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.

Contextual and Temporal Constraints for Attentional Capture: Commentary on Theeuwes' 2023 Review "The Attentional Capture Debate: When Can We Avoid Salient Distractors and when Not?"

Salient distractors demand our attention. Their salience, derived from intensity, relative contrast or learned relevance, captures our limited information capacity. This is typically an adaptive response as salient stimuli may require an immediate change in behaviour. However, sometimes apparent salient distractors do not capture attention. Theeuwes, in his recent commentary, has proposed certain boundary conditions of the visual scene that result in one of two search modes, serial or parallel, that determine whether we can avoid salient distractors or not. Here, we argue that a more complete theory should consider the temporal and contextual factors that influence the very salience of the distractor itself.

Local and global reward learning in the lateral frontal cortex show differential development during human adolescence.

Reward-guided choice is fundamental for adaptive behaviour and depends on several component processes supported by prefrontal cortex. Here, across three studies, we show that two such component processes, linking reward to specific choices and estimating the global reward state, develop during human adolescence and are linked to the lateral portions of the prefrontal cortex. These processes reflect the assignment of rewards contingently to local choices, or noncontingently, to choices that make up the global reward history. Using matched experimental tasks and analysis platforms, we show the influence of both mechanisms increase during adolescence (study 1) and that lesions to lateral frontal cortex (that included and/or disconnected both orbitofrontal and insula cortex) in human adult patients (study 2) and macaque monkeys (study 3) impair both local and global reward learning. Developmental effects were distinguishable from the influence of a decision bias on choice behaviour, known to depend on medial prefrontal cortex. Differences in local and global assignments of reward to choices across adolescence, in the context of delayed grey matter maturation of the lateral orbitofrontal and anterior insula cortex, may underlie changes in adaptive behaviour.

Oxygen and the Spark of Human Brain Evolution: Complex Interactions of Metabolism and Cortical Expansion across Development and Evolution.

Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development-before and after birth and through maturation to adulthood-and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain-favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for neural plasticity sets the conditions for cognitive flexibility and ongoing learning, supporting complex group dynamics and intergenerational learning that in turn enabled improved nutrition to fuel the metabolic costs of further cortical expansion. Our proposed model delineates explicit mechanistic links among metabolism, molecular and cellular brain heterogeneity, and behavior, which may lead toward a clearer understanding of brain development and its disorders.

Characterization of structural and functional network organization after focal prefrontal lesions in humans in proof of principle study.

Lesion research classically maps behavioral effects of focal damage to the directly injured brain region. However, such damage can also have distant effects that can be assessed with modern imaging methods. Furthermore, the combination and comparison of imaging methods in a lesion model may shed light on the biological basis of structural and functional networks in the healthy brain. We characterized network organization assessed with multiple MRI imaging modalities in 13 patients with chronic focal damage affecting either superior or inferior frontal gyrus (SFG, IFG) and 18 demographically matched healthy Controls. We first defined structural and functional network parameters in Controls and then investigated grey matter (GM) and white matter (WM) differences between patients and Controls. Finally, we examined the differences in functional coupling to large-scale resting state networks (RSNs). The results suggest lesions are associated with widespread within-network GM loss at distal sites, yet leave WM and RSNs relatively preserved. Lesions to either prefrontal region also had a similar relative level of impact on structural and functional networks. The findings provide initial evidence for causal contributions of specific prefrontal regions to brain networks in humans that will ultimately help to refine models of the human brain.

10 Simple Rules for a Supportive Lab Environment.

The transition to principal investigator (PI), or lab leader, can be challenging, partially due to the need to fulfil new managerial and leadership responsibilities. One key aspect of this role, which is often not explicitly discussed, is creating a supportive lab environment. Here, we present ten simple rules to guide the new PI in the development of their own positive and thriving lab atmosphere. These rules were written and voted on collaboratively, by the students and mentees of Professor Mark Stokes, who inspired this piece.

Ten simple rules to study distractor suppression.

Distractor suppression refers to the ability to filter out distracting and task-irrelevant information. Distractor suppression is essential for survival and considered a key aspect of selective attention. Despite the recent and rapidly evolving literature on distractor suppression, we still know little about how the brain suppresses distracting information. What limits progress is that we lack mutually agreed upon principles of how to study the neural basis of distractor suppression and its manifestation in behavior. Here, we offer ten simple rules that we believe are fundamental when investigating distractor suppression. We provide guidelines on how to design conclusive experiments on distractor suppression (Rules 1-3), discuss different types of distractor suppression that need to be distinguished (Rules 4-6), and provide an overview of models of distractor suppression and considerations of how to evaluate distractor suppression statistically (Rules 7-10). Together, these rules provide a concise and comprehensive synopsis of promising advances in the field of distractor suppression. Following these rules will propel research on distractor suppression in important ways, not only by highlighting prominent issues to both new and more advanced researchers in the field, but also by facilitating communication between sub-disciplines.

Attentional Control in Subclinical Anxiety and Depression: Depression Symptoms Are Associated With Deficits in Target Facilitation, Not Distractor Inhibition.

Mood and anxiety disorders are associated with deficits in attentional control involving emotive and non-emotive stimuli. Current theories focus on impaired attentional inhibition of distracting stimuli in producing these deficits. However, standard attention tasks struggle to separate distractor inhibition from target facilitation. Here, we investigate whether distractor inhibition underlies these deficits using neutral stimuli in a behavioral task specifically designed to tease apart these two attentional processes. Healthy participants performed a four-location Posner cueing paradigm and completed self-report questionnaires measuring depressive symptoms and trait anxiety. Using regression analyses, we found no relationship between distractor inhibition and mood symptoms or trait anxiety. However, we find a relationship between target facilitation and depression. Specifically, higher depressive symptoms were associated with reduced target facilitation in a task-version in which the target location repeated over a block of trials. We suggest this may relate to findings previously linking depression with deficits in predictive coding in clinical populations.

Behavioral flexibility is associated with changes in structure and function distributed across a frontal cortical network in macaques.

One of the most influential accounts of central orbitofrontal cortex-that it mediates behavioral flexibility-has been challenged by the finding that discrimination reversal in macaques, the classic test of behavioral flexibility, is unaffected when lesions are made by excitotoxin injection rather than aspiration. This suggests that the critical brain circuit mediating behavioral flexibility in reversal tasks lies beyond the central orbitofrontal cortex. To determine its identity, a group of nine macaques were taught discrimination reversal learning tasks, and its impact on gray matter was measured. Magnetic resonance imaging scans were taken before and after learning and compared with scans from two control groups, each comprising 10 animals. One control group learned discrimination tasks that were similar but lacked any reversal component, and the other control group engaged in no learning. Gray matter changes were prominent in posterior orbitofrontal cortex/anterior insula but were also found in three other frontal cortical regions: lateral orbitofrontal cortex (orbital part of area 12 [12o]), cingulate cortex, and lateral prefrontal cortex. In a second analysis, neural activity in posterior orbitofrontal cortex/anterior insula was measured at rest, and its pattern of coupling with the other frontal cortical regions was assessed. Activity coupling increased significantly in the reversal learning group in comparison with controls. In a final set of experiments, we used similar structural imaging procedures and analyses to demonstrate that aspiration lesion of central orbitofrontal cortex, of the type known to affect discrimination learning, affected structure and activity in the same frontal cortical circuit. The results identify a distributed frontal cortical circuit associated with behavioral flexibility.

Selective inhibition of distracting input.

We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience.

Contrasting Effects of Medial and Lateral Orbitofrontal Cortex Lesions on Credit Assignment and Decision-Making in Humans.

The orbitofrontal cortex is critical for goal-directed behavior. Recent work in macaques has suggested the lateral orbitofrontal cortex (lOFC) is relatively more concerned with assignment of credit for rewards to particular choices during value-guided learning, whereas the medial orbitofrontal cortex (often referred to as ventromedial prefrontal cortex in humans; vmPFC/mOFC) is involved in constraining the decision to the relevant options. We examined whether people with damage restricted to subregions of prefrontal cortex showed the patterns of impairment observed in prior investigations of the effects of lesions to homologous regions in macaques. Groups of patients with either lOFC (predominantly right hemisphere), mOFC/vmPFC, or dorsomedial prefrontal (DMF), and a comparison group of healthy age- and education-matched controls performed a probabilistic 3-choice decision-making task. We report anatomically specific patterns of impairment. We found that credit assignment, as indexed by the normal influence of contingent relationships between choice and reward, is reduced in lOFC patients compared with Controls and mOFC/vmPFC patients. Moreover, the effects of reward contingency on choice were similar for patients with lesions in DMF or mOFC/vmPFC, compared with Controls. By contrast, mOFC/vmPFC-lesioned patients made more stochastic choices than Controls when the decision was framed by valuable distracting alternatives, suggesting that value comparisons were no longer independent of irrelevant options. Once again, there was evidence of regional specialization: patients with lOFC lesions were unimpaired relative to Controls. As in macaques, human lOFC and mOFC/vmPFC are necessary for contingent learning and value-guided decision-making, respectively.SIGNIFICANCE STATEMENT The lateral and medial regions of the orbitofrontal cortex are cytoarchitectonically distinct and have different anatomical connections. Previous investigations in macaques have shown these anatomical differences are accompanied by functional specialization for learning and decision-making. Here, for the first time, we test the predictions made by macaque studies in an experiment with humans with frontal lobe lesions, asking whether behavioral impairments can be linked to lateral or medial orbitofrontal cortex. Using equivalent tasks and computational analyses, our findings broadly replicate the pattern reported after selective lesions in monkeys. Patients with lateral orbitofrontal damage had impaired credit assignment, whereas damage to medial orbitofrontal cortex meant that patients were more likely to be distracted by irrelevant options.

Distinct Mechanisms for Distractor Suppression and Target Facilitation.

It is well established that preparatory attention improves processing of task-relevant stimuli. Although it is often more important to ignore task-irrelevant stimuli, comparatively little is known about preparatory attentional mechanisms for inhibiting expected distractions. Here, we establish that distractor inhibition is not under the same top-down control as target facilitation. Using a variant of the Posner paradigm, participants were cued to either the location of a target stimulus, the location of a distractor, or were provided no predictive information. In Experiment 1, we found that participants were able to use target-relevant cues to facilitate target processing in both blocked and flexible conditions, but distractor cueing was only effective in the blocked version of the task. In Experiment 2, we replicate these findings in a larger sample and leveraged the additional statistical power to perform individual differences analyses to tease apart potential underlying mechanisms. We found no evidence for a correlation between these two types of benefit, suggesting that flexible target cueing and distractor suppression depend on distinct cognitive mechanisms. In Experiment 3, we use EEG to show that preparatory distractor suppression is associated with a diminished P1, but we found no evidence to suggest that this effect was mediated by top-down control of oscillatory activity in the alpha band (8-12 Hz). We conclude that flexible top-down mechanisms of cognitive control are specialized for target-related attention, whereas distractor suppression only emerges when the predictive information can be derived directly from experience. This is consistent with a predictive coding model of expectation suppression. SIGNIFICANCE STATEMENT: If you were told to ignore a white bear, you might find it quite difficult. Holding something in working memory is thought to automatically facilitate feature processing, even if doing so is detrimental to the current task. Despite this paradox, it is often assumed that distractor suppression is controlled via similar top-down mechanisms of attention that prepare brain areas for target enhancement. In particular, low-frequency oscillations in visual cortex appear especially well suited for gating task-irrelevant information. We describe the results of a series of studies exploring distractor suppression and challenge this popular notion. We draw on behavioral and EEG evidence to show that selective distractor suppression operates via an alternative mechanism, such as expectation suppression within a predictive coding framework.

The extreme capsule fiber complex in humans and macaque monkeys: a comparative diffusion MRI tractography study.

We compared the course and cortical projections of white matter fibers passing through the extreme capsule in humans and macaques. Previous comparisons of this tract have suggested a uniquely human posterior projection, but these studies have always employed different techniques in the different species. Here we used the same technique, diffusion MRI, in both species to avoid attributing differences in techniques to differences in species. Diffusion MRI-based probabilistic tractography was performed from a seed area in the extreme capsule in both human and macaques. We compared in vivo data of humans and macaques as well as one high-resolution ex vivo macaque dataset. Tractography in the macaque was able to replicate most results known from macaque tracer studies, including selective innervation of frontal cortical areas and targets in the superior temporal cortex. In addition, however, we also observed some tracts that are not commonly reported in macaque tracer studies and that are more reminiscent of results previously only reported in the human. In humans, we show that the ventrolateral prefrontal cortex innervations are broadly similar to those in the macaque. These results suggest that evolutionary changes in the human extreme capsule fiber complex are likely more gradual than punctuated. Further, they demonstrate both the potential and limitations of diffusion MRI tractography.

Contrasting Roles for Orbitofrontal Cortex and Amygdala in Credit Assignment and Learning in Macaques.

Recent studies have challenged the view that orbitofrontal cortex (OFC) and amygdala mediate flexible reward-guided behavior. We trained macaques to perform an object discrimination reversal task during fMRI sessions and identified a lateral OFC (lOFC) region in which activity predicted adaptive win-stay/lose-shift behavior. Amygdala and lOFC activity was more strongly coupled on lose-shift trials. However, lOFC-amygdala coupling was also modulated by the relevance of reward information in a manner consistent with a role in establishing how credit for reward should be assigned. Day-to-day fluctuations in signals and signal coupling were correlated with day-to-day fluctuation in performance. A second experiment confirmed the existence of signals for adaptive stay/shift behavior in lOFC and reflecting irrelevant reward in the amygdala in a probabilistic learning task. Our data demonstrate that OFC and amygdala each make unique contributions to flexible behavior and credit assignment.

Testing the inter-hemispheric competition account of visual extinction with combined TMS/fMRI.

Theoretical models of visual neglect and extinction entail claims about the normal functioning of attention and parietal cortex in the healthy brain: (1) 'pseudoneglect', a commonly observed attentional bias towards left space, reflects the greater dominance of parietal cortex activity of the right versus left hemisphere; (2) the capacity to distribute attention bilaterally depends causally on the relative balance of parietal activity between the hemispheres; (3) disruption of the dominant right parietal cortex shifts this inter-hemispheric balance leftward, causing a rightward shift in attentional bias. We tested these claims using low-frequency offline transcranial magnetic stimulation (TMS) to transiently inhibit activity in the right angular gyrus/intra-parietal sulcus, followed by a visual detection task to assess changes in attentional bias, and functional magnetic resonance imaging (fMRI) to test for the predicted leftward shift in brain activity. The task required participants to covertly monitor both hemifields to detect and report the location of upcoming transient visual targets that appeared on the left, right or bilaterally. In the behavioural experiment, participants exhibited a leftward attentional bias ('pseudoneglect') at baseline, which was abolished by TMS. In the fMRI experiment, participants activated an expected network of visual, parietal and frontal cortex bilaterally during the period of covert bilateral attention. TMS shifted the relative hemispheric balance of parietal activity from right to left. The consistent direction of TMS-induced behavioural and functional change indicates a causal role for parietal inter-hemispheric balance in distributing visual attention across space.

A neural circuit covarying with social hierarchy in macaques.

Despite widespread interest in social dominance, little is known of its neural correlates in primates. We hypothesized that social status in primates might be related to individual variation in subcortical brain regions implicated in other aspects of social and emotional behavior in other mammals. To examine this possibility we used magnetic resonance imaging (MRI), which affords the taking of quantitative measurements noninvasively, both of brain structure and of brain function, across many regions simultaneously. We carried out a series of tests of structural and functional MRI (fMRI) data in 25 group-living macaques. First, a deformation-based morphometric (DBM) approach was used to show that gray matter in the amygdala, brainstem in the vicinity of the raphe nucleus, and reticular formation, hypothalamus, and septum/striatum of the left hemisphere was correlated with social status. Second, similar correlations were found in the same areas in the other hemisphere. Third, similar correlations were found in a second data set acquired several months later from a subset of the same animals. Fourth, the strength of coupling between fMRI-measured activity in the same areas was correlated with social status. The network of subcortical areas, however, had no relationship with the sizes of individuals' social networks, suggesting the areas had a simple and direct relationship with social status. By contrast a second circuit in cortex, comprising the midsuperior temporal sulcus and anterior and dorsal prefrontal cortex, covaried with both individuals' social statuses and the social network sizes they experienced. This cortical circuit may be linked to the social cognitive processes that are taxed by life in more complex social networks and that must also be used if an animal is to achieve a high social status.

Causal effect of disconnection lesions on interhemispheric functional connectivity in rhesus monkeys.

In the absence of external stimuli or task demands, correlations in spontaneous brain activity (functional connectivity) reflect patterns of anatomical connectivity. Hence, resting-state functional connectivity has been used as a proxy measure for structural connectivity and as a biomarker for brain changes in disease. To relate changes in functional connectivity to physiological changes in the brain, it is important to understand how correlations in functional connectivity depend on the physical integrity of brain tissue. The causal nature of this relationship has been called into question by patient data suggesting that decreased structural connectivity does not necessarily lead to decreased functional connectivity. Here we provide evidence for a causal but complex relationship between structural connectivity and functional connectivity: we tested interhemispheric functional connectivity before and after corpus callosum section in rhesus monkeys. We found that forebrain commissurotomy severely reduced interhemispheric functional connectivity, but surprisingly, this effect was greatly mitigated if the anterior commissure was left intact. Furthermore, intact structural connections increased their functional connectivity in line with the hypothesis that the inputs to each node are normalized. We conclude that functional connectivity is likely driven by corticocortical white matter connections but with complex network interactions such that a near-normal pattern of functional connectivity can be maintained by just a few indirect structural connections. These surprising results highlight the importance of network-level interactions in functional connectivity and may cast light on various paradoxical findings concerning changes in functional connectivity in disease states.

The organization of dorsal frontal cortex in humans and macaques.

The human dorsal frontal cortex has been associated with the most sophisticated aspects of cognition, including those that are thought to be especially refined in humans. Here we used diffusion-weighted magnetic resonance imaging (DW-MRI) and functional MRI (fMRI) in humans and macaques to infer and compare the organization of dorsal frontal cortex in the two species. Using DW-MRI tractography-based parcellation, we identified 10 dorsal frontal regions lying between the human inferior frontal sulcus and cingulate cortex. Patterns of functional coupling between each area and the rest of the brain were then estimated with fMRI and compared with functional coupling patterns in macaques. Areas in human medial frontal cortex, including areas associated with high-level social cognitive processes such as theory of mind, showed a surprising degree of similarity in their functional coupling patterns with the frontal pole, medial prefrontal, and dorsal prefrontal convexity in the macaque. We failed to find evidence for "new" regions in human medial frontal cortex. On the lateral surface, comparison of functional coupling patterns suggested correspondences in anatomical organization distinct from those that are widely assumed. A human region sometimes referred to as lateral frontal pole more closely resembled area 46, rather than the frontal pole, of the macaque. Overall the pattern of results suggest important similarities in frontal cortex organization in humans and other primates, even in the case of regions thought to carry out uniquely human functions. The patterns of interspecies correspondences are not, however, always those that are widely assumed.

On the relationship between the "default mode network" and the "social brain".

The default mode network (DMN) of the brain consists of areas that are typically more active during rest than during active task performance. Recently however, this network has been shown to be activated by certain types of tasks. Social cognition, particularly higher-order tasks such as attributing mental states to others, has been suggested to activate a network of areas at least partly overlapping with the DMN. Here, we explore this claim, drawing on evidence from meta-analyses of functional MRI data and recent studies investigating the structural and functional connectivity of the social brain. In addition, we discuss recent evidence for the existence of a DMN in non-human primates. We conclude by discussing some of the implications of these observations.

Giving credit where credit is due: orbitofrontal cortex and valuation in an uncertain world.

The orbitofrontal cortex (OFC) has long been implicated in aspects of learning and adaptive decision making in changeable environments, but its precise role has remained elusive. One potential reason is that anatomical and functional distinctions within the OFC have often been overlooked. Here, we review findings centered largely on recent lesion studies in macaque monkeys from our laboratories that have investigated the causal role of the lateral and medial parts of the OFC (LOFC and MOFC) in choice behavior in uncertain, multioption environments. MOFC appears necessary for focusing attention on only the relevant decision variables to achieve a goal. By contrast, LOFC is required to allow rapid learning in changeable environments by enabling the credit for a particular outcome to be assigned to a specific choice.