Neural encoding of musical expectations in a non-human primate.

The appreciation of music is a universal trait of humankind.1,2,3 Evidence supporting this notion includes the ubiquity of music across cultures4,5,6,7 and the natural predisposition toward music that humans display early in development.8,9,10 Are we musical animals because of species-specific predispositions? This question cannot be answered by relying on cross-cultural or developmental studies alone, as these cannot rule out enculturation.11 Instead, it calls for cross-species experiments testing whether homologous neural mechanisms underlying music perception are present in non-human primates. We present music to two rhesus monkeys, reared without musical exposure, while recording electroencephalography (EEG) and pupillometry. Monkeys exhibit higher engagement and neural encoding of expectations based on the previously seeded musical context when passively listening to real music as opposed to shuffled controls. We then compare human and monkey neural responses to the same stimuli and find a species-dependent contribution of two fundamental musical features-pitch and timing12-in generating expectations: while timing- and pitch-based expectations13 are similarly weighted in humans, monkeys rely on timing rather than pitch. Together, these results shed light on the phylogeny of music perception. They highlight monkeys' capacity for processing temporal structures beyond plain acoustic processing, and they identify a species-dependent contribution of time- and pitch-related features to the neural encoding of musical expectations.

A view-based decision mechanism for rewards in the primate amygdala.

Primates make decisions visually by shifting their view from one object to the next, comparing values between objects, and choosing the best reward, even before acting. Here, we show that when monkeys make value-guided choices, amygdala neurons encode their decisions in an abstract, purely internal representation defined by the monkey's current view but not by specific object or reward properties. Across amygdala subdivisions, recorded activity patterns evolved gradually from an object-specific value code to a transient, object-independent code in which currently viewed and last-viewed objects competed to reflect the emerging view-based choice. Using neural-network modeling, we identified a sequence of computations by which amygdala neurons implemented view-based decision making and eventually recovered the chosen object's identity when the monkeys acted on their choice. These findings reveal a neural mechanism in the amygdala that derives object choices from abstract, view-based computations, suggesting an efficient solution for decision problems with many objects.

The parietal lobe evolution and the emergence of material culture in the human genus.

Traditional and new disciplines converge in suggesting that the parietal lobe underwent a considerable expansion during human evolution. Through the study of endocasts and shape analysis, paleoneurology has shown an increased globularity of the braincase and bulging of the parietal region in modern humans, as compared to other human species, including Neandertals. Cortical complexity increased in both the superior and inferior parietal lobules. Emerging fields bridging archaeology and neuroscience supply further evidence of the involvement of the parietal cortex in human-specific behaviors related to visuospatial capacity, technological integration, self-awareness, numerosity, mathematical reasoning and language. Here, we complement these inferences on the parietal lobe evolution, with results from more classical neuroscience disciplines, such as behavioral neurophysiology, functional neuroimaging, and brain lesions; and apply these to define the neural substrates and the role of the parietal lobes in the emergence of functions at the core of material culture, such as tool-making, tool use and constructional abilities.

Evidence for a we-representation in monkeys when acting together.

A hallmark of human evolution resides in the ability to adapt our actions to those of others. This aptitude optimizes collective behavior, allowing to achieve goals unattainable by acting alone. We have previously shown that macaque monkeys are able to coordinate their actions when engaged in dyadic contexts, therefore they offer a good model to study the roots of joint action. Here, we analyze the behavior of five macaques required to perform visuomotor isometric tasks, either individually or together with a partner. By pre-cueing or not the future action condition (SOLO or TOGETHER) we investigated the existence of a 'We-representation' in monkeys. We found that pre-instructing the action context improves the dyadic performance, thanks to the emergence of an optimal kinematic setting, that facilitates inter-individual motor coordination. Our results offer empirical evidence of a 'We-representation' in macaques, that when evoked provides an overall beneficial effect on joint performance.

Shared population-level dynamics in monkey premotor cortex during solo action, joint action and action observation.

Studies of neural population dynamics of cell activity from monkey motor areas during reaching show that it mostly represents the generation and timing of motor behavior. We compared neural dynamics in dorsal premotor cortex (PMd) during the performance of a visuomotor task executed individually or cooperatively and during an observation task. In the visuomotor conditions, monkeys applied isometric forces on a joystick to guide a visual cursor in different directions, either alone or jointly with a conspecific. In the observation condition, they observed the cursor's motion guided by the partner. We found that in PMd neural dynamics were widely shared across action execution and observation, with cursor motion directions more accurately discriminated than task types. This suggests that PMd encodes spatial aspects irrespective of specific behavioral demands. Furthermore, our results suggest that largest components of premotor population dynamics, which have previously been suggested to reflect a transformation from planning to movement execution, may rather reflect higher cognitive-motor processes, such as the covert representation of actions and goals shared across tasks that require movement and those that do not.

The functional characterization of callosal connections.

The brain operates through the synaptic interaction of distant neurons within flexible, often heterogeneous, distributed systems. Histological studies have detailed the connections between distant neurons, but their functional characterization deserves further exploration. Studies performed on the corpus callosum in animals and humans are unique in that they capitalize on results obtained from several neuroscience disciplines. Such data inspire a new interpretation of the function of callosal connections and delineate a novel road map, thus paving the way toward a general theory of cortico-cortical connectivity. Here we suggest that callosal axons can drive their post-synaptic targets preferentially when coupled to other inputs endowing the cortical network with a high degree of conditionality. This might depend on several factors, such as their pattern of convergence-divergence, the excitatory and inhibitory operation mode, the range of conduction velocities, the variety of homotopic and heterotopic projections and, finally, the state-dependency of their firing. We propose that, in addition to direct stimulation of post-synaptic targets, callosal axons often play a conditional driving or modulatory role, which depends on task contingencies, as documented by several recent studies.

The Complex Hodological Architecture of the Macaque Dorsal Intraparietal Areas as Emerging from Neural Tracers and DW-MRI Tractography.

In macaque monkeys, dorsal intraparietal areas are involved in several daily visuomotor actions. However, their border and sources of cortical afferents remain loosely defined. Combining retrograde histologic tracing and MRI diffusion-based tractography, we found a complex hodology of the dorsal bank of the intraparietal sulcus (db-IPS), which can be subdivided into a rostral intraparietal area PEip, projecting to the spinal cord, and a caudal medial intraparietal area MIP lacking such projections. Both include an anterior and a posterior sector, emerging from their ipsilateral, gradient-like connectivity profiles. As tractography estimations, we used the cross-sectional area of the white matter bundles connecting each area with other parietal and frontal regions, after selecting regions of interest (ROIs) corresponding to the injection sites of neural tracers. For most connections, we found a significant correlation between the proportions of cells projecting to all sectors of PEip and MIP along the continuum of the db-IPS and tractography. The latter also revealed "false positive" but plausible connections awaiting histologic validation.

On the cortical connectivity in the macaque brain: A comparison of diffusion tractography and histological tracing data.

Diffusion-weighted magnetic resonance imaging (DW-MRI) tractography is a non-invasive tool to probe neural connections and the structure of the white matter. It has been applied successfully in studies of neurological disorders and normal connectivity. Recent work has revealed that tractography produces a high incidence of false-positive connections, often from "bottleneck" white matter configurations. The rich literature in histological connectivity analysis studies in the macaque monkey enables quantitative evaluation of the performance of tractography algorithms. In this study, we use the intricate connections of frontal, cingulate, and parietal areas, well established by the anatomical literature, to derive a symmetrical histological connectivity matrix composed of 59 cortical areas. We evaluate the performance of fifteen diffusion tractography algorithms, including global, deterministic, and probabilistic state-of-the-art methods for the connectivity predictions of 1711 distinct pairs of areas, among which 680 are reported connected by the literature. The diffusion connectivity analysis was performed on a different ex-vivo macaque brain, acquired using multi-shell DW-MRI protocol, at high spatial and angular resolutions. Across all tested algorithms, the true-positive and true-negative connections were dominant over false-positive and false-negative connections, respectively. Moreover, three-quarters of streamlines had endpoints location in agreement with histological data, on average. Furthermore, probabilistic streamline tractography algorithms show the best performances in predicting which areas are connected. Altogether, we propose a method for quantitative evaluation of tractography algorithms, which aims at improving the sensitivity and the specificity of diffusion-based connectivity analysis. Overall, those results confirm the usefulness of tractography in predicting connectivity, although errors are produced. Many of the errors result from bottleneck white matter configurations near the cortical grey matter and should be the target of future implementation of methods.

Corticocortical Systems Underlying High-Order Motor Control.

Cortical networks are characterized by the origin, destination, and reciprocity of their connections, as well as by the diameter, conduction velocity, and synaptic efficacy of their axons. The network formed by parietal and frontal areas lies at the core of cognitive-motor control because the outflow of parietofrontal signaling is conveyed to the subcortical centers and spinal cord through different parallel pathways, whose orchestration determines, not only when and how movements will be generated, but also the nature of forthcoming actions. Despite intensive studies over the last 50 years, the role of corticocortical connections in motor control and the principles whereby selected cortical networks are recruited by different task demands remain elusive. Furthermore, the synaptic integration of different cortical signals, their modulation by transthalamic loops, and the effects of conduction delays remain challenging questions that must be tackled to understand the dynamical aspects of parietofrontal operations. In this article, we evaluate results from nonhuman primate and selected rodent experiments to offer a viewpoint on how corticocortical systems contribute to learning and producing skilled actions. Addressing this subject is not only of scientific interest but also essential for interpreting the devastating consequences for motor control of lesions at different nodes of this integrated circuit. In humans, the study of corticocortical motor networks is currently based on MRI-related methods, such as resting-state connectivity and diffusion tract-tracing, which both need to be contrasted with histological studies in nonhuman primates.

Two Brains in Action: Joint-Action Coding in the Primate Frontal Cortex.

Daily life often requires the coordination of our actions with those of another partner. After 50 years (1968-2018) of behavioral neurophysiology of motor control, the neural mechanisms that allow such coordination in primates are unknown. We studied this issue by recording cell activity simultaneously from dorsal premotor cortex (PMd) of two male interacting monkeys trained to coordinate their hand forces to achieve a common goal. We found a population of "joint-action cells" that discharged preferentially when monkeys cooperated in the task. This modulation was predictive in nature, because in most cells neural activity led in time the changes of the "own" and of the "other" behavior. These neurons encoded the joint-performance more accurately than "canonical action-related cells", activated by the action per se, regardless of the individual versus interactive context. A decoding of joint-action was obtained by combining the two brains' activities, using cells with directional properties distinguished from those associated to the "solo" behaviors. Action observation-related activity studied when one monkey observed the consequences of the partner's behavior, i.e., the cursor's motion on the screen, did not sharpen the accuracy of joint-action cells' representation, suggesting that it plays no major role in encoding joint-action. When monkeys performed with a non-interactive partner, such as a computer, joint-action cells' representation of the other (non-cooperative) behavior was significantly degraded. These findings provide evidence of how premotor neurons integrate the time-varying representation of the self-action with that of a co-actor, thus offering a neural substrate for successful visuomotor coordination between individuals.SIGNIFICANCE STATEMENT The neural bases of intersubject motor coordination were studied by recording cell activity simultaneously from the frontal cortex of two interacting monkeys, trained to coordinate their hand forces to achieve a common goal. We found a new class of cells, preferentially active when the monkeys cooperated, rather than when the same action was performed individually. These "joint-action neurons" offered a neural representation of joint-behaviors by far more accurate than that provided by the "canonical action-related cells", modulated by the action per se regardless of the individual/interactive context. A neural representation of joint-performance was obtained by combining the activity recorded from the two brains. Our findings offer the first evidence concerning neural mechanisms subtending interactive visuomotor coordination between co-acting agents.

A Brief History of the Encoding of Hand Position by the Cerebral Cortex: Implications for Motor Control and Cognition.

Encoding hand position by the cerebral cortex is essential not only for the neural representation of the body image but also for different actions based on eye-hand coordination. These include reaching for visual objects as well as complex movement sequences, such as tea-making, tool use, and object construction, among many others. All these functions depend on a continuous refreshing of the hand position representation, relying on both predictive signaling and afferent information. The hand position influence on neural activity in the parietofrontal system, together with eye position signals, are the basic elements of an eye-hand matrix from which all the above functions can emerge and could be regarded as key features of a network with several entry points, command nodes and outflow pathways, as confirmed by the discovery of a direct parietospinal projection for the control of hand action. The integrity of this system is crucial for daily life, as testified by the consequences of cortical lesions, spanning from severe paralysis to complex forms of apraxia. In this review, I will sketch my personal understanding of the scientific and conceptual trajectory of a line of investigation with many unexpected influences on cortical function and disease, from motor behavior to cognition.

Parieto-frontal networks for eye-hand coordination and movements.

Eye-hand coordination lies at the core of our daily actions and interactions with objects and people around us, and is central to understanding how the brain creates internal models of the action space and generates movement within it. Eye-hand coordination remains a very complex and elusive problem, which is further complicated by its distributed representation in the brain. In fact, evolution did not confine such a crucial function to a single area, but rather assigned it to several distributed cortical and subcortical systems, where encoding mechanisms can satisfy multiple demands and the consequences of lesions are less disruptive. We will discuss evidence suggesting that eye-hand coordination is, indeed, an emerging function of internal parietal operations and of their interplay with frontal cortex, where the cortical eye and hand motor output domains reside. Therefore, coordination of eye and hand movements requires an appropriate spatiotemporal activation of the subcortical structures which control the eyes and hand. In this distributed network, information transfer between different cortical areas and with subcortical structures is based on temporally dispersed communication patterns.

Computational Architecture of the Parieto-Frontal Network Underlying Cognitive-Motor Control in Monkeys.

The statistical structure of intrinsic parietal and parieto-frontal connectivity in monkeys was studied through hierarchical cluster analysis. Based on their inputs, parietal and frontal areas were grouped into different clusters, including a variable number of areas that in most instances occupied contiguous architectonic fields. Connectivity tended to be stronger locally: that is, within areas of the same cluster. Distant frontal and parietal areas were targeted through connections that in most instances were reciprocal and often of different strength. These connections linked parietal and frontal clusters formed by areas sharing basic functional properties. This led to five different medio-laterally oriented pillar domains spanning the entire extent of the parieto-frontal system, in the posterior parietal, anterior parietal, cingulate, frontal, and prefrontal cortex. Different information processing streams could be identified thanks to inter-domain connectivity. These streams encode fast hand reaching and its control, complex visuomotor action spaces, hand grasping, action/intention recognition, oculomotor intention and visual attention, behavioral goals and strategies, and reward and decision value outcome. Most of these streams converge on the cingulate domain, the main hub of the system. All of them are embedded within a larger eye-hand coordination network, from which they can be selectively set in motion by task demands.

Parieto-frontal gradients and domains underlying eye and hand operations in the action space.

In monkeys, motor intention in its different forms emerges from a parietal-frontal gradient of visual, eye and hand signals, containing discrete dominant domains. These are formed by areas sharing cortical connections and functional properties. Within this gradient, the combination of different inputs determines the tuning properties of neurons, while local and long cortico-cortical connections shape the structure and temporal delays of the network. The pathways linking similar functional domains in parietal and frontal cortex sculpt information processing systems related to different functions, all requiring eye-hand coordination. fMRI experiments show that similar gradients lay at the core of cognitive-motor control in humans as well. This eye-hand matrix provides a framework to address, within a unitary frame, not only basic forms of motor behavior, such as reaching and grasping, but also actions of increasing complexity, such as interception of moving targets, tool use, construction of complex objects, maze analysis and solution, among others. The organization of the cerebral cortex into functional gradients and domains, beyond frontal and parietal cortices, is common to other brain regions, such as prefrontal cortex and hippocampus, and does not support views of the parieto-frontal operations based on specific and strictly segregated eye and hand modules. These can only be found at the eye and hand motor output domains in the frontal cortex, that is in the frontal eye fields and in the primary motor cortex, respectively.

Modulation of Neural Variability in Premotor, Motor, and Posterior Parietal Cortex during Change of Motor Intention.

The time course of neural variability was studied in three nodes of the parieto-frontal system: the dorsal premotor cortex (PMd, area 6), primary motor cortex (MI, area 4), and posterior parietal cortex (PPC, area 5) while monkeys made either direct reaches to visual targets or changed reach direction in response to an unexpected change of target location. These areas are crucial nodes in the distributed control of reaching and their lesion impairs trajectory formation and correction under different circumstances. During unperturbed reaches, neural variability declined before the onset of hand movement in both frontal and parietal cortex. When the original motor intention suddenly changed, neural variability displayed a complex and area-specific modulation because the perturbation of the motor state was signaled earlier in PMd than in MI and PPC. The comparison of perturbed versus unperturbed reaches revealed that, in the time between the onset of correction signal and trajectory change, identical hand movements were associated with different, therefore context-dependent, patterns of neural variability induced by the instruction to change hand movement direction. In PMd, neural variability was higher before the initiation of hand reach than before its correction, thus providing a neural underpinning to the phenomenon that it takes less time to correct than to initiate hand movement. Furthermore, neural variability was an excellent predictor of slow and fast reach corrections because it was lower during the latter than the former. We conclude that the analysis of neural variability can be an important tool for the study of complex forms of motor cognition. SIGNIFICANCE STATEMENT: No single study has been performed on neural variability during update of motor intention across monkey premotor, motor, and posterior parietal cortex. In perturbed reaches, target location changed unexpectedly during reaction time and the correction of hand trajectory required updating the original motor plan. Comparing unperturbed versus perturbed reaches revealed that neural variability displayed a complex context- and area-dependent pattern of modulation because, before trajectory correction, similar initial hand movements were associated with different patterns of variability depending on the instruction signal, and therefore on the future hand path and final destination. Furthermore, neural variability predicted both slow and fast hand movement corrections, also offering a neural underpinning to the phenomenon that it takes less time to correct than to initiate hand movement.

Posterior Parietal Cortex Encoding of Dynamic Hand Force Underlying Hand-Object Interaction.

Major achievements of primate evolution are skilled hand-object interaction and tool use, both in part dependent on parietal cortex expansion. We recorded spiking activity from macaque inferior parietal cortex during directional manipulation of an isometric tool, which required the application of hand forces to control a cursor's motion on a screen. In areas PFG/PF, the activity of ∼ 70% neurons was modulated by the hand force necessary to implement the desired target motion, reflecting an inverse model, rather than by the intended motion of the visual cursor (forward model). The population vector matched the direction and amplitude of the instantaneous force increments over time. When exposed to a new force condition, that obliged the monkey to change the force output to successfully bring the cursor to the final target, the activity of a consistent subpopulation of neurons changed in an orderly fashion and, at the end of a "Wash-out" session, retained memory of the new learned association, at the service of predictive control of force. Our findings suggest that areas PFG/PF represent a crucial node of the distributed control of hand force, by encoding instantaneous force variations and serving as a memory reservoir of hand dynamics required for object manipulation and tool use. This is coherent with previous studies in humans showing the following: (1) impaired adaptation to a new force field under TMS parietal perturbation; (2) defective control of direction of hand force after parietal lesion; and (3) fMRI activation of parietal cortex during object manipulation requiring control of fine hand forces. SIGNIFICANCE STATEMENT: Skilled object manipulation and tool use are major achievements of primate evolution, both largely dependent on posterior parietal cortex (PPC) expansion. Neurophysiological and fMRI studies in macaque and humans had documented a crucial role of PPC in encoding the hand kinematics underlying these functions, leaving to premotor and motor areas the role of specifying the underlying hand forces. We recorded spiking activity from macaque PPC during manipulation of an isometric tool and found that population activity is not only modulated by the dynamic hand force and its change over time, but also retains memory of the exerted force, as a reservoir to guide of future hand action. This suggests parallel parietal encoding of hand dynamics and kinematics during object manipulation.

Organization and evolution of parieto-frontal processing streams in macaque monkeys and humans.

The functional organization of the parieto-frontal system is crucial for understanding cognitive-motor behavior and provides the basis for interpreting the consequences of parietal lesions in humans from a neurobiological perspective. The parieto-frontal connectivity defines some main information streams that, rather than being devoted to restricted functions, underlie a rich behavioral repertoire. Surprisingly, from macaque to humans, evolution has added only a few, new functional streams, increasing however their complexity and encoding power. In fact, the characterization of the conduction times of parietal and frontal areas to different target structures has recently opened a new window on cortical dynamics, suggesting that evolution has amplified the probability of dynamic interactions between the nodes of the network, thanks to communication patterns based on temporally-dispersed conduction delays. This might allow the representation of sensory-motor signals within multiple neural assemblies and reference frames, as to optimize sensory-motor remapping within an action space characterized by different and more complex demands across evolution.

Do non-human primates cooperate? Evidences of motor coordination during a joint action task in macaque monkeys.

Humans are intensively social primates, therefore many of their actions are dedicated to communication and interaction with other individuals. Despite the progress in understanding the cognitive and neural processes that allow humans to perform cooperative actions, in non-human primates only few studies have investigated the ability to interact with a partner in order to reach a common goal. These studies have shown that in naturalistic conditions animals engage in various types of social behavior that involve forms of mutual coordination and cooperation. However, little is known on the capacity of non-human primates to actively cooperate in a controlled experimental setting, which allows full characterization of the motor parameters underlying individual action and their change during motor cooperation. To this aim, we analyzed the behavior of three pairs of macaque monkeys trained to perform solo and joint-actions by exerting a force on an isometric joystick, as to move an individual or a common cursor toward visual targets on a screen. We found that during cooperation monkeys reciprocally adapt their behavior by changing the parameters that define the spatial and temporal aspects of their action, as to fine tune their joint effort, and maximize their common performance. Furthermore the results suggest that when acting together the movement parameters that specify each actor's behavior are not only modulated during execution, but also during planning. These findings provide the first quantitative description of action coordination in non-human primates during the performance of a joint action task.

Timing and communication of parietal cortex for visuomotor control.

In both monkeys and humans, motor cognition emerges from a parietal-frontal network containing discrete dominant domains of visual, eye and hand signals, where neurons are responsible for goal and effector selection. Within these domains, the combination of different inputs shape the tuning properties of neurons, while local and long cortico-cortical connections outline the architecture of the distributed network and determine the conduction time underlying eye-hand coordination, necessary for visually guided operations in the action space. The analysis of the communication timing between parietal and frontal nodes of the network helps understanding the sensorimotor cortical delays associated to different functions, such as online control of movement and eye-hand coordination, and opens a new perspective to the study of the parieto-frontal interactions.

Correction and suppression of reaching movements in the cerebral cortex: physiological and neuropsychological aspects.

Modification or suppression of reaches occurs in everyday life. We argue that a common modular architecture, based on similar neural structures and principles of kinematic and kinetic control, is used for both direct reaches and for their on-line corrections. When a reach is corrected, both the pattern of neural activity in parietal, premotor and motor cortex and the muscle synergies associated with the first movement can be smoothly blended or sharply substituted into those associated with the second one. Premotor cortex provides the early signaling for trajectory updating, while parietal and motor cortex provide the fine-grained encoding of hand kinematics necessary to reshape the motor plan. The cortical contribution to the inhibitory control of reaching is supported by the activity of a network of frontal areas. Premotor cortex has been proposed as a key structure for reaching suppression. Consistent with this, lesions in different nodes of this network result in different forms of motor deficits, such as Optic Ataxia in parietal patients, and commission errors in frontal ones.