General mechanisms of task engagement in the primate frontal cortex.

Staying engaged is necessary to maintain goal-directed behaviors. Despite this, engagement exhibits continuous, intrinsic fluctuations. Even in experimental settings, animals, unlike most humans, repeatedly and spontaneously move between periods of complete task engagement and disengagement. We, therefore, looked at behavior in male macaques (macaca mulatta) in four tasks while recording fMRI signals. We identified consistent autocorrelation in task disengagement. This made it possible to build models capturing task-independent engagement. We identified task general patterns of neural activity linked to impending sudden task disengagement in mid-cingulate gyrus. By contrast, activity centered in perigenual anterior cingulate cortex (pgACC) was associated with maintenance of performance across tasks. Importantly, we carefully controlled for task-specific factors such as the reward history and other motivational effects, such as response vigor, in our analyses. Moreover, we showed pgACC activity had a causal link to task engagement: transcranial ultrasound stimulation of pgACC changed task engagement patterns.

Comparing mouse and human cingulate cortex organization using functional connectivity.

The subdivisions of the extended cingulate cortex of the human brain are implicated in a number of high-level behaviors and affected by a range of neuropsychiatric disorders. Its anatomy, function, and response to therapeutics are often studied using non-human animals, including the mouse. However, the similarity of human and mouse frontal cortex, including cingulate areas, is still not fully understood. Some accounts emphasize resemblances between mouse cingulate cortex and human cingulate cortex while others emphasize similarities with human granular prefrontal cortex. We use comparative neuroimaging to study the connectivity of the cingulate cortex in the mouse and human, allowing comparisons between mouse 'gold standard' tracer and imaging data, and, in addition, comparison between the mouse and the human using comparable imaging data. We find overall similarities in organization of the cingulate between species, including anterior and midcingulate areas and a retrosplenial area. However, human cingulate contains subareas with a more fine-grained organization than is apparent in the mouse and it has connections to prefrontal areas not present in the mouse. Results such as these help formally address between-species brain organization and aim to improve the translation from preclinical to human results.

Nuclei-specific hypothalamus networks predict a dimensional marker of stress in humans.

The hypothalamus is part of the hypothalamic-pituitary-adrenal axis which activates stress responses through release of cortisol. It is a small but heterogeneous structure comprising multiple nuclei. In vivo human neuroimaging has rarely succeeded in recording signals from individual hypothalamus nuclei. Here we use human resting-state fMRI (n = 498) with high spatial resolution to examine relationships between the functional connectivity of specific hypothalamic nuclei and a dimensional marker of prolonged stress. First, we demonstrate that we can parcellate the human hypothalamus into seven nuclei in vivo. Using the functional connectivity between these nuclei and other subcortical structures including the amygdala, we significantly predict stress scores out-of-sample. Predictions use 0.0015% of all possible brain edges, are specific to stress, and improve when using nucleus-specific compared to whole-hypothalamus connectivity. Thus, stress relates to connectivity changes in precise and functionally meaningful subcortical networks, which may be exploited in future studies using interventions in stress disorders.

A frontopolar-temporal circuit determines the impact of social information in macaque decision making.

When choosing, primates are guided not only by personal experience of objects but also by social information such as others' attitudes toward the objects. Crucially, both sources of information-personal and socially derived-vary in reliability. To choose optimally, one must sometimes override choice guidance by personal experience and follow social cues instead, and sometimes one must do the opposite. The dorsomedial frontopolar cortex (dmFPC) tracks reliability of social information and determines whether it will be attended to guide behavior. To do this, dmFPC activity enters specific patterns of interaction with a region in the mid-superior temporal sulcus (mSTS). Reversible disruption of dmFPC activity with transcranial ultrasound stimulation (TUS) led macaques to fail to be guided by social information when it was reliable but to be more likely to use it when it was unreliable. By contrast, mSTS disruption uniformly downregulated the impact of social information on behavior.

Changing connectivity between premotor and motor cortex changes inter-areal communication in the human brain.

The ventral premotor cortex (PMv) is an important component of cortico-cortical pathways mediating prefrontal control over primary motor cortex (M1) function. Paired associative stimulation (ccPAS) is known to change PMv influence over M1 in humans, which manifests differently depending on the behavioural context. Here we show that these changes in influence are functionally linked to PMv-M1 phase synchrony changes induced by repeated paired stimulation of the two areas. PMv-to-M1 ccPAS leads to increased phase synchrony in alpha and beta bands, while reversed order M1-to-PMv ccPAS leads to decreased theta phase synchrony. These changes are visible at rest but are predictive of changes in oscillatory power in the same frequencies during movement execution and inhibition, respectively. The results unveil a link between the physiology of the motor network and the resonant frequencies mediating its interactions and provide a putative mechanism underpinning the relationship between synaptic efficacy and brain oscillations.

Intraparietal stimulation disrupts negative distractor effects in human multi-alternative decision-making.

There has been debate about whether addition of an irrelevant distractor option to an otherwise binary decision influences which of the two choices is taken. We show that disparate views on this question are reconciled if distractors exert two opposing but not mutually exclusive effects. Each effect predominates in a different part of decision space: (1) a positive distractor effect predicts high-value distractors improve decision-making; (2) a negative distractor effect, of the type associated with divisive normalisation models, entails decreased accuracy with increased distractor values. Here, we demonstrate both distractor effects coexist in human decision making but in different parts of a decision space defined by the choice values. We show disruption of the medial intraparietal area (MIP) by transcranial magnetic stimulation (TMS) increases positive distractor effects at the expense of negative distractor effects. Furthermore, individuals with larger MIP volumes are also less susceptible to the disruption induced by TMS. These findings also demonstrate a causal link between MIP and the impact of distractors on decision-making via divisive normalisation.

Imagining the future self through thought experiments.

The ability of the mind to conceptualize what is not present is essential. It allows us to reason counterfactually about what might have happened had events unfolded differently or had another course of action been taken. It allows us to think about what might happen - to perform 'Gedankenexperimente' (thought experiments) - before we act. However, the cognitive and neural mechanisms mediating this ability are poorly understood. We suggest that the frontopolar cortex (FPC) keeps track of and evaluates alternative choices (what we might have done), whereas the anterior lateral prefrontal cortex (alPFC) compares simulations of possible future scenarios (what we might do) and evaluates their reward values. Together, these brain regions support the construction of suppositional scenarios.

Neural activity tracking identity and confidence in social information.

Humans learn about the environment either directly by interacting with it or indirectly by seeking information about it from social sources such as conspecifics. The degree of confidence in the information obtained through either route should determine the impact that it has on adapting and changing behaviour. We examined whether and how behavioural and neural computations differ during non-social learning as opposed to learning from social sources. Trial-wise confidence judgements about non-social and social information sources offered a window into this learning process. Despite matching exactly the statistical features of social and non-social conditions, confidence judgements were more accurate and less changeable when they were made about social as opposed to non-social information sources. In addition to subjective reports of confidence, differences were also apparent in the Bayesian estimates of participants' subjective beliefs. Univariate activity in dorsomedial prefrontal cortex and posterior temporoparietal junction more closely tracked confidence about social as opposed to non-social information sources. In addition, the multivariate patterns of activity in the same areas encoded identities of social information sources compared to non-social information sources.

People's decisions are influenced by their beliefs, which may be based on advice from other humans or, alternatively, on information from non-human sources such as road signs. But which sources do we find more reliable? Although scientists have studied the importance of social context in the way we process information, it is not fully understood how the brain processes information differently depending on who provides it. Trudel et al. investigated the differences in the way humans evaluate information from human sources, such as advisors, compared to non-human sources, like inanimate objects, by monitoring brain activity and analyzing the results using a computational approach. In the experiments, 24 participants received a reward for locating a hidden dot on a circle under two different conditions: they either received a clue on the dot's location from an image of a human face (social condition), representing an advisor, or from an inanimate object (non-social condition). Participants received information from many different advisors and inanimate objects, and the accuracy of the clues given by any of them varied from source to source. Each time, participants reported whether they thought the advice was reliable. The results of monitoring the participants' brain activity showed that they used different strategies when assessing the reliability of advice from a human than when the information came from a non-human source. Additionally, participants based their judgments about an advisor more strongly on past experiences with them, that is, if an advisor had given them good advice in the past, they were more likely to rely on their advice. Conversely, judgments about an inanimate object were based more strongly on recent experiences with that object. Interestingly, participants were more certain when making judgments about the accuracy of cues given by advisors compared to inanimate objects, and they also updated their assessment of human sources less according to new evidence that contradicted their initial belief. This suggests that people may form more stable opinions about the reliability of sources when they receive information in social contexts, possibly because they expect more consistent behavior from humans. This stability in judgments about advisors was also reflected in the signal of brain areas that are often involved when interacting with others. The work of Trudel et al. shows that even the suggestion that the source of a piece of advice is human can change how we process the information. This is especially important because humans spend increasingly more time in the digital world. Awareness of our biased assessment of human sources will have implications for designing interactive tools to guide human decision-making as well as strategies to develop critical thinking.

Causal role of a neural system for separating and selecting multidimensional social cognitive information.

People are multi-faceted, typically good at some things but bad at others, and a critical aspect of social judgement is the ability to focus on those traits relevant for the task at hand. However, it remains unknown how the brain supports such context-dependent social judgement. Here, we examine how people represent multidimensional individuals, and how the brain extracts relevant information and filters out irrelevant information when comparing individuals within a specific dimension. Using human fMRI, we identify distinct neural representations in dorsomedial prefrontal cortex (dmPFC) and anterior insula (AI) supporting separation and selection of information for context-dependent social judgement. Causal evaluation using non-invasive brain stimulation shows that AI disruption alters the impact of relevant information on social comparison, whereas dmPFC disruption only affects the impact of irrelevant information. This neural circuit is distinct from the one supporting integration across, as opposed to separation of, different features of a multidimensional cognitive space.

Relationship between nuclei-specific amygdala connectivity and mental health dimensions in humans.

There has been increasing interest in using neuroimaging measures to predict psychiatric disorders. However, predictions usually rely on large brain networks and large disorder heterogeneity. Thus, they lack both anatomical and behavioural specificity, preventing the advancement of targeted interventions. Here we address both challenges. First, using resting-state functional magnetic resonance imaging, we parcellated the amygdala, a region implicated in mood disorders, into seven nuclei. Next, a questionnaire factor analysis provided subclinical mental health dimensions frequently altered in anxious-depressive individuals, such as negative emotions and sleep problems. Finally, for each behavioural dimension, we identified the most predictive resting-state functional connectivity between individual amygdala nuclei and highly specific regions of interest, such as the dorsal raphe nucleus in the brainstem or medial frontal cortical regions. Connectivity in circumscribed amygdala networks predicted behaviours in an independent dataset. Our results reveal specific relations between mental health dimensions and connectivity in precise subcortical networks.

A macroscopic link between interhemispheric tract myelination and cortico-cortical interactions during action reprogramming.

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.

Hebbian activity-dependent plasticity in white matter.

Synaptic plasticity is required for learning and follows Hebb's rule, the computational principle underpinning associative learning. In recent years, a complementary type of brain plasticity has been identified in myelinated axons, which make up the majority of brain's white matter. Like synaptic plasticity, myelin plasticity is required for learning, but it is unclear whether it is Hebbian or whether it follows different rules. Here, we provide evidence that white matter plasticity operates following Hebb's rule in humans. Across two experiments, we find that co-stimulating cortical areas to induce Hebbian plasticity leads to relative increases in cortical excitability and associated increases in a myelin marker within the stimulated fiber bundle. We conclude that Hebbian plasticity extends beyond synaptic changes and can be observed in human white matter fibers.

Medial and orbital frontal cortex in decision-making and flexible behavior.

The medial frontal cortex and adjacent orbitofrontal cortex have been the focus of investigations of decision-making, behavioral flexibility, and social behavior. We review studies conducted in humans, macaques, and rodents and argue that several regions with different functional roles can be identified in the dorsal anterior cingulate cortex, perigenual anterior cingulate cortex, anterior medial frontal cortex, ventromedial prefrontal cortex, and medial and lateral parts of the orbitofrontal cortex. There is increasing evidence that the manner in which these areas represent the value of the environment and specific choices is different from subcortical brain regions and more complex than previously thought. Although activity in some regions reflects distributions of reward and opportunities across the environment, in other cases, activity reflects the structural relationships between features of the environment that animals can use to infer what decision to take even if they have not encountered identical opportunities in the past.

The effect of apathy and compulsivity on planning and stopping in sequential decision-making.

Real-life decision-making often comprises sequences of successive decisions about whether to take opportunities as they are encountered or keep searching for better ones instead. We investigated individual differences related to such sequential decision-making and link them especially to apathy and compulsivity in a large online sample (discovery sample: n = 449 and confirmation sample: n = 756). Our cognitive model revealed distinct changes in the way participants evaluated their environments and planned their own future behaviour. Apathy was linked to decision inertia, i.e., automatically persisting with a sequence of searches for longer than appropriate given the value of searching. Thus, despite being less motivated, they did not avoid the effort associated with longer searches. In contrast, compulsivity was linked to self-reported insensitivity to the cost of continuing with a sequence of searches. The objective measures of behavioural cost insensitivity were clearly linked to compulsivity only in the discovery sample. While the confirmation sample showed a similar effect, it did not reach significance. Nevertheless, in both samples, participants reported awareness of such bias (experienced as "overchasing"). In addition, this awareness made them report preemptively avoiding situations related to the bias. However, we found no evidence of them actually preempting more in the task, which might mean a misalignment of their metacognitive beliefs or that our behavioural measures were incomplete. In summary, individual variation in distinct, fundamental aspects of sequential decision-making can be linked to variation in 2 measures of behavioural traits associated with psychological illness in the normal population.

Complementary roles of serotonergic and cholinergic systems in decisions about when to act.

Decision-making not only involves deciding about which action to choose but when and whether to initiate an action in the first place. Macaque monkeys tracked number of dots on a screen and could choose when to make a response. The longer the animals waited before responding, the more dots appeared on the screen and the higher the probability of reward. Monkeys waited longer before making a response when a trial's value was less than the environment's average value. Recordings of brain activity with fMRI revealed that activity in dorsal raphe nucleus (DRN)-a key source of serotonin (5-HT)-tracked average value of the environment. By contrast, activity in the basal forebrain (BF)-an important source of acetylcholine (ACh)-was related to decision time to act as a function of immediate and recent past context. Interactions between DRN and BF and the anterior cingulate cortex (ACC), another region with action initiation-related activity, occurred as a function of the decision time to act. Next, we performed two psychopharmacological studies. Manipulating systemic 5-HT by citalopram prolonged the time macaques waited to respond for a given opportunity. This effect was more evident during blocks with long inter-trial intervals (ITIs) where good opportunities were sparse. Manipulating systemic acetylcholine (ACh) by rivastigmine reduced the time macaques waited to respond given the immediate and recent past context, a pattern opposite to the effect observed with 5-HT. These findings suggest complementary roles for serotonin/DRN and acetylcholine/BF in decisions about when to initiate an action.

Interactions between ventrolateral prefrontal and anterior cingulate cortex during learning and behavioural change.

Hypotheses and beliefs guide credit assignment - the process of determining which previous events or actions caused an outcome. Adaptive hypothesis formation and testing are crucial in uncertain and changing environments in which associations and meanings are volatile. Despite primates' abilities to form and test hypotheses, establishing what is causally responsible for the occurrence of particular outcomes remains a fundamental challenge for credit assignment and learning. Hypotheses about what surprises are due to stochasticity inherent in an environment as opposed to real, systematic changes are necessary for identifying the environment's predictive features, but are often hard to test. We review evidence that two highly interconnected frontal cortical regions, anterior cingulate cortex and ventrolateral prefrontal area 47/12o, provide a biological substrate for linking two crucial components of hypothesis-formation and testing: the control of information seeking and credit assignment. Neuroimaging, targeted disruptions, and neurophysiological studies link an anterior cingulate - 47/12o circuit to generation of exploratory behaviour, non-instrumental information seeking, and interpretation of subsequent feedback in the service of credit assignment. Our observations support the idea that information seeking and credit assignment are linked at the level of neural circuits and explain why this circuit is important for ensuring behaviour is flexible and adaptive.

Ultrasound modulation of macaque prefrontal cortex selectively alters credit assignment-related activity and behavior.

Credit assignment is the association of specific instances of reward to the specific events, such as a particular choice, that caused them. Without credit assignment, choice values reflect an approximate estimate of how good the environment was when the choice was made­the global reward state­rather than exactly which outcome the choice caused. Combined transcranial ultrasound stimulation (TUS) and functional magnetic resonance imaging in macaques demonstrate credit assignment­related activity in prefrontal area 47/12o, and when this signal was disrupted with TUS, choice value representations across the brain were impaired. As a consequence, behavior was no longer guided by choice value, and decision-making was poorer. By contrast, global reward state­related activity in the adjacent anterior insula remained intact and determined decision-making after prefrontal disruption.

Reassessing associations between white matter and behaviour with multimodal microstructural imaging.

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2∗). Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone. To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40-200 may be required to detect such joint multimodal effects, depending on the task being considered. These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WM's relationship with behaviour, suggesting that variable biological effects may be shaping their interaction.

A habenula-insular circuit encodes the willingness to act.

The decision that it is worth doing something rather than nothing is a core yet understudied feature of voluntary behaviour. Here we study "willingness to act", the probability of making a response given the context. Human volunteers encountered opportunities to make effortful actions in order to receive rewards, while watching a movie inside a 7 T MRI scanner. Reward and other context features determined willingness-to-act. Activity in the habenula tracked trial-by-trial variation in participants' willingness-to-act. The anterior insula encoded individual environment features that determined this willingness. We identify a multi-layered network in which contextual information is encoded in the anterior insula, converges on the habenula, and is then transmitted to the supplementary motor area, where the decision is made to either act or refrain from acting via the nigrostriatal pathway.

Increasing and decreasing interregional brain coupling increases and decreases oscillatory activity in the human brain.

The origins of oscillatory activity in the brain are currently debated, but common to many hypotheses is the notion that they reflect interactions between brain areas. Here, we examine this possibility by manipulating the strength of coupling between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1), and examine the impact on oscillatory activity in the motor system measurable in the electroencephalogram. We either increased or decreased the strength of coupling while holding the impact on each component area in the pathway constant. This was achieved by stimulating PMv and M1 with paired pulses of transcranial magnetic stimulation using two different patterns, only one of which increases the influence exerted by PMv over M1. While the stimulation protocols differed in their temporal patterning, they were comprised of identical numbers of pulses to M1 and PMv. We measured the impact on activity in alpha, beta, and theta bands during a motor task in which participants either made a preprepared action (Go) or withheld it (No-Go). Augmenting cortical connectivity between PMv and M1, by evoking synchronous pre- and postsynaptic activity in the PMv-M1 pathway, enhanced oscillatory beta and theta rhythms in Go and No-Go trials, respectively. Little change was observed in the alpha rhythm. By contrast, diminishing the influence of PMv over M1 decreased oscillatory beta and theta rhythms in Go and No-Go trials, respectively. This suggests that corticocortical communication frequencies in the PMv-M1 pathway can be manipulated following Hebbian spike-timing-dependent plasticity.