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Rutsuko Ito - One of the best experts on this subject based on the ideXlab platform.
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Perirhinal Cortex is Involved in the Resolution of Learned Approach-Avoidance Conflict Associated with Discrete Objects.
Cerebral cortex (New York N.Y. : 1991), 2021Co-Authors: Sonja Chu, Rutsuko Ito, Edward B. O'neil, Sathesan Thavabalasingam, Matthew Margerison, Yuanfang Zhao, Andy C. H. LeeAbstract:The rodent ventral and primate anterior hippocampus have been implicated in Approach-Avoidance (AA) Conflict processing. It is unclear, however, whether this structure contributes to AA Conflict detection and/or resolution, and if its involvement extends to conditions of AA Conflict devoid of spatial/contextual information. To investigate this, neurologically healthy human participants first learned to approach or avoid single novel visual objects with the goal of maximizing earned points. Approaching led to point gain and loss for positive and negative objects, respectively, whereas avoidance had no impact on score. Pairs of these objects, each possessing nonConflicting (positive-positive/negative-negative) or Conflicting (positive-negative) valences, were then presented during functional magnetic resonance imaging. Participants either made an AA decision to score points (Decision task), indicated whether the objects had identical or differing valences (Memory task), or followed a visual instruction to approach or avoid (Action task). Converging multivariate and univariate results revealed that within the medial temporal lobe, perirhinal cortex, rather than the anterior hippocampus, was predominantly associated with object-based AA Conflict resolution. We suggest the anterior hippocampus may not contribute equally to all learned AA Conflict scenarios and that stimulus information type may be a critical and overlooked determinant of the neural mechanisms underlying AA Conflict behavior.
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The ventral hippocampus is necessary for cue-elicited, but not outcome driven Approach-Avoidance Conflict decisions: a novel operant choice decision-making task.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2020Co-Authors: Bilgehan Çavdaroğlu, Sadia Riaz, Andy C. H. Lee, Elton H. L. Yeung, Rutsuko ItoAbstract:Approach-Avoidance Conflict is induced when an organism encounters a stimulus that carries both positive and negative attributes. Accumulating evidence implicates the ventral hippocampus (VH) in the detection and resolution of Approach-Avoidance Conflict, largely on the basis of maze-based tasks assaying innate and conditioned responses to situations of Conflict. However, its role in discrete trial Approach-Avoidance decision-making has yet to be elucidated. In this study, we designed a novel cued operant Conflict decision-making task in which rats were required to choose and respond for a low reward option or high reward option paired with varying shock intensities on a differential reinforcement of low rates of responding schedule. Post training, the VH was chemogenetically inhibited while animals performed the task with the usual outcomes delivered, and with the presentation of cues associated with the reward vs. Conflict options only (extinction condition). We found that VH inhibition led to an avoidance of the Conflict option and longer latency to choose this option when decision-making was being made on the basis of cues alone with no outcomes. Consistent with these findings, VH-inhibited animals spent more time in the central component of the elevated plus maze (EPM), indicating a potential deficit in decision-making under innate forms of Approach-Avoidance Conflict. Taken together, these findings implicate the VH in cue-driven Approach-Avoidance decisions in the face of motivational Conflict.
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Exploring the interaction between Approach-Avoidance Conflict and memory processing.
Memory (Hove England), 2019Co-Authors: Sonja Chu, Rutsuko Ito, Sathesan Thavabalasingam, Laurie Hamel, Supreet Aashat, Jonathan Tay, Andy C. H. LeeAbstract:The medial temporal lobe (MTL) has been implicated in Approach-Avoidance (AA) Conflict processing, which arises when a stimulus is imbued with both positive and negative valences. Notably, since the MTL has been traditionally viewed as a mnemonic brain region, a pertinent question is how AA Conflict and memory processing interact with each other behaviourally. We conducted two behavioural experiments to examine whether increased AA Conflict processing has a significant impact on incidental mnemonic encoding and inferential reasoning. In Experiment 1, participants first completed a reward and punishment AA task and were subsequently administered a surprise recognition memory test for stimuli that were presented during high and no AA Conflict trials. In Experiment 2, participants completed a reward and punishment task in which they learned the valences of objects presented in pairs (AB, BC pairs). Next, we assessed their ability to integrate information across these pairs (infer A-C relationships) and examined whether inferential reasoning was more challenging across objects with Conflicting compared to non-Conflicting incentive values. We observed that increased motivational Conflict did not significantly impact encoding or inferential reasoning. Potential explanations for these findings are considered, including the possibility that AA Conflict and memory processing are not necessarily intertwined behaviourally.
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Double dissociation of learned Approach-Avoidance Conflict processing and spatial pattern separation along the dorsoventral axis of the dentate gyrus.
Hippocampus, 2019Co-Authors: Dylan C M Yeates, Alicia Ussling, Andy C. H. Lee, Rutsuko ItoAbstract:The ventral portion of the rodent hippocampus (HPC; anterior in primates) has been implicated in the detection and resolution of Approach-Avoidance Conflict, which arises when an organism encounters a stimulus that predicts both positive and negative outcomes. Previous work has found differential regulation of Approach-Avoidance Conflict behavior by the CA3 and CA1 subfields, with inhibition of ventral CA3 increasing approach toward Conflicting stimuli and inhibition of the ventral CA1 potentiating avoidance. Here, we sought to extend these findings by investigating the role of the dentate gyrus (DG), the input region of the HPC, in learned Approach-Avoidance Conflict processing in rats. Animals were first trained to acquire three different visuotactile cue-outcome associations in separate arms of a Y-maze (appetitive, aversive, and neutral). Postacquisition, they were administered a "Conflict test," in which they were presented with a choice between exploring an arm in which the appetitive and aversive cues were concurrently presented (Conflict stimulus), and another arm containing the neutral stimulus. GABAR-mediated inactivation of the ventral DG, but not dorsal DG, potentiated approach behavior toward the Conflict stimulus, similar to the effects of ventral CA3 inactivation. In contrast, dorsal DG, but not ventral DG, inactivation was found to impair performance on a metric spatial discrimination task, which is commonly used as a test of pattern separation. The findings of this study demonstrate a robust double dissociation between the ventral and dorsal aspects of the DG, in line with previous reports of functional differences along the longitudinal axis of the HPC.
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Dissociative effects of dorsomedial striatum D1 and D2 receptor antagonism in the regulation of anxiety and learned Approach-Avoidance Conflict decision-making.
Neuropharmacology, 2018Co-Authors: David Nguyen, Suzanne Erb, Erind Alushaj, Rutsuko ItoAbstract:The dorsal striatum is traditionally known for its role in sensorimotor integration. However, the dorsomedial striatum (DMS) has also been implicated in cost-benefit Conflict processing, a role more readily attributed to the ventral striatum (VS), as a site of limbic-motor integration. We recently showed that dopaminergic D1 (D1R) and D2 receptors (D2R) in the VS exert dissociable control over cue-elicited Approach-Avoidance decision-making, in the presence of Conflicting motivational stimuli. We therefore sought to investigate the contribution of DMS dopaminergic receptors in the regulation of cue-elicited and innate Approach-Avoidance decision-making. Using a conditioned mixed-valence Conflict paradigm, we trained rats in a three-arm radial maze to associate visuotactile cues with appetitive, aversive, and neutral outcomes. Rats then received an intra-DMS or intra-dorsolateral striatum (DLS) microinfusion of D1-like antagonist (SCH23390) or D2-like antagonist (sulpiride), and were then tested for the expression of Approach-Avoidance behavior in a Conflict scenario, wherein the appetitive and aversive cues were superimposed within a single maze arm. The results revealed that DMS (but not DLS) D1R antagonism, suppressed approach towards the Conflict arm while DMS (but not DLS) D2R antagonism enhanced approach. All rats were subsequently administered an elevated plus maze test as a measure of innate Approach-Avoidance Conflict (anxiety). DMS D1R antagonism decreased anxiety, while DMS D2R and both DLS D1R and D2R antagonism increased anxiety. Our findings suggest that under motivational Conflict, activation of DMS D1-like receptors facilitates approach, while activation of D2-like receptors suppress approach behavior. Furthermore, anxiety is regulated by dorsal striatal-mediated dopaminergic mechanisms.
David Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Dissociative effects of dorsomedial striatum D1 and D2 receptor antagonism in the regulation of anxiety and learned Approach-Avoidance Conflict decision-making.
Neuropharmacology, 2018Co-Authors: David Nguyen, Suzanne Erb, Erind Alushaj, Rutsuko ItoAbstract:The dorsal striatum is traditionally known for its role in sensorimotor integration. However, the dorsomedial striatum (DMS) has also been implicated in cost-benefit Conflict processing, a role more readily attributed to the ventral striatum (VS), as a site of limbic-motor integration. We recently showed that dopaminergic D1 (D1R) and D2 receptors (D2R) in the VS exert dissociable control over cue-elicited Approach-Avoidance decision-making, in the presence of Conflicting motivational stimuli. We therefore sought to investigate the contribution of DMS dopaminergic receptors in the regulation of cue-elicited and innate Approach-Avoidance decision-making. Using a conditioned mixed-valence Conflict paradigm, we trained rats in a three-arm radial maze to associate visuotactile cues with appetitive, aversive, and neutral outcomes. Rats then received an intra-DMS or intra-dorsolateral striatum (DLS) microinfusion of D1-like antagonist (SCH23390) or D2-like antagonist (sulpiride), and were then tested for the expression of Approach-Avoidance behavior in a Conflict scenario, wherein the appetitive and aversive cues were superimposed within a single maze arm. The results revealed that DMS (but not DLS) D1R antagonism, suppressed approach towards the Conflict arm while DMS (but not DLS) D2R antagonism enhanced approach. All rats were subsequently administered an elevated plus maze test as a measure of innate Approach-Avoidance Conflict (anxiety). DMS D1R antagonism decreased anxiety, while DMS D2R and both DLS D1R and D2R antagonism increased anxiety. Our findings suggest that under motivational Conflict, activation of DMS D1-like receptors facilitates approach, while activation of D2-like receptors suppress approach behavior. Furthermore, anxiety is regulated by dorsal striatal-mediated dopaminergic mechanisms.
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Dissociable roles of the nucleus accumbens D1 and D2 receptors in regulating cue-elicited Approach-Avoidance Conflict decision-making
Psychopharmacology, 2018Co-Authors: David Nguyen, Victoria Fugariu, Suzanne Erb, Rutsuko ItoAbstract:Rationale Approach and avoidance decisions are made when an animal experiences a state of motivational Conflict inflicted by stimuli imbued with both positive and negative valences. The nucleus accumbens (NAc), a site where valenced information and action selection converge, has recently been found to be critically involved in the resolution of Approach-Avoidance Conflict. However, the individual roles of the region’s dopamine receptor D1 (D1R)- and D2 (D2R)-expressing medium spiny neurons (MSNs) in regulating Conflict resolution have not been well established. Objectives Here, we examined the roles of NAc D1R and D2R in cue-elicited Approach-Avoidance decision-making. Methods Using a conditioned mixed-valence Conflict paradigm, rats were initially trained in a radial maze to associate separate visuotactile cues with sucrose reward, foot shock punishment, and no outcome. Following acquisition of the cue-outcome associations, rats were subjected to a conditioned Approach-Avoidance Conflict scenario, in which they were presented with a maze arm containing a superimposition of the reward and punishment cues, and another arm containing neutral cues. Results Post-training intra-NAc D1R antagonism (SCH23390) led to an avoidance of the arm containing the mixed-valence cue over the neutral arm, whereas intra-NAc D2R antagonism (sulpiride) resulted in rats exhibiting a preference for the mixed-valence arm. Conclusion Our results suggest that NAc D1R and D2R exert differential control over decision-making involving cue-elicited Approach-Avoidance Conflict resolution.
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Dissociable roles of the nucleus accumbens D1 and D2 receptors in regulating cue-elicited Approach-Avoidance Conflict decision-making.
Psychopharmacology, 2018Co-Authors: David Nguyen, Victoria Fugariu, Suzanne Erb, Rutsuko ItoAbstract:Approach and avoidance decisions are made when an animal experiences a state of motivational Conflict inflicted by stimuli imbued with both positive and negative valences. The nucleus accumbens (NAc), a site where valenced information and action selection converge, has recently been found to be critically involved in the resolution of Approach-Avoidance Conflict. However, the individual roles of the region’s dopamine receptor D1 (D1R)- and D2 (D2R)-expressing medium spiny neurons (MSNs) in regulating Conflict resolution have not been well established. Here, we examined the roles of NAc D1R and D2R in cue-elicited Approach-Avoidance decision-making. Using a conditioned mixed-valence Conflict paradigm, rats were initially trained in a radial maze to associate separate visuotactile cues with sucrose reward, foot shock punishment, and no outcome. Following acquisition of the cue-outcome associations, rats were subjected to a conditioned Approach-Avoidance Conflict scenario, in which they were presented with a maze arm containing a superimposition of the reward and punishment cues, and another arm containing neutral cues. Post-training intra-NAc D1R antagonism (SCH23390) led to an avoidance of the arm containing the mixed-valence cue over the neutral arm, whereas intra-NAc D2R antagonism (sulpiride) resulted in rats exhibiting a preference for the mixed-valence arm. Our results suggest that NAc D1R and D2R exert differential control over decision-making involving cue-elicited Approach-Avoidance Conflict resolution.
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Aberrant Approach-Avoidance Conflict resolution following repeated cocaine pre-exposure.
Psychopharmacology, 2015Co-Authors: David Nguyen, Anett Schumacher, Suzanne Erb, Rutsuko ItoAbstract:Rationale Addiction is characterized by persistence to seek drug reinforcement despite negative consequences. Drug-induced aberrations in approach and avoidance processing likely facilitate the sustenance of addiction pathology. Currently, the effects of repeated drug exposure on the resolution of Conflicting approach and avoidance motivational signals have yet to be thoroughly investigated.
Andy C. H. Lee - One of the best experts on this subject based on the ideXlab platform.
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Perirhinal Cortex is Involved in the Resolution of Learned Approach-Avoidance Conflict Associated with Discrete Objects.
Cerebral cortex (New York N.Y. : 1991), 2021Co-Authors: Sonja Chu, Rutsuko Ito, Edward B. O'neil, Sathesan Thavabalasingam, Matthew Margerison, Yuanfang Zhao, Andy C. H. LeeAbstract:The rodent ventral and primate anterior hippocampus have been implicated in Approach-Avoidance (AA) Conflict processing. It is unclear, however, whether this structure contributes to AA Conflict detection and/or resolution, and if its involvement extends to conditions of AA Conflict devoid of spatial/contextual information. To investigate this, neurologically healthy human participants first learned to approach or avoid single novel visual objects with the goal of maximizing earned points. Approaching led to point gain and loss for positive and negative objects, respectively, whereas avoidance had no impact on score. Pairs of these objects, each possessing nonConflicting (positive-positive/negative-negative) or Conflicting (positive-negative) valences, were then presented during functional magnetic resonance imaging. Participants either made an AA decision to score points (Decision task), indicated whether the objects had identical or differing valences (Memory task), or followed a visual instruction to approach or avoid (Action task). Converging multivariate and univariate results revealed that within the medial temporal lobe, perirhinal cortex, rather than the anterior hippocampus, was predominantly associated with object-based AA Conflict resolution. We suggest the anterior hippocampus may not contribute equally to all learned AA Conflict scenarios and that stimulus information type may be a critical and overlooked determinant of the neural mechanisms underlying AA Conflict behavior.
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The ventral hippocampus is necessary for cue-elicited, but not outcome driven Approach-Avoidance Conflict decisions: a novel operant choice decision-making task.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2020Co-Authors: Bilgehan Çavdaroğlu, Sadia Riaz, Andy C. H. Lee, Elton H. L. Yeung, Rutsuko ItoAbstract:Approach-Avoidance Conflict is induced when an organism encounters a stimulus that carries both positive and negative attributes. Accumulating evidence implicates the ventral hippocampus (VH) in the detection and resolution of Approach-Avoidance Conflict, largely on the basis of maze-based tasks assaying innate and conditioned responses to situations of Conflict. However, its role in discrete trial Approach-Avoidance decision-making has yet to be elucidated. In this study, we designed a novel cued operant Conflict decision-making task in which rats were required to choose and respond for a low reward option or high reward option paired with varying shock intensities on a differential reinforcement of low rates of responding schedule. Post training, the VH was chemogenetically inhibited while animals performed the task with the usual outcomes delivered, and with the presentation of cues associated with the reward vs. Conflict options only (extinction condition). We found that VH inhibition led to an avoidance of the Conflict option and longer latency to choose this option when decision-making was being made on the basis of cues alone with no outcomes. Consistent with these findings, VH-inhibited animals spent more time in the central component of the elevated plus maze (EPM), indicating a potential deficit in decision-making under innate forms of Approach-Avoidance Conflict. Taken together, these findings implicate the VH in cue-driven Approach-Avoidance decisions in the face of motivational Conflict.
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Exploring the interaction between Approach-Avoidance Conflict and memory processing.
Memory (Hove England), 2019Co-Authors: Sonja Chu, Rutsuko Ito, Sathesan Thavabalasingam, Laurie Hamel, Supreet Aashat, Jonathan Tay, Andy C. H. LeeAbstract:The medial temporal lobe (MTL) has been implicated in Approach-Avoidance (AA) Conflict processing, which arises when a stimulus is imbued with both positive and negative valences. Notably, since the MTL has been traditionally viewed as a mnemonic brain region, a pertinent question is how AA Conflict and memory processing interact with each other behaviourally. We conducted two behavioural experiments to examine whether increased AA Conflict processing has a significant impact on incidental mnemonic encoding and inferential reasoning. In Experiment 1, participants first completed a reward and punishment AA task and were subsequently administered a surprise recognition memory test for stimuli that were presented during high and no AA Conflict trials. In Experiment 2, participants completed a reward and punishment task in which they learned the valences of objects presented in pairs (AB, BC pairs). Next, we assessed their ability to integrate information across these pairs (infer A-C relationships) and examined whether inferential reasoning was more challenging across objects with Conflicting compared to non-Conflicting incentive values. We observed that increased motivational Conflict did not significantly impact encoding or inferential reasoning. Potential explanations for these findings are considered, including the possibility that AA Conflict and memory processing are not necessarily intertwined behaviourally.
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Double dissociation of learned Approach-Avoidance Conflict processing and spatial pattern separation along the dorsoventral axis of the dentate gyrus.
Hippocampus, 2019Co-Authors: Dylan C M Yeates, Alicia Ussling, Andy C. H. Lee, Rutsuko ItoAbstract:The ventral portion of the rodent hippocampus (HPC; anterior in primates) has been implicated in the detection and resolution of Approach-Avoidance Conflict, which arises when an organism encounters a stimulus that predicts both positive and negative outcomes. Previous work has found differential regulation of Approach-Avoidance Conflict behavior by the CA3 and CA1 subfields, with inhibition of ventral CA3 increasing approach toward Conflicting stimuli and inhibition of the ventral CA1 potentiating avoidance. Here, we sought to extend these findings by investigating the role of the dentate gyrus (DG), the input region of the HPC, in learned Approach-Avoidance Conflict processing in rats. Animals were first trained to acquire three different visuotactile cue-outcome associations in separate arms of a Y-maze (appetitive, aversive, and neutral). Postacquisition, they were administered a "Conflict test," in which they were presented with a choice between exploring an arm in which the appetitive and aversive cues were concurrently presented (Conflict stimulus), and another arm containing the neutral stimulus. GABAR-mediated inactivation of the ventral DG, but not dorsal DG, potentiated approach behavior toward the Conflict stimulus, similar to the effects of ventral CA3 inactivation. In contrast, dorsal DG, but not ventral DG, inactivation was found to impair performance on a metric spatial discrimination task, which is commonly used as a test of pattern separation. The findings of this study demonstrate a robust double dissociation between the ventral and dorsal aspects of the DG, in line with previous reports of functional differences along the longitudinal axis of the HPC.
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Ventral Hippocampal CA1 and CA3 Differentially Mediate Learned Approach-Avoidance Conflict Processing
Current biology : CB, 2018Co-Authors: Anett Schumacher, Franz R. Villaruel, Alicia Ussling, Sadia Riaz, Andy C. H. Lee, Rutsuko ItoAbstract:Summary Approach-Avoidance Conflict arises when an animal encounters a stimulus that is associated simultaneously with positive and negative valences [1]. The effective resolution of Approach-Avoidance Conflict is critical for survival and is believed to go awry in a number of mental disorders, such as anxiety and addiction. An accumulation of evidence from both rodents and humans suggests that the ventral hippocampus (anterior in humans) plays a key role in Approach-Avoidance Conflict processing [2–8], with one influential model proposing that this structure modulates behavioral inhibition in the face of Conflicting goals by increasing the influence of negative valences [9]. Very little is known, however, about the contributions of specific hippocampal subregions to this process—an important issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced an avoidance of a Conflict cue imbued with both learned positive and learned negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference for the Conflict cue. In contrast, dorsal CA1- and CA3-inactivated rats showed no change in Conflict behavior, and furthermore, additional behavioral tasks confirmed that the observed pattern of Approach-Avoidance findings could not be explained by other factors, such as differential alterations in novelty detection or locomotor activity. Our data demonstrate that ventral CA1 and CA3 subserve distinct and opposing roles in Approach-Avoidance Conflict processing and provide important insight into the functions and circuitry of the ventral hippocampus.
Dominik R. Bach - One of the best experts on this subject based on the ideXlab platform.
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Hippocampal representation of threat features and behavior in a human Approach-Avoidance Conflict anxiety task
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Aslan Abivardi, Saurabh Khemka, Dominik R. BachAbstract:Decisions under threat are crucial to survival and require integration of distinct situational features, such as threat probability and magnitude. Recent evidence from human lesion and neuroimaging studies implicated anterior hippocampus (aHC) and amygdala in Approach-Avoidance decisions under threat, and linked their integrity to cautious behavior. Here we sought to elucidate how threat dimensions and behavior are represented in these structures. Twenty human participants (11 female) completed an Approach-Avoidance Conflict task during high-resolution fMRI. Participants could gather tokens under threat of capture by a virtual predator, which would lead to token loss. Threat probability (predator wake-up rate) and magnitude (amount of token loss) varied on each trial. To disentangle effects of threat features, and ensuing behavior, we performed a multifold parametric analysis. We found that high threat probability and magnitude related to BOLD signal in left aHC/entorhinal cortex. However, BOLD signal in this region was better explained by avoidance behavior than by these threat features. A priori ROI analysis confirmed the relation of aHC BOLD response with avoidance. Exploratory subfield analysis revealed that this relation was specific to anterior CA2/3 but not CA1. Left lateral amygdala responded to low and high, but not intermediate, threat probability. Our results suggest that aHC BOLD signal is better explained by avoidance behavior than by threat features in Approach-Avoidance Conflict. Rather than representing threat features in a monotonic manner, it appears that aHC may compute Approach-Avoidance decisions based on integration of situational threat features represented in other neural structures.SIGNIFICANCE STATEMENT An effective threat anticipation system is crucial to survival across species. Natural threats, however, are diverse and have distinct features. To be able to adapt to different modes of danger, the brain needs to recognize these features, integrate them, and use them to modify behavior. Our results disclose the human anterior hippocampus as a likely arbiter of Approach-Avoidance decisions harnessing compound environmental information while partially replicating previous findings and blending into recent efforts to illuminate the neural basis of Approach-Avoidance Conflict in humans.
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Disentangling Hippocampal and Amygdala Contribution to Human Anxiety-Like Behavior.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019Co-Authors: Dominik R. Bach, René Hurlemann, Martina Hoffmann, Carsten Finke, Christoph J. PlonerAbstract:Anxiety comprises a suite of behaviors to deal with potential threat and is often modeled in Approach-Avoidance Conflict tasks. Collectively, these tests constitute a predominant preclinical model of anxiety disorder. A body of evidence suggests that both ventral hippocampus and amygdala lesions impair anxiety-like behavior, but the relative contribution of these two structures is unclear. A possible reason is that Approach-Avoidance Conflict tasks involve a series of decisions and actions, which may be controlled by distinct neural mechanisms that are difficult to disentangle from behavioral readouts. Here, we capitalize on a human Approach-Avoidance Conflict test, implemented as computer game, that separately measures several action components. We investigate three patients of both sexes with unspecific unilateral medial temporal lobe (MTL) damage, one male with selective bilateral hippocampal (HC), and one female with selective bilateral amygdala lesions, and compare them to matched controls. MTL and selective HC lesions, but not selective amygdala lesions, increased approach decision when possible loss was high. In contrast, MTL and selective amygdala lesions, but not selective HC lesions, increased return latency. Additionally, selective HC and selective amygdala lesions reduced approach latency. In a task targeted at revealing subjective assumptions about the structure of the computer game, MTL and selective HC lesions impacted on reaction time generation but not on the subjective task structure. We conclude that deciding to approach reward under threat relies on hippocampus but not amygdala, whereas vigor of returning to safety depends on amygdala but not on hippocampus.SIGNIFICANCE STATEMENT Approach-Avoidance Conflict tests are widely investigated in rodents, and increasingly in humans, to understand the neural basis of anxiety-like behavior. However, the contribution of the most relevant brain regions, ventral hippocampus and amygdala, is incompletely understood. We use a human computerized test that separates different action components and find that hippocampus, but not amygdala, lesions impair approach decisions, whereas amygdala, but not hippocampus, lesions impair the vigor of return to safety.
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Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.
Translational psychiatry, 2018Co-Authors: Dominik R. Bach, Christoph W. Korn, Johanna Vunder, Antonia BantelAbstract:Valproate is an anticonvulsant drug with strong preclinical evidence for reducing anxiety behaviour in rodents but no clear clinical evidence. To motivate clinical trials, we here investigate the use of valproate in a translational human model of anxiety behaviour. In a double-blind, randomised, placebo-controlled trial, n = 118 healthy participants played a previously validated approach/avoidance Conflict computer game to measure anxiety-like behaviour, while under 400 mg valproate, under 200 mg of the established anxiolytic/anticonvulsant pregabalin, or under placebo. Saccadic peak velocity and subjective ratings were assessed to control for drug-induced sedation. Compared to placebo, valproate and pregabaline were anxiolytic in the primary outcome, and several secondary outcomes. Bayesian model comparison decisively demonstrated no differences between the two drugs. Subjective and objective sedation was significantly more pronounced under pregabalin than valproate, but did not explain anxiolytic effects. We demonstrate acute anxiolytic properties of valproate in healthy humans. Both drugs have similar anxiolytic properties at the doses used. Valproate is less sedative than pregabalin. Our results suggest clinical trials on the use of valproate in anxiolytic treatment. More generally, we propose a strategy of screening drugs in human preclinical models that can directly be compared across species, such as the approach/avoidance Conflict computer game used here. This approach could thus facilitate translational anxiety research.
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Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach-Avoidance Conflict Test
Biological psychiatry, 2017Co-Authors: Christoph W. Korn, Júlia Miró, Lluís Fuentemilla, Johanna Vunder, René Hurlemann, Dominik R. BachAbstract:Rodent Approach-Avoidance Conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed Approach-Avoidance Conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation. In a preregistered, randomized, double-blind, placebo-controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach-Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions. Lorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report. Our results establish the translational validity of human Approach-Avoidance Conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Human Hippocampus Arbitrates Approach-Avoidance Conflict.
Current biology : CB, 2014Co-Authors: Dominik R. Bach, Marc Guitart-masip, Pau A. Packard, Júlia Miró, Mercè Falip, Lluís Fuentemilla, Raymond J. DolanAbstract:Animal models of human anxiety often invoke a Conflict between approach and avoidance. In these, a key behavioral assay comprises passive avoidance of potential threat and inhibition, both thought to be controlled by ventral hippocampus. Efforts to translate these approaches to clinical contexts are hampered by the fact that it is not known whether humans manifest analogous Approach-Avoidance dispositions and, if so, whether they share a homologous neurobiological substrate. Here, we developed a paradigm to investigate the role of human hippocampus in arbitrating an Approach-Avoidance Conflict under varying levels of potential threat. Across four experiments, subjects showed analogous behavior by adapting both passive avoidance behavior and behavioral inhibition to threat level. Using functional magnetic resonance imaging (fMRI), we observe that threat level engages the anterior hippocampus, the human homolog of rodent ventral hippocampus. Testing patients with selective hippocampal lesions, we demonstrate a causal role for the hippocampus with patients showing reduced passive avoidance behavior and inhibition across all threat levels. Our data provide the first human assay for Approach-Avoidance Conflict akin to that of animal anxiety models. The findings bridge rodent and human research on passive avoidance and behavioral inhibition and furnish a framework for addressing the neuronal underpinnings of human anxiety disorders, where our data indicate a major role for the hippocampus.
Ann M. Graybiel - One of the best experts on this subject based on the ideXlab platform.
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Striatal Beta Oscillation and Neuronal Activity in the Primate Caudate Nucleus Differentially Represent Valence and Arousal Under Approach-Avoidance Conflict.
Frontiers in neuroscience, 2020Co-Authors: Ken-ichi Amemori, Satoko Amemori, Daniel J. Gibson, Ann M. GraybielAbstract:An Approach-Avoidance (Ap-Av) Conflict arises when an individual has to decide whether to accept or reject a compound offer that has features indicating both reward and punishment. During value judgments of likes and dislikes, arousal responses simultaneously emerge and influence reaction times and the frequency of behavioral errors. In Ap-Av decision-making, reward and punishment differentially influence valence and arousal, allowing us to dissociate their neural processing. The primate caudate nucleus (CN) has been implicated in affective judgment, but it is still unclear how neural responses in the CN represent decision-related variables underlying choice. To address this issue, we recorded spikes and local field potentials (LFPs) from the CN while macaque monkeys performed an Ap-Av decision-making task. We analyzed 450 neuronal units and 667 beta oscillatory activities recorded during the performance of the task. To examine how these activities represented valence, we focused on beta-band responses and unit activities that encoded the chosen value (ChV) of the compound offer as derived from an econometric model. Unit activities exhibited either positive (65.0% = 26/40) or negative (35.0% = 14/40) correlations with the ChV, whereas beta responses exhibited almost exclusively positive correlations with the ChV (98.4% = 62/63). We examined arousal representation by focusing on beta responses and unit activities that encoded the frequency of omission errors (FOE), which were negatively correlated with arousal. The unit activities were either positively (65.3% = 17/26) or negatively (34.6% = 9/26) correlated with the FOE, whereas the beta responses were almost entirely positively correlated with the FOE (95.8% = 23/24). We found that the temporal onset of the beta-band responses occurred sequentially across conditions: first, the negative-value, then low-arousal, and finally, high-value conditions. These findings suggest the distinctive roles of CN beta oscillations that were sequentially activated for the valence and arousal conditions. By identifying dissociable groups of CN beta-band activity responding in relation to valence and arousal, we demonstrate that the beta responses mainly exhibited selective activation for the high-valence and low-arousal conditions, whereas the unit activities simultaneously recorded in the same experiments responded to chosen value and other features of decision-making under Approach-Avoidance Conflict.
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Approach-Avoidance Conflict in Major Depressive Disorder: Congruent Neural Findings in Humans and Nonhuman Primates
Biological psychiatry, 2019Co-Authors: Maria Ironside, Ken-ichi Amemori, Callie L. Mcgrath, Mads Lund Pedersen, Min Su Kang, Satoko Amemori, Michael J. Frank, Ann M. Graybiel, Diego A. PizzagalliAbstract:Abstract Background Maladaptive Approach-Avoidance behavior has been implicated in the pathophysiology of major depressive disorder (MDD), but the neural basis of these abnormalities in decision making remains unclear. Capitalizing on recent preclinical findings, we adapted an Approach-Avoidance Conflict task from nonhuman primate research for use in human functional magnetic resonance imaging (fMRI). Methods Forty-two female participants, including 18 unmedicated individuals with current MDD (mean age 25.2 ± 5.1 years) and 24 psychiatrically healthy control subjects (mean age 26.3 ± 7.6 years) completed the adapted Approach-Avoidance task during fMRI. To probe potential mechanistic factors underlying the observed behavioral and fMRI findings and to inform interpretation of putative group differences, we examined electrophysiological data from 2 female Macaca mulatta monkeys performing the Approach-Avoidance Conflict task mimicked in the fMRI study. Results Findings demonstrated congruent neural correlates of Approach-Avoidance Conflict and aversive responsiveness in the anterior cingulate cortex, including the pregenual cortex, of human subjects and macaques (humans: p Conclusions Findings indicate that there is conservation of anterior cingulate activation across species and that frontal and striatal regions, in unmedicated humans with MDD, are abnormally responsive during cost-benefit decision making. We suggest that these disruptions could be valuable candidates for translational biomarkers.