Activation and disruption of a neural mechanism for novel choice in monkeys.

Neural mechanisms that mediate the ability to make value-guided decisions have received substantial attention in humans and animals1-6. Experiments in animals typically involve long training periods. By contrast, choices in the real world often need to be made between new options spontaneously. It is therefore possible that the neural mechanisms targeted in animal studies differ from those required for new decisions, which are typical of human imaging studies. Here we show that the primate medial frontal cortex (MFC)7 is involved in making new inferential choices when the options have not been previously experienced. Macaques spontaneously inferred the values of new options via similarities with the component parts of previously encountered options. Functional magnetic resonance imaging (fMRI) suggested that this ability was mediated by the MFC, which is rarely investigated in monkeys3; MFC activity reflected different processes of comparison for unfamiliar and familiar options. Multidimensional representations of options in the MFC used a coding scheme resembling that of grid cells, which is well known in spatial navigation8,9, to integrate dimensions in this non-physical space10 during novel decision-making. By contrast, the orbitofrontal cortex held specific object-based value representations1,11. In addition, minimally invasive ultrasonic disruption12 of MFC, but not adjacent tissue, altered the estimation of novel choice values.

Multiple systems in macaques for tracking prediction errors and other types of surprise.

Animals learn from the past to make predictions. These predictions are adjusted after prediction errors, i.e., after surprising events. Generally, most reward prediction errors models learn the average expected amount of reward. However, here we demonstrate the existence of distinct mechanisms for detecting other types of surprising events. Six macaques learned to respond to visual stimuli to receive varying amounts of juice rewards. Most trials ended with the delivery of either 1 or 3 juice drops so that animals learned to expect 2 juice drops on average even though instances of precisely 2 drops were rare. To encourage learning, we also included sessions during which the ratio between 1 and 3 drops changed. Additionally, in all sessions, the stimulus sometimes appeared in an unexpected location. Thus, 3 types of surprising events could occur: reward amount surprise (i.e., a scalar reward prediction error), rare reward surprise, and visuospatial surprise. Importantly, we can dissociate scalar reward prediction errors-rewards that deviated from the average reward amount expected-and rare reward events-rewards that accorded with the average reward expectation but that rarely occurred. We linked each type of surprise to a distinct pattern of neural activity using functional magnetic resonance imaging. Activity in the vicinity of the dopaminergic midbrain only reflected surprise about the amount of reward. Lateral prefrontal cortex had a more general role in detecting surprising events. Posterior lateral orbitofrontal cortex specifically detected rare reward events regardless of whether they followed average reward amount expectations, but only in learnable reward environments.

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.

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.

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.

A Basal Forebrain-Cingulate Circuit in Macaques Decides It Is Time to Act.

The medial frontal cortex has been linked to voluntary action, but an explanation of why decisions to act emerge at particular points in time has been lacking. We show that, in macaques, decisions about whether and when to act are predicted by a set of features defining the animal's current and past context; for example, respectively, cues indicating the current average rate of reward and recent previous voluntary action decisions. We show that activity in two brain areas-the anterior cingulate cortex and basal forebrain-tracks these contextual factors and mediates their effects on behavior in distinct ways. We use focused transcranial ultrasound to selectively and effectively stimulate deep in the brain, even as deep as the basal forebrain, and demonstrate that alteration of activity in the two areas changes decisions about when to act.