Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia.

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

What does preferential viewing tell us about the neurobiology of recognition memory?

The two tests most widely used in nonhuman primates to assess the neurobiology of recognition memory produce conflicting results. Preferential viewing tests (e.g., visual paired comparison) produce robust impairments following hippocampal lesions, whereas matching tests (e.g., delayed nonmatching-to-sample) often show complete sparing. Here, we review the data, the proposed explanations for this discrepancy, and then critically evaluate those explanations. The most likely explanation is that preferential viewing tests are not a process-pure assessment of recognition memory, but also test elements of novelty-seeking, habituation, and motivation. These confounds likely explain the conflicting results. Thus, we propose that memory researchers should prefer explicit matching tests and readers interested in the neural substrates of recognition memory should give explicit matching tests greater interpretive weight.

Prefrontal-Amygdala Pathways for Object and Social Value Representation.

This special focus article was prepared to honor the memory of our National Institutes of Health colleague, friend, and mentor Leslie G. Ungerleider, who passed away in December 2020, and is based on a presentation given at a symposium held in her honor at the National Institutes of Health in September 2022. In this article, we describe an extension of Leslie Ungerleider's influential work on the object analyzer pathway in which the inferior temporal visual cortex interacts with the amygdala, and then discuss a broader role for the amygdala in stimulus-outcome associative learning in humans and nonhuman primates. We summarize extant data from our and others' laboratories regarding two distinct frontal-amygdala circuits that subserve nonsocial and social valuation processes. Both neuropsychological and neurophysiological data suggest a role for the OFC in nonsocial valuation and the ACC in social valuation. More recent evidence supports the possibility that the amygdala functions in conjunction with these frontal regions to subserve these distinct, complex valuation processes. We emphasize the dynamic nature of valuation processes and advocate for additional research on amygdala-frontal interactions in these domains.

Motor System-Dependent Effects of Amygdala and Ventral Striatum Lesions on Explore-Exploit Behaviors.

Deciding whether to forego immediate rewards or explore new opportunities is a key component of flexible behavior and is critical for the survival of the species. Although previous studies have shown that different cortical and subcortical areas, including the amygdala and ventral striatum (VS), are implicated in representing the immediate (exploitative) and future (explorative) value of choices, the effect of the motor system used to make choices has not been examined. Here, we tested male rhesus macaques with amygdala or VS lesions on two versions of a three-arm bandit task where choices were registered with either a saccade or an arm movement. In both tasks we presented the monkeys with explore-exploit tradeoffs by periodically replacing familiar options with novel options that had unknown reward probabilities. We found that monkeys explored more with saccades but showed better learning with arm movements. VS lesions caused the monkeys to be more explorative with arm movements and less explorative with saccades, although this may have been due to an overall decrease in performance. VS lesions affected the monkeys' ability to learn novel stimulus-reward associations in both tasks, while after amygdala lesions this effect was stronger when choices were made with saccades. Further, on average, VS and amygdala lesions reduced the monkeys' ability to choose better options only when choices were made with a saccade. These results show that learning reward value associations to manage explore-exploit behaviors is motor system dependent and they further define the contributions of amygdala and VS to reinforcement learning.

The amygdala is not necessary for the familiarity aspect of recognition memory.

Dual-process accounts of item recognition posit two memory processes: slow but detailed recollection, and quick but vague familiarity. It has been proposed, based on prior rodent work, that the amygdala is critical for the familiarity aspect of item recognition. Here, we evaluated this proposal in male rhesus monkeys (Macaca mulatta) with selective bilateral excitotoxic amygdala damage. We used four established visual memory tests designed to assess different aspects of familiarity, all administered on touchscreen computers. Specifically, we assessed monkeys' tendencies to make low-latency false alarms, to make false alarms to recently seen lures, to produce curvilinear ROC curves, and to discriminate stimuli based on repetition across days. Three of the four tests showed no familiarity impairment and the fourth was explained by a deficit in reward processing. Consistent with this, amygdala damage did produce an anticipated deficit in reward processing in a three-arm-bandit gambling task, verifying the effectiveness of the lesions. Together, these results contradict prior rodent work and suggest that the amygdala is not critical for the familiarity aspect of item recognition.

Prefrontal influences on the function of the neural circuitry underlying anxious temperament in primates.

Anxious temperament, characterized by heightened behavioral and physiological reactivity to potential threat, is an early childhood risk factor for the later development of stress-related psychopathology. Using a well-validated nonhuman primate model, we tested the hypothesis that the prefrontal cortex (PFC) is critical in regulating the expression of primate anxiety-like behavior, as well as the function of subcortical components of the anxiety-related neural circuit. We performed aspiration lesions of a narrow 'strip' of the posterior orbitofrontal cortex (OFC) intended to disrupt both cortex and axons entering, exiting and coursing through the pOFC, particularly those of the uncinate fasciculus (UF), a white matter tract that courses adjacent to and through this region. The OFC is of particular interest as a potential regulatory region because of its extensive reciprocal connections with amygdala, other subcortical structures and other frontal lobe regions. We validated this lesion method by demonstrating marked lesion-induced decreases in the microstructural integrity of the UF, which contains most of the fibers that connect the ventral PFC with temporal lobe structures as well as with other frontal regions. While the lesions resulted in modest decreases in threat-related behavior, they substantially decreased metabolism in components of the circuit underlying threat processing. These findings provide evidence for the importance of structural connectivity between the PFC and key subcortical structures in regulating the functions of brain regions known to be involved in the adaptive and maladaptive expression of anxiety.

The motivational role of the ventral striatum and amygdala in learning from gains and losses.

The ventral striatum (VS) and amygdala are two structures often implicated as essential structures for learning. The literature addressing the contribution of these areas to learning, however, is not entirely consistent. We propose that these inconsistencies are due to learning environments and the effect they have on motivation. To differentiate aspects of learning from environmental factors that affect motivation, we ran a series of experiments with varying task factors. We compared monkeys (Macaca mulatta) with VS lesions, amygdala lesions, and unoperated controls on reinforcement learning (RL) tasks that involve learning from both gains and losses as well as from deterministic and stochastic schedules of reinforcement. We found that for all three groups, performance varied by experiment. All three groups modulated their behavior in the same directions, to varying degrees, across the three experiments. This behavioral modulation is why we find deficits in some experiments, but not others. The amount of effort animals exhibited differed depending on the learning environment. Our results suggest that the VS is important for the amount of effort animals will give in rich deterministic and relatively leaner stochastic learning enivornments. We also showed that monkeys with amygdala lesions can learn stimulus-based RL in stochastic environments and environments with loss and conditioned reinforcers. These results show that learning environments shape motivation and that the VS is essential for distinct aspects of motivated behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reevaluating the role of the hippocampus in memory: A meta-analysis of neurotoxic lesion studies in nonhuman primates.

The hippocampus and perirhinal cortex are both broadly implicated in memory; nevertheless, their relative contributions to visual item recognition and location memory remain disputed. Neuropsychological studies in nonhuman primates that examine memory function after selective damage to medial temporal lobe structures report various levels of memory impairment-ranging from minor deficits to profound amnesia. The discrepancies in published findings have complicated efforts to determine the exact magnitude of visual item recognition and location memory impairments following damage to the hippocampus and/or perirhinal cortex. To provide the most accurate estimate to date of the overall effect size, we use meta-analytic techniques on data aggregated from 26 publications that assessed visual item recognition and/or location memory in nonhuman primates with and without selective neurotoxic lesions of the hippocampus or perirhinal cortex. We estimated the overall effect size, evaluated the relation between lesion extent and effect size, and investigated factors that may account for between-study variation. Grouping studies by lesion target and testing method, separate meta-analyses were conducted. One meta-analysis indicated that impairments on tests of visual item recognition were larger after lesions of perirhinal cortex than after lesions of the hippocampus. A separate meta-analysis showed that performance on tests of location memory was severely impaired by lesions of the hippocampus. For the most part, meta-regressions indicated that greater impairment corresponds with greater lesion extent; paradoxically, however, more extensive hippocampal lesions predicted smaller impairments on tests of visual item recognition. We conclude the perirhinal cortex makes a larger contribution than the hippocampus to visual item recognition, and the hippocampus predominately contributes to spatial navigation.

Attention to Stimuli of Learned versus Innate Biological Value Relies on Separate Neural Systems.

The neural bases of attention, a set of neural processes that promote behavioral selection, is a subject of intense investigation. In humans, rewarded cues influence attention, even when those cues are irrelevant to the current task. Because the amygdala plays a role in reward processing, and the activity of amygdala neurons has been linked to spatial attention, we reasoned that the amygdala may be essential for attending to rewarded images. To test this possibility, we used an attentional capture task, which provides a quantitative measure of attentional bias. Specifically, we compared reaction times (RTs) of adult male rhesus monkeys with bilateral amygdala lesions and unoperated controls as they made a saccade away from a high- or low-value rewarded image to a peripheral target. We predicted that: (1) RTs will be longer for high- compared with low-value images, revealing attentional capture by rewarded stimuli; and (2) relative to controls, monkeys with amygdala lesions would exhibit shorter RT for high-value images. For comparison, we assessed the same groups of monkeys for attentional capture by images of predators and conspecifics, categories thought to have innate biological value. In performing the attentional capture task, all monkeys were slowed more by high-value relative to low-value rewarded images. Contrary to our prediction, amygdala lesions failed to disrupt this effect. When presented with images of predators and conspecifics, however, monkeys with amygdala lesions showed significantly diminished attentional capture relative to controls. Thus, separate neural pathways are responsible for allocating attention to stimuli with learned versus innate value.SIGNIFICANCE STATEMENT Valuable objects attract attention. The amygdala is known to contribute to reward processing and the encoding of object reward value. We therefore examined whether the amygdala is necessary for allocating attention to rewarded objects. For comparison, we assessed the amygdala's contribution to attending to objects with innate biological value: predators and conspecifics. We found that the macaque amygdala is necessary for directing attention to images with innate biological value, but not for directing attention to recently learned reward-predictive images. These findings indicate that the amygdala makes selective contributions to attending to valuable objects. The data are relevant to mental health disorders, such as social anxiety disorders and small animal phobias, that arise from biased attention to select categories of objects.

Selective prefrontal-amygdala circuit interactions underlie social and nonsocial valuation in rhesus macaques.

Lesion studies in macaques suggest dissociable functions of the orbitofrontal cortex (OFC) and medial frontal cortex (MFC), with OFC being essential for goal-directed decision making and MFC supporting social cognition. Bilateral amygdala damage results in impairments in both of these domains. There are extensive reciprocal connections between these prefrontal areas and the amygdala; however, it is not known whether the dissociable roles of OFC and MFC depend on functional interactions with the amygdala. To test this possibility, we compared the performance of male rhesus macaques (Macaca mulatta) with crossed surgical disconnection of the amygdala and either MFC (MFC x AMY, n=4) or OFC (OFC x AMY, n=4) to a group of unoperated controls (CON, n=5). All monkeys were assessed for their performance on two tasks to measure: (1) food-retrieval latencies while viewing videos of social and nonsocial stimuli in a test of social interest, and (2) object choices based on current food value using reinforcer devaluation in a test of goal-directed decision making. Compared to the CON group, the MFC x AMY group, but not the OFC x AMY group, showed significantly reduced food-retrieval latencies while viewing videos of conspecifics, indicating reduced social valuation and/or interest. By contrast, on the devaluation task, group OFC x AMY, but not group MFC x AMY, displayed deficits on object choices following changes in food value. These data indicate that the MFC and OFC must functionally interact with the amygdala to support normative social and nonsocial valuation, respectively.Significance StatementAscribing value to conspecifics (social) vs. objects (nonsocial) may be supported by distinct but overlapping brain networks. Here we test whether two nonoverlapping regions of the prefrontal cortex, the medial frontal cortex and the orbitofrontal cortex, must causally interact with the amygdala to sustain social valuation and goal-directed decision making, respectively. We found that these prefrontal-amygdala circuits are functionally dissociable, lending support for the idea that medial frontal and orbital frontal cortex make independent contributions to cognitive appraisals of the environment. These data provide a neural framework for distinct value assignment processes and may enhance our understanding of the cognitive deficits observed following brain injury or in the development of mental health disorders.

Prefrontal cortex interactions with the amygdala in primates.

This review addresses functional interactions between the primate prefrontal cortex (PFC) and the amygdala, with emphasis on their contributions to behavior and cognition. The interplay between these two telencephalic structures contributes to adaptive behavior and to the evolutionary success of all primate species. In our species, dysfunction in this circuitry creates vulnerabilities to psychopathologies. Here, we describe amygdala-PFC contributions to behaviors that have direct relevance to Darwinian fitness: learned approach and avoidance, foraging, predator defense, and social signaling, which have in common the need for flexibility and sensitivity to specific and rapidly changing contexts. Examples include the prediction of positive outcomes, such as food availability, food desirability, and various social rewards, or of negative outcomes, such as threats of harm from predators or conspecifics. To promote fitness optimally, these stimulus-outcome associations need to be rapidly updated when an associative contingency changes or when the value of a predicted outcome changes. We review evidence from nonhuman primates implicating the PFC, the amygdala, and their functional interactions in these processes, with links to experimental work and clinical findings in humans where possible.

Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex.

Decision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted "U" relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased, and the relationship between HR and RTs was altered. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a population-coding analysis, we show that after bilateral amygdala lesions, the balance of encoding in dACC is skewed away from signaling either reward value or choice direction toward HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex.

Autonomic arousal tracks outcome salience not valence in monkeys making social decisions.

The evolutionary and neural underpinnings of human prosociality are still being identified. A growing body of evidence suggests that some species find the sight of another individual receiving a reward reinforcing, called vicarious reinforcement, and that this capacity is supported by a network of brain areas including the anterior cingulate cortex (ACC) and the amygdala. At the same time, analyses of autonomic arousal have been increasingly used to contextualize and guide neural research, especially for studies of reward processing. Here, we characterized the autonomic pupil response of eight monkeys across two laboratories in two different versions of a vicarious reinforcement paradigm. Monkeys were cued as to whether an upcoming reward would be delivered to them, another monkey, or nobody and could accept or decline the offer. As expected, all monkeys in both laboratories showed a marked preference for juice to the self, together with a reliable prosocial preference for juice to a social partner compared to juice to nobody. However, contrary to our expectations, we found that pupils were widest in anticipation of juice to the self, moderately sized in anticipation of juice to nobody, and narrowest in anticipation of juice to a social partner. This effect was seen across both laboratories and regardless of specific task parameters. The seemingly paradoxical pupil effect can be explained by a model in which pupil size tracks outcome salience, prosocial tendencies track outcome valence, and the relation between salience and valence is U-shaped. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial.

IMPORTANCE: Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking. OBJECTIVE: To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)-negative primary breast cancer. DESIGN, SETTING, AND PARTICIPANTS: The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020. INTERVENTIONS: Patients received celecoxib, 400 mg, or placebo once daily for 2 years. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete. RESULTS: A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients' tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rank P = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years' treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02429427 and isrctn.org Identifier: ISRCTN48254013.

The magical orbitofrontal cortex.

This special issue, commissioned after the 4th Quadrennial Meeting on Orbitofrontal Cortex Function held in Paris in November of 2019 (https://ofc2019.sciencesconf.org/), is intended to provide a snapshot of this ongoing transformation; we hope that the ideas presented herein will provide a foundation for the next stage in the evolution of our understanding of this magical brain region. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Evolution, Emotion, and Episodic Engagement.

Although rodent research provides important insights into neural correlates of human psychology, new cortical areas, connections, and cognitive abilities emerged during primate evolution, including human evolution. Comparison of human brains with those of nonhuman primates reveals two aspects of human brain evolution particularly relevant to emotional disorders: expansion of homotypical association areas and expansion of the hippocampus. Two uniquely human cognitive capacities link these phylogenetic developments with emotion: a subjective sense of participating in and reexperiencing remembered events and a limitless capacity to imagine details of future events. These abilities provided evolving humans with selective advantages, but they also created proclivities for emotional problems. The first capacity evokes the "reliving" of past events in the "here-and-now," accompanied by emotional responses that occurred during memory encoding. It contributes to risk for stress-related syndromes, such as posttraumatic stress disorder. The second capacity, an ability to imagine future events without temporal limitations, facilitates flexible, goal-related behavior by drawing on and creating a uniquely rich array of mental representations. It promotes goal achievement and reduces errors, but the mental construction of future events also contributes to developmental aspects of anxiety and mood disorders. With maturation of homotypical association areas, the concrete concerns of childhood expand to encompass the abstract apprehensions of adolescence and adulthood. These cognitive capacities and their dysfunction are amenable to a research agenda that melds experimental therapeutic interventions, cognitive neuropsychology, and developmental psychology in both humans and nonhuman primates.

The visual prefrontal cortex of anthropoids: interaction with temporal cortex in decision making and its role in the making of "visual animals".

The ventral prefrontal cortex (PFC) of primates-a region strongly implicated in decision making-receives highly processed visual sensory inputs from the inferior temporal cortex (ITC) and perirhinal cortex (PRC) and can therefore be considered visual PFC. Usually, the functions of temporal cortex and visual PFC have been discussed in separate literatures. By considering them together, we aim to clarify the ways in which fronto-temporal networks guide decision making. After discussing the ways in which visual PFC interacts with temporal cortex to promote decision making, we offer specific predictions about the selective roles of the ITC- and PRC-based fronto-temporal networks. Finally, we suggest that an increased reliance on visual PFC in anthropoid primates led to our emergence as 'visual' animals.

No evidence that monkeys attribute mental states to animated shapes in the Heider-Simmel videos.

Human Theory of Mind (ToM) is so automatic and pervasive that we spontaneously attribute mental states to animated abstract shapes, as evidenced by the classic Heider-Simmel findings. The extent to which this represents a fundamental characteristic of primate social cognition is debated. Prior research suggests that monkeys spontaneously predict behavior and attribute basic goals to conspecifics, but it remains unclear whether, like humans, they spontaneously ascribe mental states to animated shapes. Here, we address this question by analyzing rhesus monkeys' viewing patterns of the classic Heider-Simmel animations. We hypothesized that if rhesus monkeys also spontaneously attribute mental states to animated shapes, then, like humans, they would have the longest fixation durations for theory of mind animations, medium duration fixation for goal-directed animations, and shortest fixations for animations with random motion. In contrast, if attributing mental states to animations is specific to humans and perhaps other apes, then we predict no differences in looking time across animation categories. Unlike humans, monkeys did not fixate longer on ToM videos. Critically, monkeys' viewing patterns did not correlate with humans' viewing patterns or intentionality ratings from previously published research. The only major difference in viewing patterns between animation categories tracked differences in low-level visual motion. Thus, monkeys do not view the classic Heider-Simmel animations like humans do and we found no evidence that they spontaneously attribute mental states to animated shapes.

Effects of Amygdala Lesions on Object-Based Versus Action-Based Learning in Macaques.

The neural systems that underlie reinforcement learning (RL) allow animals to adapt to changes in their environment. In the present study, we examined the hypothesis that the amygdala would have a preferential role in learning the values of visual objects. We compared a group of monkeys (Macaca mulatta) with amygdala lesions to a group of unoperated controls on a two-armed bandit reversal learning task. The task had two conditions. In the What condition, the animals had to learn to select a visual object, independent of its location. And in the Where condition, the animals had to learn to saccade to a location, independent of the object at the location. In both conditions choice-outcome mappings reversed in the middle of the block. We found that monkeys with amygdala lesions had learning deficits in both conditions. Monkeys with amygdala lesions did not have deficits in learning to reverse choice-outcome mappings. Rather, amygdala lesions caused the monkeys to become overly sensitive to negative feedback which impaired their ability to consistently select the more highly valued action or object. These results imply that the amygdala is generally necessary for RL.