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.

Validity of chronometric TMS for probing the time-course of word production: a modified replication.

In the present study, we used chronometric TMS to probe the time-course of 3 brain regions during a picture naming task. The left inferior frontal gyrus, left posterior middle temporal gyrus, and left posterior superior temporal gyrus were all separately stimulated in 1 of 5 time-windows (225, 300, 375, 450, and 525 ms) from picture onset. We found posterior temporal areas to be causally involved in picture naming in earlier time-windows, whereas all 3 regions appear to be involved in the later time-windows. However, chronometric TMS produces nonspecific effects that may impact behavior, and furthermore, the time-course of any given process is a product of both the involved processing stages along with individual variation in the duration of each stage. We therefore extend previous work in the field by accounting for both individual variations in naming latencies and directly testing for nonspecific effects of TMS. Our findings reveal that both factors influence behavioral outcomes at the group level, underlining the importance of accounting for individual variations in naming latencies, especially for late processing stages closer to articulation, and recognizing the presence of nonspecific effects of TMS. The paper advances key considerations and avenues for future work using chronometric TMS to study overt production.

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.

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.

Longitudinal connections and the organization of the temporal cortex in macaques, great apes, and humans.

The temporal association cortex is considered a primate specialization and is involved in complex behaviors, with some, such as language, particularly characteristic of humans. The emergence of these behaviors has been linked to major differences in temporal lobe white matter in humans compared with monkeys. It is unknown, however, how the organization of the temporal lobe differs across several anthropoid primates. Therefore, we systematically compared the organization of the major temporal lobe white matter tracts in the human, gorilla, and chimpanzee great apes and in the macaque monkey. We show that humans and great apes, in particular the chimpanzee, exhibit an expanded and more complex occipital-temporal white matter system; additionally, in humans, the invasion of dorsal tracts into the temporal lobe provides a further specialization. We demonstrate the reorganization of different tracts along the primate evolutionary tree, including distinctive connectivity of human temporal gray matter.

Human Lateral Frontal Pole Contributes to Control over Emotional Approach-Avoidance Actions.

Regulation of emotional behavior is essential for human social interactions. Recent work has exposed its cognitive complexity, as well as its unexpected reliance on portions of the anterior PFC (aPFC) also involved in exploration, relational reasoning, and counterfactual choice, rather than on dorsolateral and medial prefrontal areas involved in several forms of cognitive control. This study anatomically qualifies the contribution of aPFC territories to the regulation of prepotent approach-avoidance action tendencies elicited by emotional faces, and explores a possible structural pathway through which this emotional action regulation might be implemented. We provide converging evidence from task-based fMRI, diffusion-weighted imaging, and functional connectivity fingerprints for a novel neural element in emotional regulation. Task-based fMRI in human male participants (N = 40) performing an emotional approach-avoidance task identified aPFC territories involved in the regulation of action tendencies elicited by emotional faces. Connectivity fingerprints, based on diffusion-weighted imaging and resting-state connectivity, localized those task-defined frontal regions to the lateral frontal pole (FPl), an anatomically defined portion of the aPFC that lacks a homologous counterpart in macaque brains. Probabilistic tractography indicated that 10%-20% of interindividual variation in emotional regulation abilities is accounted for by the strength of structural connectivity between FPl and amygdala. Evidence from an independent replication sample (N = 50; 10 females) further substantiated this result. These findings provide novel neuroanatomical evidence for incorporating FPl in models of control over human action tendencies elicited by emotional faces.SIGNIFICANCE STATEMENT Successful regulation of emotional behaviors is a prerequisite for successful participation in human society, as is evidenced by the social isolation and loss of occupational opportunities often encountered by people suffering from emotion regulation disorders, such as social-anxiety disorder and psychopathy. Knowledge about the precise cortical regions and connections supporting this control is crucial for understanding both the nature of computations needed to successfully traverse the space of possible actions in social situations, and the potential interventions that might result in efficient treatment of social-emotional disorders. This study provides evidence for a precise cortical region (lateral frontal pole) and a structural pathway (the ventral amygdalofugal bundle) through which a cognitively complex form of emotional action regulation might be implemented in the human brain.

Low-beta repetitive transcranial magnetic stimulation to human dorsolateral prefrontal cortex during object recognition memory sample presentation, at a task-related frequency observed in local field potentials in homologous macaque cortex, impairs subsequent recollection but not familiarity.

According to dual-process signal-detection (DPSD) theories, short- and long-term recognition memory draws upon both familiarity and recollection. It remains unclear how primate prefrontal cortex (PFC) contributes to these processes, but frequency-specific neuronal activities are considered to play a key role. In Experiment 1, nonhuman primate (NHP) local field potential (LFP) electrophysiological recordings in macaque left dorsolateral PFC (dlPFC) revealed performance-related differences in a low-beta frequency range during the sample presentation phase of a visual object recognition memory task. Experiment 2 employed a similar task in humans and targeted left dlPFC (and vertex as a control) with repetitive transcranial magnetic stimulation (rTMS) at 12.5 Hz during occasional sample presentations. This low-beta frequency rTMS to dlPFC decreased DPSD derived indices of recollection, but not familiarity, in subsequent memory tests of the targeted samples after short delays. The same number of rTMS pulses over the same total duration albeit at a random frequency had no effect on either recollection or familiarity. Neither stimulation protocols had any causal effect upon behaviour when targeted to the control site (vertex). In this study, our hypotheses for our human TMS study were derived from our observations in NHPs; this approach might inspire further translational research through investigation of homologous brain regions and tasks across species using similar neuroscientific methodologies to advance the neural mechanism of recognition memory in primates.

The Human Ventromedial Prefrontal Cortex: Sulcal Morphology and Its Influence on Functional Organization.

The ventromedial prefrontal cortex (vmPFC), which comprises several distinct cytoarchitectonic areas, is a key brain region supporting decision-making processes, and it has been shown to be one of the main hubs of the Default Mode Network, a network classically activated during resting state. We here examined the interindividual variability in the vmPFC sulcal morphology in 57 humans (37 females) and demonstrated that the presence/absence of the inferior rostral sulcus and the subgenual intralimbic sulcus influences significantly the sulcal organization of this region. Furthermore, the sulcal organization influences the location of the vmPFC peak of the Default Mode Network, demonstrating that the location of functional activity can be affected by local sulcal patterns. These results are critical for the investigation of the function of the vmPFC and show that taking into account the sulcal variability might be essential to guide the interpretation of neuroimaging studies.SIGNIFICANCE STATEMENT The ventromedial prefrontal cortex (vmPFC) is one of the main hubs of the Default Mode Network and plays a central role in value coding and decision-making. The present study provides a complete description of the interindividual variability of anatomical morphology of this large portion of prefrontal cortex and its relation to functional organization. We have shown that two supplementary medial sulci predominantly determine the organization of the vmPFC, which in turn affects the location of the functional peak of activity in this region. Those results show that taking into account the variability in sulcal patterns might be essential to guide the interpretation of neuroimaging studies of the human brain and of the vmPFC in particular.

Cerebral coherence between communicators marks the emergence of meaning.

How can we understand each other during communicative interactions? An influential suggestion holds that communicators are primed by each other's behaviors, with associative mechanisms automatically coordinating the production of communicative signals and the comprehension of their meanings. An alternative suggestion posits that mutual understanding requires shared conceptualizations of a signal's use, i.e., "conceptual pacts" that are abstracted away from specific experiences. Both accounts predict coherent neural dynamics across communicators, aligned either to the occurrence of a signal or to the dynamics of conceptual pacts. Using coherence spectral-density analysis of cerebral activity simultaneously measured in pairs of communicators, this study shows that establishing mutual understanding of novel signals synchronizes cerebral dynamics across communicators' right temporal lobes. This interpersonal cerebral coherence occurred only within pairs with a shared communicative history, and at temporal scales independent from signals' occurrences. These findings favor the notion that meaning emerges from shared conceptualizations of a signal's use.

Neural mechanisms of communicative innovation.

Human referential communication is often thought as coding-decoding a set of symbols, neglecting that establishing shared meanings requires a computational mechanism powerful enough to mutually negotiate them. Sharing the meaning of a novel symbol might rely on similar conceptual inferences across communicators or on statistical similarities in their sensorimotor behaviors. Using magnetoencephalography, we assess spectral, temporal, and spatial characteristics of neural activity evoked when people generate and understand novel shared symbols during live communicative interactions. Solving those communicative problems induced comparable changes in the spectral profile of neural activity of both communicators and addressees. This shared neuronal up-regulation was spatially localized to the right temporal lobe and the ventromedial prefrontal cortex and emerged already before the occurrence of a specific communicative problem. Communicative innovation relies on neuronal computations that are shared across generating and understanding novel shared symbols, operating over temporal scales independent from transient sensorimotor behavior.

Hierarchical organization of parietofrontal circuits during goal-directed action.

Two parietofrontal networks share the control of goal-directed movements: a dorsomedial circuit that includes the superior parieto-occipital sulcus (sPOS) and a dorsolateral circuit comprising the anterior intraparietal sulcus (aIPS). These circuits are thought to independently control either reach and grip components (a functional dissociation), or planning and execution phases of grasping movements (a temporal dissociation). However, recent evidence of functional and temporal overlap between these circuits has undermined those models. Here, we test an alternative model that subsumes previous accounts: the dorsolateral and dorsomedial circuits operate at different hierarchical levels, resulting in functional and temporal dependencies between their computations. We asked human participants to grasp a visually presented object, manipulating movement complexity by varying object slant. We used concurrent single-pulse transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe and record neurophysiological activity in the two circuits. Changes in alpha-band oscillations (8-12 Hz) characterized the effects of task manipulations and TMS interferences over aIPS and sPOS. Increasing the complexity of the grasping movement was accompanied by alpha-suppression over dorsomedial parietofrontal regions, including sPOS, during both planning and execution stages. TMS interference over either aIPS or sPOS disrupted this index of dorsomedial computations; early when aIPS was perturbed, later when sPOS was perturbed, indicating that the dorsomedial circuit is temporally dependent on aIPS. TMS over sPOS enhanced alpha-suppression in inferior parietal cortex, indicating that the dorsolateral circuit can compensate for a transient sPOS perturbation. These findings suggest that both circuits specify the same grasping parameters, with dorsomedial computations depending on dorsolateral contributions.

Reduced serotonin transporter availability decreases prefrontal control of the amygdala.

After a threatening event, the risk of developing social psychopathologies is increased in short-allele (s) carriers of the serotonin transporter gene. The amygdala becomes overresponsive to emotional stimuli, an effect that could be driven by local hypersensitivity or by reduced prefrontal regulation. This study distinguishes between these two hypotheses by using dynamic causal modeling of fMRI data acquired in a preselected cohort of human s-carriers and homozygous long-allele carriers. Increased amygdala activity in s-carriers originates from reduced prefrontal inhibitory regulation when social emotional behavior needs to be controlled, suggesting a mechanism for increased vulnerability to psychopathologies.

The relationship between parameters and effects in transcranial ultrasonic stimulation.

Transcranial ultrasonic stimulation (TUS) is rapidly gaining traction for non-invasive human neuromodulation, with a pressing need to establish protocols that maximise neuromodulatory efficacy. In this review, we aggregate and examine empirical evidence for the relationship between tunable TUS parameters and in vitro and in vivo outcomes. Based on this multiscale approach, TUS researchers can make better informed decisions about optimal parameter settings. Importantly, we also discuss the challenges involved in extrapolating results from prior empirical work to future interventions, including the translation of protocols between models and the complex interaction between TUS protocols and the brain. A synthesis of the empirical evidence suggests that larger effects will be observed at lower frequencies within the sub-MHz range, higher intensities and pressures than commonly administered thus far, and longer pulses and pulse train durations. Nevertheless, we emphasise the need for cautious interpretation of empirical data from different experimental paradigms when basing protocols on prior work as we advance towards refined TUS parameters for human neuromodulation.

Biophysical effects and neuromodulatory dose of transcranial ultrasonic stimulation.

Transcranial ultrasonic stimulation (TUS) has the potential to usher in a new era for human neuroscience by allowing spatially precise and high-resolution non-invasive targeting of both deep and superficial brain regions. Currently, fundamental research on the mechanisms of interaction between ultrasound and neural tissues is progressing in parallel with application-focused research. However, a major hurdle in the wider use of TUS is the selection of optimal parameters to enable safe and effective neuromodulation in humans. In this paper, we will discuss the major factors that determine both the safety and efficacy of TUS. We will discuss the thermal and mechanical biophysical effects of ultrasound, which underlie its biological effects, in the context of their relationships with tunable parameters. Based on this knowledge of biophysical effects, and drawing on concepts from radiotherapy, we propose a framework for conceptualising TUS dose.

ITRUSST consensus on standardised reporting for transcranial ultrasound stimulation.

As transcranial ultrasound stimulation (TUS) advances as a precise, non-invasive neuromodulatory method, there is a need for consistent reporting standards to enable comparison and reproducibility across studies. To this end, the International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST) formed a subcommittee of experts across several domains to review and suggest standardised reporting parameters for low intensity TUS, resulting in the guide presented here. The scope of the guide is limited to reporting the ultrasound aspects of a study. The guide and supplementary material provide a simple checklist covering the reporting of: (1) the transducer and drive system, (2) the drive system settings, (3) the free field acoustic parameters, (4) the pulse timing parameters, (5) in situ estimates of exposure parameters in the brain, and (6) intensity parameters. Detailed explanations for each of the parameters, including discussions on assumptions, measurements, and calculations, are also provided.

ITRUSST Consensus on Standardised Reporting for Transcranial Ultrasound Stimulation.

As transcranial ultrasound stimulation (TUS) advances as a precise, non-invasive neuromodulatory method, there is a need for consistent reporting standards to enable comparison and reproducibility across studies. To this end, the International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST) formed a subcommittee of experts across several domains to review and suggest standardised reporting parameters for low intensity TUS, resulting in the guide presented here. The scope of the guide is limited to reporting the ultrasound aspects of a study. The guide and supplementary material provide a simple checklist covering the reporting of: (1) the transducer and drive system, (2) the drive system settings, (3) the free field acoustic parameters, (4) the pulse timing parameters, (5) in situ estimates of exposure parameters in the brain, and (6) intensity parameters. Detailed explanations for each of the parameters, including discussions on assumptions, measurements, and calculations, are also provided.

Auditory confounds can drive online effects of transcranial ultrasonic stimulation in humans.

Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Furthermore, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Furthermore, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.

Cortical dynamics of sensorimotor integration during grasp planning.

Our sensorimotor interactions with objects are guided by their current spatial and perceptual features, as well as by learned object knowledge. A fresh red tomato is grasped differently than a soft overripe tomato, even when those objects possess the same spatial metrics of size and shape. Objects' spatial and perceptual features need to be integrated during grasping, but those features are analyzed in two anatomically distinct neural pathways. The anterior intraparietal sulcus (aIPS) might support the integration of those features. We combine transcranial magnetic stimulation (TMS) interference, EEG recordings, and psychophysical methods to test aIPS causal contributions to sensorimotor integration, characterizing the dynamics of those contributions during motor planning. Human subjects performing grasping movements were provided with visual information about a target object, namely spatial and pictorial cues, whose availability and information value were independently modulated on each trial. Maximally informative visual cues, irrespective of their spatial or perceptual nature, led to enhanced motor preparatory activity early during movement planning, and to stronger spatial congruency between finger trajectories and target object. Disturbing aIPS activity with single-pulse TMS within 200 ms after object presentation reduced those electrophysiological and behavioral indices of enhanced motor planning. TMS interference with aIPS also disturbed subjects' ability to use learned object knowledge during motor planning. These results indicate that aIPS is necessary for the fast generation of a new motor plan on the basis of both spatial and pictorial cues. Furthermore, as learned object knowledge becomes available, aIPS comes to strongly depend on this prior information for structuring the motor plan.

Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans.

Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive technique for focally modulating human brain function. The mechanisms and neurochemical substrates underlying TUS neuromodulation in humans and how these relate to excitation and inhibition are still poorly understood. In 24 healthy controls, we separately stimulated two deep cortical regions and investigated the effects of theta-burst TUS, a protocol shown to increase corticospinal excitability, on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and functional connectivity. We show that theta-burst TUS in humans selectively reduces GABA levels in the posterior cingulate, but not the dorsal anterior cingulate cortex. Functional connectivity increased following TUS in both regions. Our findings suggest that TUS changes overall excitability by reducing GABAergic inhibition and that changes in TUS-mediated neuroplasticity last at least 50 mins after stimulation. The difference in TUS effects on the posterior and anterior cingulate could suggest state- or location-dependency of the TUS effect-both mechanisms increasingly recognized to influence the brain's response to neuromodulation.

Three-layer model with absorption for conservative estimation of the maximum acoustic transmission coefficient through the human skull for transcranial ultrasound stimulation.

Transcranial ultrasound stimulation (TUS) has been shown to be a safe and effective technique for non-invasive superficial and deep brain stimulation. Safe and efficient translation to humans requires estimating the acoustic attenuation of the human skull. Nevertheless, there are no international guidelines for estimating the impact of the skull bone. A tissue independent, arbitrary derating was developed by the U.S. Food and Drug Administration to take into account tissue absorption (0.3 dB/cm-MHz) for diagnostic ultrasound. However, for the case of transcranial ultrasound imaging, the FDA model does not take into account the insertion loss induced by the skull bone, nor the absorption by brain tissue. Therefore, the estimated absorption is overly conservative which could potentially limit TUS applications if the same guidelines were to be adopted. Here we propose a three-layer model including bone absorption to calculate the maximum pressure transmission through the human skull for frequencies ranging between 100 kHz and 1.5 MHz. The calculated pressure transmission decreases with the frequency and the thickness of the bone, with peaks for each thickness corresponding to a multiple of half the wavelength. The 95th percentile maximum transmission was calculated over the accessible surface of 20 human skulls for 12 typical diameters of the ultrasound beam on the skull surface, and varies between 40% and 78%. To facilitate the safe adjustment of the acoustic pressure for short ultrasound pulses, such as transcranial imaging or transcranial ultrasound stimulation, a table summarizes the maximum pressure transmission for each ultrasound beam diameter and each frequency.