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Cognitive and neural mechanisms underlying bipolar disorder (BD) and its treatment are still poorly understood. Here we examined the role of adaptations in risk-taking using a reward-guided decision-making task. We recruited volunteers with high (n = 40) scores on the Mood Disorder Questionnaire, MDQ, suspected of high risk for bipolar disorder and those with low-risk scores (n = 37). We also recruited patients diagnosed with BD who were assigned (randomized, double-blind) to six weeks of lithium (n = 19) or placebo (n = 16) after a two-week baseline period (n = 22 for FMRI). Participants completed mood ratings daily over 50 (MDQ study) or 42 (BD study) days, as well as a risky decision-making task and functional magnetic resonance imaging. The task measured adaptation of risk taking to past outcomes (increased risk aversion after a previous win vs. loss, 'outcome history'). While the low MDQ group was risk averse after a win, this was less evident in the high MDQ group and least so in the patients with BD. During fMRI, 'outcome history' was linked to medial frontal pole activation at the time of the decision and this activation was reduced in the high risk MDQ vs. the low risk MDQ group. While lithium did not reverse the pattern of BD in the task, nor changed clinical symptoms of mania or depression, it changed reward processing in the dorsolateral prefrontal cortex. Participants' modulation of risk-taking in response to reward outcomes was reduced as a function of risk for BD and diagnosed BD. These results provide a model for how reward may prime escalation of risk-related behaviours in bipolar disorder and how mood stabilising treatments may work., Competing Interests: Competing interests: The study was funded by a Wellcome Trust Strategic Award (CONBRIO: Collaborative Oxford Network for Bipolar Research to Improve Outcomes, reference No. 102,616/Z). JRG, CJH, PJH and KEAS are supported by the Oxford Health NIHR Biomedical Research Centre. MFSR is funded by the Wellcome Trust (221794/Z/20/Z). The Wellcome Centre for Integrative Neuroimaging is supported by core funding from the Wellcome Trust (203139/Z/16/Z). JS has been funded by the Institut National de la Santé et de la Recherche Médicale, the Biotechnology and Biological Sciences Research Council (BB/V004999/1, Discovery Fellowship) and Medical Research Council (MR/N014448/1, Skills Development Fellowship). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. JS, PP, NN, LZA, NK, JG, MFSR report no biomedical financial interests or potential conflicts of interest. CJH has received consultancy payments from P1vital, Lundbeck, Compass Pathways, IESO, Zogenix (now UCB). PJH reports receiving an honorarium for editorial work for Biological Psychiatry and Biological Psychiatry Global Open Science. ACN was non-executive director at the Oxford Health Foundation Trust during a period overlapping with the study. KEAS has received consultancy payment from Yale University., (© 2025. The Author(s).)

The value of a third potential option or distractor can alter the way in which decisions are made between two other options. Two hypotheses have received empirical support: that a high value distractor improves the accuracy with which decisions between two other options are made and that it impairs accuracy. Recently, however, it has been argued that neither observation is replicable. Inspired by neuroimaging data showing that high value distractors have different impacts on prefrontal and parietal regions, we designed a dual route decision-making model that mimics the neural signals of these regions. Here we show in the dual route model and empirical data that both enhancement and impairment effects are robust phenomena but predominate in different parts of the decision space defined by the options' and the distractor's values. However, beyond these constraints, both effects co-exist under similar conditions. Moreover, both effects are robust and observable in six experiments., Competing Interests: BC, CL, AL, MK, MR No competing interests declared, (© 2020, Chau et al.)

To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique. To date, investigations report short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting 'offline' changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 s of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS caused stimulated areas to interact more selectively with the rest of the brain. In a within-subject design, we observe regionally specific TUS effects for two medial frontal brain regions - supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes., Competing Interests: LV, CG, DF, CC, DJ, HA, LR, MS, BA, SL, MK, KK, RM, MR, PP, JA, JS No competing interests declared, (© 2019, Verhagen et al.)

The search for the anatomical basis of language has traditionally been a search for specializations. More recently such research has focused both on aspects of brain organization that are unique to humans and aspects shared with other primates. This work has mostly concentrated on the architecture of connections between brain areas. However, as specializations can take many guises, comparison of anatomical organization across species is often complicated. We demonstrate how viewing different types of specializations within a common framework allows one to better appreciate both shared and unique aspects of brain organization. We illustrate this point by discussing recent insights into the anatomy of the dorsal language pathway to the frontal cortex and areas for laryngeal control in the motor cortex., Competing Interests: Conflict of interest statement Nothing declared.

To make good decisions, humans need to learn about and integrate different sources of appetitive and aversive information. While serotonin has been linked to value-based decision-making, its role in learning is less clear, with acute manipulations often producing inconsistent results. Here, we show that when the effects of a selective serotonin reuptake inhibitor (SSRI, citalopram) are studied over longer timescales, learning is robustly improved. We measured brain activity with functional magnetic resonance imaging (fMRI) in volunteers as they performed a concurrent appetitive (money) and aversive (effort) learning task. We found that 2 weeks of citalopram enhanced reward and effort learning signals in a widespread network of brain regions, including ventromedial prefrontal and anterior cingulate cortex. At a behavioral level, this was accompanied by more robust reward learning. This suggests that serotonin can modulate the ability to learn via a mechanism that is independent of stimulus valence. Such effects may partly underlie SSRIs' impact in treating psychological illnesses. Our results highlight both a specific function in learning for serotonin and the importance of studying its role across longer timescales.

Dorsal anterior cingulate cortex (dACC) mediates updating and maintenance of cognitive models of the world used to drive adaptive reward-guided behavior. We investigated the neurochemical underpinnings of this process. We used magnetic resonance spectroscopy in humans, to measure levels of glutamate and GABA in dACC. We examined their relationship to neural signals in dACC, measured with fMRI, and cognitive task performance. Both inhibitory and excitatory neurotransmitters in dACC were predictive of the strength of neural signals in dACC and behavioral adaptation. Glutamate levels were correlated, first, with stronger neural activity representing information to be learnt about the tasks' costs and benefits and, second, greater use of this information in the guidance of behavior. GABA levels were negatively correlated with the same neural signals and the same indices of behavioral influence. Our results suggest that glutamate and GABA in dACC affect the encoding and use of past experiences to guide behavior., Competing Interests: The authors declare that no competing interests exist.

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., Competing Interests: The authors declare no competing financial interests.

Dorsal anterior cingulate cortex (dACC) carries a wealth of value-related information necessary for regulating behavioral flexibility and persistence. It signals error and reward events informing decisions about switching or staying with current behavior. During decision-making, it encodes the average value of exploring alternative choices (search value), even after controlling for response selection difficulty, and during learning, it encodes the degree to which internal models of the environment and current task must be updated. dACC value signals are derived in part from the history of recent reward integrated simultaneously over multiple time scales, thereby enabling comparison of experience over the recent and extended past. Such ACC signals may instigate attentionally demanding and difficult processes such as behavioral change via interactions with prefrontal cortex. However, the signal in dACC that instigates behavioral change need not itself be a conflict or difficulty signal.

In many natural environments the value of a choice gradually gets better or worse as circumstances change. Discerning such trends makes predicting future choice values possible. We show that humans track such trends by comparing estimates of recent and past reward rates, which they are able to hold simultaneously in the dorsal anterior cingulate cortex (dACC). Comparison of recent and past reward rates with positive and negative decision weights is reflected by opposing dACC signals indexing these quantities. The relative strengths of time-linked reward representations in dACC predict whether subjects persist in their current behaviour or switch to an alternative. Computationally, trend-guided choice can be modelled by using a reinforcement-learning mechanism that computes a longer-term estimate (or expectation) of prediction errors. Using such a model, we find a relative predominance of expected prediction errors in dACC, instantaneous prediction errors in the ventral striatum and choice signals in the ventromedial prefrontal cortex.

To survive, humans must estimate their own ability and the abilities of others. We found that, although people estimated their abilities on the basis of their own performance in a rational manner, their estimates of themselves were partly merged with the performance of others. Reciprocally, their ability estimates for others also reflected their own, as well as the others', performance. Self-other mergence operated in a context-dependent manner: interacting with high or low performers, respectively, enhanced and diminished own ability estimates in cooperative contexts, but the opposite occurred in competitive contexts. Self-other mergence not only influenced subjective evaluations, it also affected how people subsequently objectively adjusted their performance. Perigenual anterior cingulate cortex tracked one's own performance. Dorsomedial frontal area 9 tracked others' performances, but also integrated contextual and self-related information. Self-other mergence increased with the strength of self and other representations in area 9, suggesting it carries interdependent representations of self and other., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The anterior cingulate cortex (ACC) is implicated in a broad range of behaviors and cognitive processes, but it has been unclear what contribution, if any, the ACC makes to social behavior. We argue that anatomical and functional evidence suggests that a specific sub-region of ACC-in the gyrus (ACCg)-plays a crucial role in processing social information. We propose that the computational properties of the ACCg support a contribution to social cognition by estimating how motivated other individuals are and dynamically updating those estimates when further evidence suggests they have been erroneous. Notably this model, based on vicarious motivation and error processing, provides a unified account of neurophysiological and neuroimaging evidence that the ACCg is sensitive to costs, benefits, and errors during social interactions. Furthermore, it makes specific, testable predictions about a key mechanism that may underpin variability in socio-cognitive abilities in health and disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

When an organism receives a reward, it is crucial to know which of many candidate actions caused this reward. However, recent work suggests that learning is possible even when this most fundamental assumption is not met. We used novel reward-guided learning paradigms in two fMRI studies to show that humans deploy separable learning mechanisms that operate in parallel. While behavior was dominated by precise contingent learning, it also revealed hallmarks of noncontingent learning strategies. These learning mechanisms were separable behaviorally and neurally. Lateral orbitofrontal cortex supported contingent learning and reflected contingencies between outcomes and their causal choices. Amygdala responses around reward times related to statistical patterns of learning. Time-based heuristic mechanisms were related to activity in sensorimotor corticostriatal circuitry. Our data point to the existence of several learning mechanisms in the human brain, of which only one relies on applying known rules about the causal structure of the task., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The great promise of comparative neuroscience is to understand why brains differ by investigating the relations between variations in the organization of different brains, their evolutionary history, and their current ecological niche. For this approach to be successful, the organization of different brains needs to be quantifiable. Here, we present an approach to formally comparing the connectivity of different cortical areas across different brains. We exploit the fact that cortical regions can be characterized by the unique pattern of connectivity, the so-called connectivity fingerprint. By comparing connectivity fingerprints between cortical areas in the human and non-human primate brain we can identify between-species homologs, but also illustrate that is driving differences between species. We illustrate the approach by comparing the organization of the frontal cortex between humans and macaques, showing general similarities combined with some differences in the lateral frontal pole., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Natural environments are complex, and a single choice can lead to multiple outcomes. Agents should learn which outcomes are due to their choices and therefore relevant for future decisions and which are stochastic in ways common to all choices and therefore irrelevant for future decisions between options. We designed an experiment in which human participants learned the varying reward and effort magnitudes of two options and repeatedly chose between them. The reward associated with a choice was randomly real or hypothetical (i.e., participants only sometimes received the reward magnitude associated with the chosen option). The real/hypothetical nature of the reward on any one trial was, however, irrelevant for learning the longer-term values of the choices, and participants ought to have only focused on the informational content of the outcome and disregarded whether it was a real or hypothetical reward. However, we found that participants showed an irrational choice bias, preferring choices that had previously led, by chance, to a real reward in the last trial. Amygdala and ventromedial prefrontal activity was related to the way in which participants' choices were biased by real reward receipt. By contrast, activity in dorsal anterior cingulate cortex, frontal operculum/anterior insula, and especially lateral anterior prefrontal cortex was related to the degree to which participants resisted this bias and chose effectively in a manner guided by aspects of outcomes that had real and more sustained relationships with particular choices, suppressing irrelevant reward information for more optimal learning and decision making., Significance Statement: In complex natural environments, a single choice can lead to multiple outcomes. Human agents should only learn from outcomes that are due to their choices, not from outcomes without such a relationship. We designed an experiment to measure learning about reward and effort magnitudes in an environment in which other features of the outcome were random and had no relationship with choice. We found that, although people could learn about reward magnitudes, they nevertheless were irrationally biased toward repeating certain choices as a function of the presence or absence of random reward features. Activity in different brain regions in the prefrontal cortex either reflected the bias or reflected resistance to the bias., (Copyright © 2015 Scholl, Kolling et al.)

Cost-benefit analysis in decision making takes place in everyday life for animals and humans alike. In this issue, a neural circuit specific for modulating these behaviors is identified in rats and reveals elusive functional distinctions between long-mysterious anatomical features of the brain., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Reward-guided decision-making depends on a network of brain regions. Among these are the orbitofrontal and the anterior cingulate cortex. However, it is difficult to ascertain if these areas constitute anatomical and functional unities, and how these areas correspond between monkeys and humans. To address these questions we looked at connectivity profiles of these areas using resting-state functional MRI in 38 humans and 25 macaque monkeys. We sought brain regions in the macaque that resembled 10 human areas identified with decision making and brain regions in the human that resembled six macaque areas identified with decision making. We also used diffusion-weighted MRI to delineate key human orbital and medial frontal brain regions. We identified 21 different regions, many of which could be linked to particular aspects of reward-guided learning, valuation, and decision making, and in many cases we identified areas in the macaque with similar coupling profiles.

Correlations in brain activity between two areas (functional connectivity) have been shown to relate to their underlying structural connections. We examine the possibility that functional connectivity also reflects short-term changes in synaptic efficacy. We demonstrate that paired transcranial magnetic stimulation (TMS) near ventral premotor cortex (PMv) and primary motor cortex (M1) with a short 8-ms inter-pulse interval evoking synchronous pre- and post-synaptic activity and which strengthens interregional connectivity between the two areas in a pattern consistent with Hebbian plasticity, leads to increased functional connectivity between PMv and M1 as measured with functional magnetic resonance imaging (fMRI). Moreover, we show that strengthening connectivity between these nodes has effects on a wider network of areas, such as decreasing coupling in a parallel motor programming stream. A control experiment revealed that identical TMS pulses at identical frequencies caused no change in fMRI-measured functional connectivity when the inter-pulse-interval was too long for Hebbian-like plasticity., Competing Interests: The authors declare that no competing interests exist.

The medial frontal cortex (MFC) is critical for cost-benefit decision-making. Generally, cognitive and reward-based behaviour in rodents is not thought to be lateralised within the brain. In this study, however, we demonstrate that rats with unilateral MFC lesions show a profound change in decision-making on an effort-based decision-making task. Furthermore, unilateral MFC lesions have a greater effect when the rat has to choose to put in more effort for a higher reward when it is on the contralateral side of space to the lesion. Importantly, this could not be explained by motor impairments as these animals did not show a turning bias in separate experiments. In contrast, rats with unilateral dopaminergic midbrain lesions did exhibit a motoric turning bias, but were unimpaired on the effort-based decision-making task. This rare example of a cognitive deficit caused by a unilateral cortical lesion in the rat brain indicates that the MFC may have a specialised and lateralised role in evaluating the costs and benefits of actions directed to specific spatial locations., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

N-methyl-D-aspartate (NMDA) receptors are known to fulfill crucial functions in many forms of learning and plasticity. More recently, biophysical models, however, have suggested an additional role of NMDA receptors in evidence integration for decision-making, going beyond their role in learning. We designed a task to study the role of NMDA receptors in human reward-guided learning and decision-making. Human participants were assigned to receive either 250 mg of the partial NMDA agonist d-cycloserine (n=20) or matching placebo capsules (n=27). Reward-guided learning and decision-making were assessed using a task in which participants had to integrate learnt and explicitly shown value information to maximize their monetary wins and minimize their losses. To tease apart the effects of NMDA on learning and decision-making we used simple learning models. D-cycloserine shifted decision-making towards a more optimal integration of the learnt and the explicitly shown information, in the absence of a direct learning effect. In conclusion, our results reveal a distinct role for NMDA receptors in reward-guided decision-making. We discuss these findings in the context of NMDA's roles in neuronal super-additivity and as crucial for evidence integration for decisions.

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., Competing Interests: The authors have declared that no competing interests exist.

Despite widespread interest in neural mechanisms of decision-making, most investigations focus on decisions between just two options. Here we adapt a biophysically plausible model of decision-making to predict how a key decision variable, the value difference signal-encoding how much better one choice is than another-changes with the value of a third, but unavailable, alternative. The model predicts a surprising failure of optimal decision-making: greater difficulty choosing between two options in the presence of a third very poor, as opposed to very good, alternative. Both investigation of human decision-making and functional magnetic resonance imaging-based measurements of value difference signals in ventromedial prefrontal cortex (vmPFC) bore out this prediction. The vmPFC signal decreased in the presence of low-value third alternatives, and vmPFC effect sizes predicted individual variation in suboptimal decision-making in the presence of multiple alternatives. The effect contrasts with that of divisive normalization in parietal cortex.

Human ventrolateral frontal cortex (vlFC) is identified with cognitive processes such as language and cognitive flexibility. The relationship between it and the vlFC of other primates has therefore been the subject of particular speculation. We used a combination of structural and functional neuroimaging methods to identify key components of human vlFC. We compared how vlFC areas interacted with other brain areas in 25 humans and 25 macaques using the same methods. We identified a core set of 11 vlFC components that interacted in similar ways with similar distributed circuits in both species and, in addition, one distinctively human component in ventrolateral frontal pole. Fundamental differences in interactions with posterior auditory association areas in the two species were also present-these were ubiquitous throughout posterior human vlFC but channeled to different frontal regions in monkeys. Finally, there were some differences in interregional interactions within vlFC in the two species., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Using multivoxel pattern analysis (MVPA), we studied how distributed visual representations in human occipitotemporal cortex are modulated by attention and link their modulation to concurrent activity in frontal and parietal cortex. We detected similar occipitotemporal patterns during a simple visuoperceptual task and an attention-to-working-memory task in which one or two stimuli were cued before being presented among other pictures. Pattern strength varied from highest to lowest when the stimulus was the exclusive focus of attention, a conjoint focus, and when it was potentially distracting. Although qualitatively similar effects were seen inside regions relatively specialized for the stimulus category and outside, the former were quantitatively stronger. By regressing occipitotemporal pattern strength against activity elsewhere in the brain, we identified frontal and parietal areas exerting top-down control over, or reading information out from, distributed patterns in occipitotemporal cortex. Their interactions with patterns inside regions relatively specialized for that stimulus category were higher than those with patterns outside those regions and varied in strength as a function of the attentional condition. One area, the frontal operculum, was distinguished by selectively interacting with occipitotemporal patterns only when they were the focus of attention. There was no evidence that any frontal or parietal area actively inhibited occipitotemporal representations even when they should be ignored and were suppressed. Using MVPA to decode information within these frontal and parietal areas showed that they contained information about attentional context and/or readout information from occipitotemporal cortex to guide behavior but that frontal regions lacked information about category identity.

Brains use predictive models to facilitate the processing of expected stimuli or planned actions. Under a predictive model, surprising (low probability) stimuli or actions necessitate the immediate reallocation of processing resources, but they can also signal the need to update the underlying predictive model to reflect changes in the environment. Surprise and updating are often correlated in experimental paradigms but are, in fact, distinct constructs that can be formally defined as the Shannon information (IS) and Kullback-Leibler divergence (DKL) associated with an observation. In a saccadic planning task, we observed that distinct behaviors and brain regions are associated with surprise/IS and updating/DKL. Although surprise/IS was associated with behavioral reprogramming as indexed by slower reaction times, as well as with activity in the posterior parietal cortex [human lateral intraparietal area (LIP)], the anterior cingulate cortex (ACC) was specifically activated during updating of the predictive model (DKL). A second saccade-sensitive region in the inferior posterior parietal cortex (human 7a), which has connections to both LIP and ACC, was activated by surprise and modulated by updating. Pupillometry revealed a further dissociation between surprise and updating with an early positive effect of surprise and late negative effect of updating on pupil area. These results give a computational account of the roles of the ACC and two parietal saccade regions, LIP and 7a, by which their involvement in diverse tasks can be understood mechanistically. The dissociation of functional roles between regions within the reorienting/reprogramming network may also inform models of neurological phenomena, such as extinction and Balint syndrome, and neglect.

A computational approach to functional specialization suggests that brain systems can be characterized in terms of the types of computations they perform, rather than their sensory or behavioral domains. We contrasted the neural systems associated with two computationally distinct forms of predictive model: a reinforcement-learning model of the environment obtained through experience with discrete events, and continuous dynamic forward modeling. By manipulating the precision with which each type of prediction could be used, we caused participants to shift computational strategies within a single spatial prediction task. Hence (using fMRI) we showed that activity in two brain systems (typically associated with reward learning and motor control) could be dissociated in terms of the forms of computations that were performed there, even when both systems were used to make parallel predictions of the same event. A region in parietal cortex, which was sensitive to the divergence between the predictions of the models and anatomically connected to both computational networks, is proposed to mediate integration of the two predictive modes to produce a single behavioral output., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: The authors declare no conflict of interest.

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.

The human ability to infer the thoughts and beliefs of others, often referred to as "theory of mind," as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of-mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor.

Discussions of the neural underpinnings of social cognition frequently emphasize the distinctiveness of human social cognition. Here, however, we review the discovery of similar correlations between neural networks and social networks in humans and other primates. We suggest that component parts of these neural networks in dorsal frontal cortex, anterior cingulate cortex (ACC), and superior temporal sulcus (STS) are linked to basic social cognitive processes common to several primate species including monitoring the actions of others, assigning importance to others, and orienting behavior toward or away from others. Changes in activity in other brain regions occur in tandem with changes in social status and may be related to the different types of behaviors associated with variation in social status., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although damage to the medial frontal cortex causes profound decision-making impairments, it has been difficult to pinpoint the relative contributions of key anatomical subdivisions. Here we use function magnetic resonance imaging to examine the contributions of human ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) during sequential choices between multiple alternatives--two key features of choices made in ecological settings. By carefully constructing options whose current value at any given decision was dissociable from their longer term value, we were able to examine choices in current and long-term frames of reference. We present evidence showing that activity at choice and feedback in vmPFC and dACC was tied to the current choice and the best long-term option, respectively. vmPFC, mid-cingulate, and posterior cingulate cortex encoded the relative value between the chosen and next best option at each sequential decision, whereas dACC encoded the relative value of adapting choices from the option with the highest value in the longer term. Furthermore, at feedback we identify temporally dissociable effects that predict repetition of the current choice and adaptation away from the long-term best option in vmPFC and dACC, respectively. These functional dissociations at choice and feedback suggest that sequential choices are subject to competing cortical mechanisms.

A central question in cognitive neuroscience regards the means by which options are compared and decisions are resolved during value-guided choice. It is clear that several component processes are needed; these include identifying options, a value-based comparison, and implementation of actions to execute the decision. What is less clear is the temporal precedence and functional organisation of these component processes in the brain. Competing models of decision making have proposed that value comparison may occur in the space of alternative actions, or in the space of abstract goods. We hypothesized that the signals observed might in fact depend upon the framing of the decision. We recorded magnetoencephalographic data from humans performing value-guided choices in which two closely related trial types were interleaved. In the first trial type, each option was revealed separately, potentially causing subjects to estimate each action's value as it was revealed and perform comparison in action-space. In the second trial type, both options were presented simultaneously, potentially leading to comparison in abstract goods-space prior to commitment to a specific action. Distinct activity patterns (in distinct brain regions) on the two trial types demonstrated that the observed frame of reference used for decision making indeed differed, despite the information presented being formally identical, between the two trial types. This provides a potential reconciliation of conflicting accounts of value-guided choice.

Information relevant for social interactions is thought to be processed in specific neural circuits. Recent studies shed new light on how that social information is encoded and processed by different brain areas., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We evaluate the merits of different conceptualizations of frontal cortex function in value-guided decision-making. According to one view each frontal cortical region is concerned with a different aspect of the process of learning about and evaluating choices and then selecting actions. An alternative view, however, sees sets of decision-making circuits working in parallel within the frontal lobes in order to make different types of decisions. While there is a neural circuit for making choices between pairs of simultaneously presented items in the manner that is frequently assessed in the laboratory, there is also evidence that other frontal lobe circuits have evolved to make other types of choices such as those made during the course of foraging., (Copyright © 2012. Published by Elsevier Ltd.)

To decide effectively, information must not only be integrated from multiple sources, but it must be distributed across the brain if it is to influence structures such as motor cortex that execute choices. Human participants integrated information from multiple, but only partially informative, cues in a probabilistic reasoning task in an optimal manner. We tested whether lateralization of alpha- and beta-band oscillatory brain activity over sensorimotor cortex reflected decision variables such as the sum of the evidence provided by observed cues, a key quantity for decision making, and whether this could be dissociated from an update signal reflecting processing of the most recent cue stimulus. Alpha- and beta-band activity in the electroencephalogram reflected the logarithm of the likelihood ratio associated with the each piece of information witnessed, and the same quantity associated with the previous cues. Only the beta-band, however, reflected the most recent cue in a manner that suggested it reflected updating processes associated with cue processing. In a second experiment, transcranial magnetic stimulation-induced disruption was used to demonstrate that the intraparietal sulcus played a causal role both in decision making and in the appearance of sensorimotor beta-band activity.

Controversy surrounds the role of the temporoparietal junction (TPJ) area of the human brain. Although TPJ has been implicated both in reorienting of attention and social cognition, it is still unclear whether these functions have the same neural basis. Indeed, whether TPJ is a precisely identifiable cortical region or a cluster of subregions with separate functions is still a matter of debate. Here, we examined the structural and functional connectivity of TPJ, testing whether TPJ is a unitary area with a heterogeneous functional connectivity profile or a conglomerate of regions with distinctive connectivity. Diffusion-weighted imaging tractrography-based parcellation identified 3 separate regions in TPJ. Resting-state functional connectivity was then used to establish which cortical networks each of these subregions participates in. A dorsal cluster in the middle part of the inferior parietal lobule showed resting-state functional connectivity with, among other areas, lateral anterior prefrontal cortex. Ventrally, an anterior TPJ cluster interacted with ventral prefrontal cortex and anterior insula, while a posterior TPJ cluster interacted with posterior cingulate, temporal pole, and anterior medial prefrontal cortex. These results indicate that TPJ can be subdivided into subregions on the basis of its structural and functional connectivity.

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.

Cognitive flexibility is known to depend on the striatum. However, the striatum does not act in isolation to bias cognitive flexibility. In particular, cognitive flexibility also implicates the frontal cortex. Here we tested the hypothesis that the human frontal cortex controls cognitive flexibility by regulating striatal function via topographically specific frontostriatal connections. To this end, we exploited a repetitive transcranial magnetic stimulation (TMS) protocol over frontal cortex that is known to increase dopamine release in the striatum. This intervention was combined with functional magnetic resonance imaging to determine the functional and topographic specificity of its consequences at the whole brain level. Participants were scanned both before and after off-line TMS while performing a cognitive switching task that is known to depend on a specific striatal substructure, the putamen. Frontal stimulation perturbed task-specific functional signals in the putamen, while reducing fronto-striatal functional connectivity. There were no such effects of TMS over the medial parietal cortex. These data strengthen the hypothesis that cognitive flexibility involves topographic frontal control of striatal function.

Behavioral economic studies involving limited numbers of choices have provided key insights into neural decision-making mechanisms. By contrast, animals' foraging choices arise in the context of sequences of encounters with prey or food. On each encounter, the animal chooses whether to engage or, if the environment is sufficiently rich, to search elsewhere. The cost of foraging is also critical. We demonstrate that humans can alternate between two modes of choice, comparative decision-making and foraging, depending on distinct neural mechanisms in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) using distinct reference frames; in ACC, choice variables are represented in invariant reference to foraging or searching for alternatives. Whereas vmPFC encodes values of specific well-defined options, ACC encodes the average value of the foraging environment and cost of foraging.

The orbitofrontal cortex and adjacent ventromedial prefrontal cortex carry reward representations and mediate flexible behaviour when circumstances change. Here we review how recent experiments in humans and macaques have confirmed the existence of a major difference between the functions of the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex (mOFC) on the one hand and the lateral orbitofrontal cortex (lOFC) on the other. These differences, however, may not be best accounted for in terms of specializations for reward and error/punishment processing as is commonly assumed. Instead we argue that both lesion and functional magnetic resonance imaging studies reveal that the lOFC is concerned with the assignment of credit for both reward and error outcomes to the choice of specific stimuli and with the linking of specific stimulus representations to representations of specific types of reward outcome. By contrast, we argue that the ventromedial prefrontal cortex/mOFC is concerned with evaluation, value-guided decision-making and maintenance of a choice over successive decisions. Despite the popular view that they cause perseveration of behaviour and inability to inhibit repetition of a previously made choice, we found that lesions in neither orbitofrontal subdivision caused perseveration. On the contrary, lesions in the lOFC made animals switch more rapidly between choices when they were finding it difficult to assign reward values to choices. Lesions in the mOFC caused animals to lose their normal predisposition to repeat previously successful choices, suggesting that the mOFC does not just mediate value comparison in choice but also facilitates maintenance of the same choice if it has been successful., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)