires integrating reward expectations with probabilistic beliefs about reward contingencies. Little is known, however, about how the prefrontal cortex (PFC), which subserves decision-making, combines these quantities. Here, using computational modelling and neuroimaging, we show that the ventromedial PFC encodes both reward expectations and proper beliefs about reward contingencies, while the dorsomedial PFC combines these quantities and guides choices that are at variance with those predicted by optimal decision theory: instead of integrating reward expectations with beliefs, the dorsomedial PFC built context-dependent reward expectations commensurable to beliefs and used these quantities as two concurrent appetitive components, driving choices. This neural mechanism accounts for well-known risk aversion effects in human decision-making. The results reveal that the irrationality of human choices commonly theorized as deriving from optimal computations over false beliefs, actually stems from suboptimal neural heuristics over rational beliefs about reward contingencies.

Ordinal distance effect in working memory: simultaneous and sequential designs

Event Abstract Back to Event Ordinal distance effect in working memory: simultaneous and sequential designs Myrtille Dewulf1*, Wim Gevers1 and Sophie Antoine1 1 Free University of Brussels, Belgium Working memory refers to our ability to actively maintain and process a limited amount of information during a brief period of time. Crucial for our daily-life activities are not only the items to be memorized, but also their order. One behavioural signature of the processing of order information in working memory is the ordinal distance effect: when two probes are presented in the same order as in the memorised sequence, participants are slower when the probes are at close than at distant positions in the memorised sequence (e.g., Marshuetz et al., 2000). In these studies, items of the memory set were presented simultaneously, making ordinal and physical distance to co-vary: a larger ordinal distance implies a larger physical distance. It is thus possible that physical distance contributes to the effect, although it was only attributed to the ordinal distance between items. In the present study, we use a within-subject design in which we compare the ordinal distance effect when the items of the memory set are presented simultaneously and when the items are presented sequentially (i.e. one after the other). Interestingly, we did not replicate the typical distance effect, not in the simultaneous nor in the sequential condition. Our results seem to indicate that different processes are at place for small distances and for large distances (serial search strategy versus comparison processes, Turconi et al., 2006). Also, there was no important difference between the two conditions, implying that physical distance does not play a major role. References Marshuetz, C., Smith, E. E., Jonides, J., DeGutis, J., & Chenevert, T. L. (2000). Order information in working memory: fMRI evidence for parietal and prefrontal mechanisms. Journal of cognitive neuroscience, 12(2), 130-144. Turconi, E., Campbell, J. I. D., & Seron, X. (2006). Numerical order and quantity processing in number comparison. Cognition, 98(3), 273-285. Keywords: verbal working memory (VWM), working memory, distance effect, ordinal distance, Physical distance Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019. Presentation Type: Poster presentation Topic: Behavioral/Systems Neuroscience Citation: Dewulf M, Gevers W and Antoine S (2019). Ordinal distance effect in working memory: simultaneous and sequential designs. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00022 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 01 May 2019; Published Online: 27 Sep 2019. * Correspondence: PhD. Myrtille Dewulf, Free University of Brussels, Brussels, Brussels, 1050, Belgium, myrtille.dewulf@ulb.ac.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Myrtille Dewulf Wim Gevers Sophie Antoine Google Myrtille Dewulf Wim Gevers Sophie Antoine Google Scholar Myrtille Dewulf Wim Gevers Sophie Antoine PubMed Myrtille Dewulf Wim Gevers Sophie Antoine Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Bouncing back: Brain rehabilitation amid opioid and stimulant epidemics.

Recent methamphetamine and opioid use epidemics are a major public health concern. Chronic stimulant and opioid use are characterized by significant psychosocial, physical and mental health costs, repeated relapse, and heightened risk of early death. Neuroimaging research highlights deficits in brain processes and circuitry that are linked to responsivity to drug cues over natural rewards as well as suboptimal goal-directed decision-making. Despite the need for interventions, little is known about (1) how the brain changes with prolonged abstinence or as a function of various treatments; and (2) how symptoms change as a result of neuromodulation. This review focuses on the question: What do we know about changes in brain function during recovery from opioids and stimulants such as methamphetamine and cocaine? We provide a detailed overview and critique of published research employing a wide array of neuroimaging methods - functional and structural magnetic resonance imaging, electroencephalography, event-related potentials, diffusion tensor imaging, and multiple brain stimulation technologies along with neurofeedback - to track or induce changes in drug craving, abstinence, and treatment success in stimulant and opioid users. Despite the surge of methamphetamine and opioid use in recent years, most of the research on neuroimaging techniques for recovery focuses on cocaine use. This review highlights two main findings: (1) interventions can lead to improvements in brain function, particularly in frontal regions implicated in goal-directed behavior and cognitive control, paired with reduced drug urges/craving; and (2) the targeting of striatal mechanisms implicated in drug reward may not be as cost-effective as prefrontal mechanisms, given that deep brain stimulation methods require surgery and months of intervention to produce effects. Overall, more studies are needed to replicate and confirm findings, particularly for individuals with opioid and methamphetamine use disorders.

Prefrontal Contributions to Attention and Working Memory.

The processes of attention and working memory are conspicuously interlinked, suggesting that they may involve overlapping neural mechanisms. Working memory (WM) is the ability to maintain information in the absence of sensory input. Attention is the process by which a specific target is selected for further processing, and neural resources directed toward that target. The content of WM can be used to direct attention, and attention can in turn determine which information is encoded into WM. Here we discuss the similarities between attention and WM and the role prefrontal cortex (PFC) plays in each. First, at the theoretical level, we describe how attention and WM can both rely on models based on attractor states. Then we review the evidence for an overlap between the areas involved in both functions, especially the frontal eye field (FEF) portion of the prefrontal cortex. We also discuss similarities between the neural changes in visual areas observed during attention and WM. At the cellular level, we review the literature on the role of prefrontal DA in both attention and WM at the behavioral and neural levels. Finally, we summarize the anatomical evidence for an overlap between prefrontal mechanisms involved in attention and WM. Altogether, a summary of pharmacological, electrophysiological, behavioral, and anatomical evidence for a contribution of the FEF part of prefrontal cortex to attention and WM is provided.

The Role of Frontostriatal Systems in Instructed Reinforcement Learning: Evidence From Genetic and Experimentally-Induced Variation.

Instructions have a powerful effect on learning and decision-making, biasing choice even in the face of disconfirming feedback. Detrimental biasing effects have been reported in a number of studies in which instruction was given prior to trial-and-error learning. Previous work has attributed individual differences in instructional bias to variations in prefrontal and striatal dopaminergic genes, suggesting a role for prefrontally-mediated cognitive control processes in biasing learning. The current study replicates and extends these findings. Human subjects performed a probabilistic reinforcement learning task after receiving inaccurate instructions about the quality of one of the options. In order to establish a causal relationship between prefrontal cortical mechanisms and instructional bias, we applied transcranial direct current stimulation over dorsolateral prefrontal cortex (anodal, cathodal, or sham) while subjects performed the task. We additionally genotyped subjects for the COMT Val158Met genetic polymorphism, which influences the breakdown of prefrontal dopamine, and for the DAT1/SLC6A3 variable number tandem repeat, which affects expression of striatal dopamine transporter. We replicated the finding that the COMT Met allele is associated with increased instructional bias and further demonstrated that variation in DAT1 has similar effects to variation in COMT, with 9-repeat carriers demonstrating increased bias relative to 10-repeat homozygotes. Consistent with increased top-down regulation of reinforcement learning, anodal subjects demonstrated greater bias relative to sham, though this effect was present only early in training. In contrast, there was no effect of cathodal stimulation. Finally, we fit computational models to subjects' data to better characterize the mechanisms underlying instruction bias. A novel choice bias model, in which instructions influence decision-making rather than learning, was found to best account for subjects' behavior. Overall, these data provide further evidence for the role of frontostriatal interactions in biasing instructed reinforcement learning, which adds to the growing literature documenting both costs and benefits of cognitive control.

Differential fear conditioning generates prefrontal neural ensembles of safety signals

Fear discrimination is critical for survival, while fear generalization is effective for avoiding dangerous situations. Overgeneralized fear is a typical symptom of anxiety disorders, including generalized anxiety disorder and posttraumatic stress disorder (PTSD). Previous research demonstrated that fear discrimination learning is mediated by prefrontal mechanisms. While the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) are recognized for their excitatory and inhibitory effects on the fear circuit, respectively, the mechanisms driving fear discrimination are unidentified. To obtain insight into the mechanisms underlying context-specific fear discrimination, we investigated prefrontal neuronal ensembles representing distinct experiences associated with learning to disambiguate between dangerous and similar, but not identical, harmless stimuli. Here, we show distinct quantitative activation differences in response to conditioned and generalized fear experiences, as well as modulation of the neuronal ensembles associated with successful acquisition of context-safety contingencies. These findings suggest that prefrontal neuronal ensembles patterns code functional context-danger and context-safety relationships. The PL subdivision of the mPFC monitors context-danger associations to conditioned fear, whereas differential conditioning sparks additional ensembles associated with the inhibition of generalized fear in both the PL and IL subdivisions of the mPFC. Our data suggest that fear discrimination learning is associated with the modulation of prefrontal subpopulations in a subregion- and experience-specific fashion, and the learning of appropriate responses to conditioned and initially generalized fear experiences is driven by gradual updating and rebalancing of the prefrontal memory representations.

Solving the prefrontal conundrum of high-order anxiety: conciliating HOTEC and hypofrontality. A theoretical review

ABSTRACTIntroduction: According to the High-order Theory of Emotional Consciousness (HOTEC), every emotional process is a conscious and high-order state of mind carried out by the General Networks of Cognition (GNC), which consists mainly of prefrontal mechanisms. This means that anxiety is also an emotional state of mind carried out by the GNC (positive correlation). However, numerous studies have suggested what is commonly called “hypofrontality” during states of anxiety (negative correlation), which seems to give rise to a theoretical and empirical contraction.Methods: I present a theoretical review to address the following issue: how to advocate a HOTEC view of anxiety in the face of a growing paradigm of hypofrontality during states of anxiety?Results: Here I propose that dmPFC, the dACC, and the anterior insula are GNC areas positively correlated with anxiety, which, along with the prefrontal areas responsible for regulating the activation of survival circuits and driving the attention to adaptive ways to overcome potential threats, form an interconnective model of anticipatory and regulatory mechanisms related to learned threats based on autobiographical memories.Conclusions: Through this model, I propose that HOTEC is still a valid way to approach and understand both healthy and unhealthy anxious states of mind.