Summary The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their application, particularly in deep areas of the primate brain. Here, we demonstrate that a focused transcranial ultrasound stimulation (TUS) protocol impacts activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, the anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions, but such relationships are reduced after sonication, specifically for the targeted areas. Dissociable and focal effects on neural activity could not be explained by auditory confounds.

very day, chacma baboons, an old world primate, navigate to and from the safety of their sleeping post and distant foraging or watering sites 1. The decision to move to alternative locations is not simply guided by accumulation of sensory evidence for that choice but by internal representation or memory of the alternative choice's value. The same is true when they move back toward the sleeping post in the evening. While sensory and associative decision-making have been well-studied 2 , less is known about how representations of counterfactual choices-choices not currently taken but which may be taken in the

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.

People and other animals learn the values of choices by observing the contingencies between them and their outcomes. However, decisions are not guided by choice-linked reward associations alone; macaques also maintain a memory of the general, average reward ratethe global reward statein an environment. Remarkably, global reward state affects the way that each choice outcome is valued and influences future decisions so that the impact of both choice success and failure is different in rich and poor environments. Successful choices are more likely to be repeated but this is especially the case in rich environments. Unsuccessful choices are more likely to be abandoned but this is especially likely in poor environments. Functional magnetic resonance imaging (fMRI) revealed two distinct patterns of activity, one in anterior insula and one in the dorsal raphe nucleus, that track global reward state as well as specific outcome events.

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.

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To understand brain circuits it is necessary both to record and manipulate their activity.Transcranial ultrasound (TUS) is a promising non-invasive brain stimulation technique. To date, investigations have focused on 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 seconds of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS' impact can be demonstrated by showing such patterns change for stimulated areas. We report 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.

Evolutionary adaptations of the human brain are the basis for our unique abilities such as language. An expansion of the arcuate fasciculus (AF), the dorsal language tract, in the human lineage involving left lateralization is considered canonical, but this hypothesis has not been tested in relation to other architectural adaptations in the human brain. Using diffusion-weighted MRI, we examined AF in the human and macaque and quantified species differences in white matter architecture and surface representations. To compare surface results in the two species, we transformed macaque representations to human space using a landmark-based monkey-to-human cortical expansion model. We found that the human dorsal AF, but not the ventral inferior fronto-occipital fasciculus (IFO), is left-lateralized. In the monkey AF is not lateralized. Moreover, compared to the macaque, human AF is relatively increased with respect to IFO. A comparison of human and transformed macaque surface representations suggests that cortical expansion alone cannot account for the species differences in the surface representation of AF. Our results show that the human AF has undergone critical anatomical modifications in comparison with the macaque AF. More generally, this work demonstrates that studies on the human brain specializations underlying the language connectome can benefit from current methodological advances in comparative neuroanatomy.