Spike-timing-dependent plasticity induction reveals dissociable supplementary- and premotor-motor pathways to automatic imitation.

Humans tend to spontaneously imitate others' behavior, even when detrimental to the task at hand. The action observation network (AON) is consistently recruited during imitative tasks. However, whether automatic imitation is mediated by cortico-cortical projections from AON regions to the primary motor cortex (M1) remains speculative. Similarly, the potentially dissociable role of AON-to-M1 pathways involving the ventral premotor cortex (PMv) or supplementary motor area (SMA) in automatic imitation is unclear. Here, we used cortico-cortical paired associative stimulation (ccPAS) to enhance or hinder effective connectivity in PMv-to-M1 and SMA-to-M1 pathways via Hebbian spike-timing-dependent plasticity (STDP) to test their functional relevance to automatic and voluntary motor imitation. ccPAS affected behavior under competition between task rules and prepotent visuomotor associations underpinning automatic imitation. Critically, we found dissociable effects of manipulating the strength of the two pathways. While strengthening PMv-to-M1 projections enhanced automatic imitation, weakening them hindered it. On the other hand, strengthening SMA-to-M1 projections reduced automatic imitation but also reduced interference from task-irrelevant cues during voluntary imitation. Our study demonstrates that driving Hebbian STDP in AON-to-M1 projections induces opposite effects on automatic imitation that depend on the targeted pathway. Our results provide direct causal evidence of the functional role of PMv-to-M1 projections for automatic imitation, seemingly involved in spontaneously mirroring observed actions and facilitating the tendency to imitate them. Moreover, our findings support the notion that SMA exerts an opposite gating function, controlling M1 to prevent overt motor behavior when inadequate to the context.

Meta-learning of human motor adaptation via the dorsal premotor cortex.

Meta-learning enables us to learn how to learn the same or similar tasks more efficiently. Decision-making literature theorizes that a prefrontal network, including the orbitofrontal and anterior cingulate cortices, underlies meta-learning of decision making by reinforcement learning. Recently, computationally similar meta-learning has been theorized and empirically demonstrated in motor adaptation. However, it remains unclear whether meta-learning of motor adaptation also relies on a prefrontal network. Considering hierarchical information flow from the prefrontal to motor cortices, this study explores whether meta-learning is processed in the dorsolateral prefrontal cortex (DLPFC) or in the dorsal premotor cortex (PMd), which is situated upstream of the primary motor cortex, but downstream of the DLPFC. Transcranial magnetic stimulation (TMS) was delivered to either PMd or DLPFC during a motor meta-learning task, in which human participants were trained to regulate the rate and retention of motor adaptation to maximize rewards. While motor adaptation itself was intact, TMS to PMd, but not DLPFC, attenuated meta-learning, impairing the ability to regulate motor adaptation to maximize rewards. Further analyses revealed that TMS to PMd attenuated meta-learning of memory retention. These results suggest that meta-learning of motor adaptation relies more on the premotor area than on a prefrontal network. Thus, while PMd is traditionally viewed as crucial for planning motor actions, this study suggests that PMd is also crucial for meta-learning of motor adaptation, processing goal-directed planning of how long motor memory should be retained to fit the long-term goal of motor adaptation.

Dynamic spatial representation of self and others' actions in the macaque frontal cortex.

Modulation of neuronal firing rates by the spatial locations of physical objects is a widespread phenomenon in the brain. However, little is known about how neuronal responses to the actions of biological entities are spatially tuned and whether such spatially tuned responses are affected by social contexts. These issues are of key importance for understanding the neural basis of embodied social cognition, such as imitation and perspective-taking. Here, we show that spatial representation of actions can be dynamically changed depending on others' social relevance and agents of action. Monkeys performed a turn-taking choice task with a real monkey partner sitting face-to-face or a filmed partner in prerecorded videos. Three rectangular buttons (left, center, and right) were positioned in front of the subject and partner as their choice targets. We recorded from single neurons in two frontal nodes in the social brain, the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC). When the partner was filmed rather than real, spatial preference for partner-actions was markedly diminished in MPFC, but not PMv, neurons. This social context-dependent modulation in the MPFC was also evident for self-actions. Strikingly, a subset of neurons in both areas switched their spatial preference between self-actions and partner-actions in a diametrically opposite manner. This observation suggests that these cortical areas are associated with coordinate transformation in ways consistent with an actor-centered perspective-taking coding scheme. The PMv may subserve such functions in context-independent manners, whereas the MPFC may do so primarily in social contexts.

Architectural experience influences the processing of others' body expressions.

The interplay between space and cognition is a crucial issue in Neuroscience leading to the development of multiple research fields. However, the relationship between architectural space and the movement of the inhabitants and their interactions has been too often neglected, failing to provide a unifying view of architecture's capacity to modulate social cognition broadly. We bridge this gap by requesting participants to judge avatars' emotional expression (high vs. low arousal) at the end of their promenade inside high- or low-arousing architectures. Stimuli were presented in virtual reality to ensure a dynamic, naturalistic experience. High-density electroencephalography (EEG) was recorded to assess the neural responses to the avatar's presentation. Observing highly aroused avatars increased Late Positive Potentials (LPP), in line with previous evidence. Strikingly, 250 ms before the occurrence of the LPP, P200 amplitude increased due to the experience of low-arousing architectures, reflecting an early greater attention during the processing of body expressions. In addition, participants stared longer at the avatar's head and judged the observed posture as more arousing. Source localization highlighted a contribution of the dorsal premotor cortex to both P200 and LPP. In conclusion, the immersive and dynamic architectural experience modulates human social cognition. In addition, the motor system plays a role in processing architecture and body expressions suggesting that the space and social cognition interplay is rooted in overlapping neural substrates. This study demonstrates that the manipulation of mere architectural space is sufficient to influence human social cognition.

Differential Formation of Motor Cortical Dynamics during Movement Preparation According to the Predictability of Go Timing.

The motor cortex not only executes but also prepares movement, as motor cortical neurons exhibit preparatory activity that predicts upcoming movements. In movement preparation, animals adopt different strategies in response to uncertainties existing in nature such as the unknown timing of when a predator will attack-an environmental cue informing "go." However, how motor cortical neurons cope with such uncertainties is less understood. In this study, we aim to investigate whether and how preparatory activity is altered depending on the predictability of "go" timing. We analyze firing activities of the anterior lateral motor cortex in male mice during two auditory delayed-response tasks each with predictable or unpredictable go timing. When go timing is unpredictable, preparatory activities immediately reach and stay in a neural state capable of producing movement anytime to a sudden go cue. When go timing is predictable, preparation activity reaches the movement-producible state more gradually, to secure more accurate decisions. Surprisingly, this preparation process entails a longer reaction time. We find that as preparatory activity increases in accuracy, it takes longer for a neural state to transition from the end of preparation to the start of movement. Our results suggest that the motor cortex fine-tunes preparatory activity for more accurate movement using the predictability of go timing.

Differential Modulation of Local Field Potentials in the Primary and Premotor Cortices during Ipsilateral and Contralateral Reach to Grasp in Macaque Monkeys.

Hand movements are associated with modulations of neuronal activity across several interconnected cortical areas, including the primary motor cortex (M1) and the dorsal and ventral premotor cortices (PMd and PMv). Local field potentials (LFPs) provide a link between neuronal discharges and synaptic inputs. Our current understanding of how LFPs vary in M1, PMd, and PMv during contralateral and ipsilateral movements is incomplete. To help reveal unique features in the pattern of modulations, we simultaneously recorded LFPs in these areas in two macaque monkeys performing reach and grasp movements with either the right or left hand. The greatest effector-dependent differences were seen in M1, at low (≤13 Hz) and γ frequencies. In premotor areas, differences related to hand use were only present in low frequencies. PMv exhibited the greatest increase in low frequencies during instruction cues and the smallest effector-dependent modulation during movement execution. In PMd, δ oscillations were greater during contralateral reach and grasp, and ß activity increased during contralateral grasp. In contrast, ß oscillations decreased in M1 and PMv. These results suggest that while M1 primarily exhibits effector-specific LFP activity, premotor areas compute more effector-independent aspects of the task requirements, particularly during movement preparation for PMv and production for PMd. The generation of precise hand movements likely relies on the combination of complementary information contained in the unique pattern of neural modulations contained in each cortical area. Accordingly, integrating LFPs from premotor areas and M1 could enhance the performance and robustness of brain-machine interfaces.

Neuronal population dynamics during motor plan cancellation in nonhuman primates.

To understand the cortical neuronal dynamics behind movement generation and control, most studies have focused on tasks where actions were planned and then executed using different instances of visuomotor transformations. However, to fully understand the dynamics related to movement control, one must also study how movements are actively inhibited. Inhibition, indeed, represents the first level of control both when different alternatives are available and only one solution could be adopted and when it is necessary to maintain the current position. We recorded neuronal activity from a multielectrode array in the dorsal premotor cortex (PMd) of monkeys performing a countermanding reaching task that requires, in a subset of trials, them to cancel a planned movement before its onset. In the analysis of the neuronal state space of PMd, we found a subspace in which activities conveying temporal information were confined during active inhibition and position holding. Movement execution required activities to escape from this subspace toward an orthogonal subspace and, furthermore, surpass a threshold associated with the maturation of the motor plan. These results revealed further details in the neuronal dynamics underlying movement control, extending the hypothesis that neuronal computation confined in an "output-null" subspace does not produce movements.

An abstract categorical decision code in dorsal premotor cortex.

The dorsal premotor cortex (DPC) has classically been associated with a role in preparing and executing the physical motor variables during cognitive tasks. While recent work has provided nuanced insights into this role, here we propose that DPC also participates more actively in decision-making. We recorded neuronal activity in DPC while two trained monkeys performed a vibrotactile categorization task, utilizing two partially overlapping ranges of stimulus values that varied on two physical attributes: vibrotactile frequency and amplitude. We observed a broad heterogeneity across DPC neurons, the majority of which maintained the same response patterns across attributes and ranges, coding in the same periods, mixing temporal and categorical dynamics. The predominant categorical signal was maintained throughout the delay, movement periods and notably during the intertrial period. Putting the entire population's data through two dimensionality reduction techniques, we found strong temporal and categorical representations without remnants of the stimuli's physical parameters. Furthermore, projecting the activity of one population over the population axes of the other yielded identical categorical and temporal responses. Finally, we sought to identify functional subpopulations based on the combined activity of all stimuli, neurons, and time points; however, we found that single-unit responses mixed temporal and categorical dynamics and couldn't be clustered. All these point to DPC playing a more decision-related role than previously anticipated.

Loss of Motor Cortical Inputs to the Red Nucleus after CNS Disorders in Nonhuman Primates.

The premotor (PM) and primary motor (M1) cortical areas broadcast voluntary motor commands through multiple neuronal pathways, including the corticorubral projection that reaches the red nucleus (RN). However, the respective contribution of M1 and PM to corticorubral projections as well as changes induced by motor disorders or injuries are not known in nonhuman primates. Here, we quantified the density and topography of axonal endings of the corticorubral pathway in RN in intact monkeys, as well as in monkeys subjected to either cervical spinal cord injury (SCI), Parkinson's disease (PD)-like symptoms or primary motor cortex injury (MCI). Twenty adult macaque monkeys of either sex were injected with the biotinylated dextran amine anterograde tracer either in PM or in M1. We developed a semiautomated algorithm to reliably detect and count axonal boutons within the magnocellular and parvocellular (pRN) subdivisions of RN. In intact monkeys, PM and M1 preferentially target the medial part of the ipsilateral pRN, reflecting its somatotopic organization. Projection of PM to the ipsilateral pRN is denser than that of M1, matching previous observations for the corticotectal, corticoreticular, and corticosubthalamic projections (Fregosi et al., 2018, 2019; Borgognon et al., 2020). In all three types of motor disorders, there was a uniform and strong decrease (near loss) of the corticorubral projections from PM and M1. The RN may contribute to functional recovery after SCI, PD, and MCI, by reducing direct cortical influence. This reduction possibly privileges direct access to the final output motor system, via emphasis on the direct corticospinal projection.SIGNIFICANCE STATEMENT We measured the corticorubral projection density arising from the PM or the M1 cortices in adult macaques. The premotor cortex sent denser corticorubral projections than the primary motor cortex, as previously observed for the corticotectal, corticoreticular, and corticosubthalamic projections. The premotor cortex may thus exert more influence than primary motor cortex onto subcortical structures. We next asked whether the corticorubral motor projections undergo lesion-dependent plasticity after either cervical spinal cord injury, Parkinson's disease-like symptoms, or primary motor cortex lesion. In all three types of pathology, there was a strong decrease of the corticorubral motor projection density, suggesting that the red nucleus may contribute to functional recovery after such motor system disorders based on a reduced direct cortical influence.

M2 Cortex Circuitry and Sensory-Induced Behavioral Alterations in Huntington's Disease: Role of Superior Colliculus.

Early and progressive cortico-striatal circuit alterations have been widely characterized in Huntington's disease (HD) patients. Cortical premotor area, M2 cortex in rodents, is the most affected cortical input to the striatum from early stages in patients and is associated to the motor learning deficits present in HD mice. Yet, M2 cortex sends additional long-range axon collaterals to diverse output brain regions beyond basal ganglia. Here, we aimed to elucidate the contribution of M2 cortex projections to HD pathophysiology in mice. Using fMRI, M2 cortex showed most prominent functional connectivity alterations with the superior colliculus (SC) in symptomatic R6/1 HD male mice. Structural alterations were also detected by tractography, although diffusion weighted imaging measurements suggested preserved SC structure and similar electrophysiological responses were obtained in the SC on optogenetic stimulation of M2 cortical axons. Male and female HD mice showed behavioral alterations linked to SC function, including decreased defensive behavioral responses toward unexpected stimuli, such as a moving robo-beetle, and decreased locomotion on an unexpected flash of light. Additionally, GCamp6f fluorescence recordings with fiber photometry showed that M2 cortex activity was engaged by the presence of a randomly moving robo-bettle, an effect absent in HD male mice. Moreover, acute chemogenetic M2 cortex inhibition in WT mice shift behavioral responses toward an HD phenotype. Collectively, our findings highlight the involvement of M2 cortex activity in visual stimuli-induced behavioral responses, which are deeply altered in the R6/1 HD mouse model.SIGNIFICANCE STATEMENT Understanding brain circuit alterations in brain disorders is critical for developing circuit-based therapeutic interventions. The cortico-striatal circuit is the most prominently disturbed in Huntington's disease (HD); and particularly, M2 cortex has a prominent role. However, the same M2 cortical neurons send additional projections to several brain regions beyond striatum. We characterized new structural and functional circuitry alterations of M2 cortex in HD mouse models and found that M2 cortex projection to the superior colliculus (SC) was deeply impaired. Moreover, we describe differential responses to unexpected sensory stimulus in HD mouse models, which relies on SC function. Our data highlight the involvement of M2 cortex in SC-dependent sensory processing and its alterations in HD pathophysiology.

Spared Premotor Areas Undergo Rapid Nonlinear Changes in Functional Organization Following a Focal Ischemic Infarct in Primary Motor Cortex of Squirrel Monkeys.

Recovery of motor function after stroke is accompanied by reorganization of movement representations in spared cortical motor regions. It is widely assumed that map reorganization parallels recovery, suggesting a causal relationship. We examined this assumption by measuring changes in motor representations in eight male and six female squirrel monkeys in the first few weeks after injury, a time when motor recovery is most rapid. Maps of movement representations were derived using intracortical microstimulation techniques in primary motor cortex (M1), ventral premotor cortex (PMv), and dorsal premotor cortex (PMd) in 14 adult squirrel monkeys before and after a focal infarct in the M1 distal forelimb area. Maps were derived at baseline and at either 2 (n = 7) or 3 weeks (n = 7) postinfarct. In PMv the forelimb maps remained unchanged at 2 weeks but contracted significantly (-42.4%) at 3 weeks. In PMd the forelimb maps expanded significantly (+110.6%) at 2 weeks but contracted significantly (-57.4%) at 3 weeks. Motor deficits were equivalent at both time points. These results highlight two features of plasticity after M1 lesions. First, significant contraction of distal forelimb motor maps in both PMv and PMd is evident by 3 weeks. Second, an unpredictable nonlinear pattern of reorganization occurs in the distal forelimb representation in PMd, first expanding at 2 weeks, and then contracting at 3 weeks postinjury. Together with previous results demonstrating reliable map expansions in PMv several weeks to months after M1 injury, the subacute time period may represent a critical window for the timing of therapeutic interventions.SIGNIFICANCE STATEMENT The relationship between motor recovery and motor map reorganization after cortical injury has rarely been examined in acute/subacute periods. In nonhuman primates, premotor maps were examined at 2 and 3 weeks after injury to primary motor cortex. Although maps are known to expand late after injury, the present study demonstrates early map expansion at 2 weeks (dorsal premotor cortex) followed by contraction at 3 weeks (dorsal and ventral premotor cortex). This nonlinear map reorganization during a time of gradual behavioral recovery suggests that the relationship between map plasticity and motor recovery is much more complex than previously thought. It also suggests that rehabilitative motor training may have its most potent effects during this early dynamic phase of map reorganization.

Fast-Spiking Interneurons of the Premotor Cortex Contribute to Initiation and Execution of Spontaneous Actions.

Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings centered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions.SIGNIFICANCE STATEMENT Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of specific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neurons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking, but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type, as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silencing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of specific spontaneous movements, possibly by sculpting response selectivity of nearby PNs.

Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

The effects of intermittent theta burst stimulation over dorsal premotor cortex on primary motor cortex plasticity in young and older adults.

Previous transcranial magnetic stimulation (TMS) research suggests that the dorsal premotor cortex (PMd) influences neuroplasticity within the primary motor cortex (M1) through indirect (I) wave interneuronal circuits. However, it is unclear how the influence of PMd on the plasticity of M1 I-waves changes with advancing age. This study therefore investigated the neuroplastic effects of intermittent theta burst stimulation (iTBS) to M1 early and late I-wave circuits when preceded by iTBS (PMd iTBS-M1 iTBS) or sham stimulation (PMd sham-M1 iTBS) to PMd in 15 young and 16 older adults. M1 excitability was assessed with motor evoked potentials (MEP) recorded from the right first dorsal interosseous using posterior-anterior (PA) and anterior-posterior (AP) current TMS at standard stimulation intensities (PA1mV, AP1mV) and reduced stimulation intensities (PA0.5mV, early I-waves; AP0.5mV, late I-waves). PMd iTBS-M1 iTBS lowered the expected facilitation of PA0.5mV (to M1 iTBS) in young and older adults (P = 0.009), whereas the intervention had no effect on AP0.5mV facilitation in either group (P = 0.305). The modulation of PA0.5mV following PMd iTBS-M1 iTBS may reflect a specific influence of PMd on different I-wave circuits that are involved in M1 plasticity within young and older adults.

Representing linguistic communicative functions in the premotor cortex.

Linguistic communication is often regarded as an action that serves a function to convey the speaker's goal to the addressee. Here, with an functional magnetic resonance imaging (fMRI) study and a lesion study, we demonstrated that communicative functions are represented in the human premotor cortex. Participants read scripts involving 2 interlocutors. Each script contained a critical sentence said by the speaker with a communicative function of either making a Promise, a Request, or a Reply to the addressee's query. With various preceding contexts, the critical sentences were supposed to induce neural activities associated with communicative functions rather than specific actions literally described by these sentences. The fMRI results showed that the premotor cortex contained more information, as revealed by multivariate analyses, on communicative functions and relevant interlocutors' attitudes than the perisylvian language regions. The lesion study results showed that, relative to healthy controls, the understanding of communicative functions was impaired in patients with lesions in the premotor cortex, whereas no reliable difference was observed between the healthy controls and patients with lesions in other brain regions. These findings convergently suggest the crucial role of the premotor cortex in representing the functions of linguistic communications, supporting that linguistic communication can be seen as an action.

Strike or ball? Batters know it better: an fMRI study of action anticipation in baseball players.

To assess whether the brain processes of action anticipation are modulated differently by perceptual and motor experiences, baseball batters, pitchers, and non-players were asked to predict the fate of pitching actions (strike or ball) while undergoing functional magnetic resonance imaging. Results showed both batters (perceptual experts of pitching action) and pitchers (motor experts) were more accurate than non-players. Furthermore, batters demonstrated higher perceptual sensitivity in discriminating strikes than non-players. All groups engaged the action observation network, putamen, and cerebellum during anticipation, while pitchers showed higher activity than non-players in the left premotor cortex, which has been implicated in the internal simulation of observed action. Only batters exhibited differences in strike versus ball pitches in their left ventral extrastriate cortex, which might be associated with the processing of relevant visual information conveyed by the observed pitcher's movement kinematics and pitch trajectory. Moreover, all groups showed higher activity selectively in the striatum, thalamus, sensorimotor cortices, and cerebellum during correct predictions than during incorrect ones, with most widespread activation in batters, reinforcing the greater involvement of the sensorimotor system in perceptual experience. Our findings demonstrate that perceptual experience might enhance action anticipation ability to a greater extent than motor experience, with overlapping but specific neural underpinnings.

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.

Conflict Detection in a Sequential Decision Task Is Associated with Increased Cortico-Subthalamic Coherence and Prolonged Subthalamic Oscillatory Response in the ß Band.

Making accurate decisions often involves the integration of current and past evidence. Here, we examine the neural correlates of conflict and evidence integration during sequential decision-making. Female and male human patients implanted with deep-brain stimulation (DBS) electrodes and age-matched and gender-matched healthy controls performed an expanded judgment task, in which they were free to choose how many cues to sample. Behaviorally, we found that while patients sampled numerically more cues, they were less able to integrate evidence and showed suboptimal performance. Using recordings of magnetoencephalography (MEG) and local field potentials (LFPs; in patients) in the subthalamic nucleus (STN), we found that ß oscillations signaled conflict between cues within a sequence. Following cues that differed from previous cues, ß power in the STN and cortex first decreased and then increased. Importantly, the conflict signal in the STN outlasted the cortical one, carrying over to the next cue in the sequence. Furthermore, after a conflict, there was an increase in coherence between the dorsal premotor cortex and STN in the ß band. These results extend our understanding of cortico-subcortical dynamics of conflict processing, and do so in a context where evidence must be accumulated in discrete steps, much like in real life. Thus, the present work leads to a more nuanced picture of conflict monitoring systems in the brain and potential changes because of disease.SIGNIFICANCE STATEMENT Decision-making often involves the integration of multiple pieces of information over time to make accurate predictions. We simultaneously recorded whole-head magnetoencephalography (MEG) and local field potentials (LFPs) from the human subthalamic nucleus (STN) in a novel task which required integrating sequentially presented pieces of evidence. Our key finding is prolonged ß oscillations in the STN, with a concurrent increase in communication with frontal cortex, when presented with conflicting information. These neural effects reflect the behavioral profile of reduced tendency to respond after conflict, as well as relate to suboptimal cue integration in patients, which may be directly linked to clinically reported side-effects of deep-brain stimulation (DBS) such as impaired decision-making and impulsivity.

Modulation of dorsal premotor cortex differentially influences I-wave excitability in primary motor cortex of young and older adults.

Previous research using transcranial magnetic stimulation (TMS) has demonstrated weakened connectivity between dorsal premotor cortex (PMd) and motor cortex (M1) with age. While this alteration is probably mediated by changes in the communication between the two regions, the effect of age on the influence of PMd on specific indirect (I) wave circuits within M1 remains unclear. The present study therefore investigated the influence of PMd on early and late I-wave excitability in M1 of young and older adults. Twenty-two young (mean ± SD, 22.9 ± 2.9 years) and 20 older (66.6 ± 4.2 years) adults participated in two experimental sessions involving either intermittent theta burst stimulation (iTBS) or sham stimulation over PMd. Changes within M1 following the intervention were assessed with motor-evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. We applied posterior-anterior (PA) and anterior-posterior (AP) current single-pulse TMS to assess corticospinal excitability (PA1mV ; AP1mV ; PA0.5mV , early; AP0.5mV , late), and paired-pulse TMS short intracortical facilitation for I-wave excitability (PA SICF, early; AP SICF, late). Although PMd iTBS potentiated PA1mV and AP1mV MEPs in both age groups (both P < 0.05), the time course of this effect was delayed for AP1mV in older adults (P = 0.001). Furthermore, while AP0.5mV , PA SICF and AP SICF were potentiated in both groups (all P < 0.05), potentiation of PA0.5mV was only apparent in young adults (P < 0.0001). While PMd influences early and late I-wave excitability in young adults, direct PMd modulation of the early circuits is specifically reduced in older adults. KEY POINTS: Interneuronal circuits responsible for late I-waves within primary motor cortex (M1) mediate projections from dorsal premotor cortex (PMd), but this communication probably changes with advancing age. We investigated the effects of intermittent theta burst stimulation (iTBS) to PMd on transcranial magnetic stimulation (TMS) measures of M1 excitability in young and older adults. We found that PMd iTBS facilitated M1 excitability assessed with posterior-anterior (PA, early I-waves) and anterior-posterior (AP, late I-waves) current TMS in young adults, with a stronger effect for AP TMS. M1 excitability assessed with AP TMS also increased in older adults following PMd iTBS, but there was no facilitation for PA TMS responses. We conclude that changes in M1 excitability following PMd iTBS are specifically reduced for the early I-waves in older adults, which could be a potential target for interventions that enhance cortical excitability in older adults.

Cortico-cortical paired associative stimulation conditioning superficial ventral premotor cortex-primary motor cortex connectivity influences motor cortical activity during precision grip.

The ventral premotor cortex (PMv) and primary motor cortex (M1) represent critical nodes of a parietofrontal network involved in grasping actions, such as power and precision grip. Here, we investigated how the functional PMv-M1 connectivity drives the dissociation between these two actions. We applied a PMv-M1 cortico-cortical paired associative stimulation (cc-PAS) protocol, stimulating M1 in both postero-anterior (PA) and antero-posterior (AP) directions, in order to induce long-term changes in the activity of different neuronal populations within M1. We evaluated the motor-evoked potential (MEP) amplitude, MEP latency and cortical silent period, in both PA and AP, during the isometric execution of precision and power grip, before and after the PMv-M1 cc-PAS. The repeated activation of the PMv-M1 cortico-cortical network with PA orientation over M1 did not change MEP amplitude or cortical silent period duration during both actions. In contrast, the PMv-M1 cc-PAS stimulation of M1 with an AP direction led to a specific modulation of precision grip motor drive. In particular, MEPs tested with AP stimulation showed a selective increase of corticospinal excitability during precision grip. These findings suggest that the more superficial M1 neuronal populations recruited by the PMv input are involved preferentially in the execution of precision grip actions. KEY POINTS: Ventral premotor cortex (PMv)-primary motor cortex (M1) cortico-cortical paired associative stimulation (cc-PAS) with different coil orientation targets dissociable neural populations. PMv-M1 cc-PAS with M1 antero-posterior coil orientation specifically modulates corticospinal excitability during precision grip. Superficial M1 populations are involved preferentially in the execution of precision grip. A plasticity induction protocol targeting the specific PMv-M1 subpopulation might have important translational value for the rehabilitation of hand function.