M1 Neurons Research Articles

Microglial activation in the motor cortex mediated NLRP3-related neuroinflammation and neuronal damage following spinal cord injury.

Spinal cord injury (SCI) is a traumatic event that can lead to neurodegeneration. Neuronal damage in the primary motor cortex (M1) can hinder motor function recovery after SCI. However, the exact mechanisms involved in neuronal damage after SCI remain incompletely understood. In this study, we found that microglia were activated in M1 after SCI, which triggered Nod-like receptor protein 3 (NLRP3) related chronic neuroinflammation and neuronal damage in vivo. Meanwhile, treatment with the microglia inhibitor minocycline reduced inflammation-induced neuronal damage in M1, protected the integrity of the motor conduction pathway, and promoted motor function recovery. Furthermore, we simulated chronic inflammation in M1 after SCI by culturing the primary neurons in primary microglia-conditioned medium, and observed that the injury to the primary neurons also occurred in vitro; however, as observed in vivo, these effects could be mitigated by minocycline treatment. Our results indicated that microglial activation in M1 mediates NLRP3-related neuroinflammation and causes the injury to M1 neurons, thereby impairing the integrity of the motor conduction pathway and inhibiting motor function recovery. These findings might contribute to the identification of novel therapeutic strategies for SCI.

Manipulation-specific cortical activity as mice handle food

Food handling offers unique yet largely unexplored opportunities to investigate how cortical activity relates to forelimb movements in a natural, ethologically essential, and kinematically rich form of manual dexterity. To determine these relationships, we recorded high-speed (1,000 fps) video and multi-channel electrophysiological cortical spiking activity while mice handled food. The high temporal resolution of the video allowed us to decompose active manipulation ("oromanual") events into characteristic submovements, enabling event-aligned analysis of cortical activity. Activity in forelimb M1 was strongly modulated during food handling, generally higher during oromanual events and lower during holding intervals. Optogenetic silencing and stimulation of forelimb M1 neurons partially affected food-handling movements, exerting suppressive and activating effects, respectively. We also extended the analysis to forelimb S1 and lateral M1, finding broadly similar oromanual-related activity across all three areas. However, each area's activity displayed a distinct timing and phasic/tonic temporal profile, which was further analyzed by non-negative matrix factorization and demonstrated to be attributable to area-specific composition of activity classes. Current or future forelimb position could be accurately predicted from activity in all three regions, indicating that the cortical activity in these areas contains high information content about forelimb movements during food handling. These results thus establish that cortical activity during food handling is manipulation specific, distributed, and broadly similar across multiple sensorimotor areas while also exhibiting area- and submovement-specific relationships with the fast kinematic hallmarks of this natural form of complex free-object-handling manual dexterity.

Dose-response relationship between the variables of unilateral optogenetic stimulation and transcallosal evoked responses in rat motor cortex.

Efficient interhemispheric integration of neural activity between left and right primary motor cortex (M1) is critical for inter-limb motor control. We employed optogenetic stimulation to establish a framework for probing transcallosal M1–M1 interactions in rats. We performed optogenetic stimulation of excitatory neurons in right M1 of male Sprague-Dawley rats. We recorded the transcallosal evoked potential in contralateral left M1 via chronically implanted electrodes. Recordings were performed under anesthesia combination of dexmedetomidine and a low concentration of isoflurane. We systematically varied the stimulation intensity and duration to characterize the relationship between stimulation parameters in right M1 and the characteristics of the evoked intracortical potentials in left M1. Optogenetic stimulation of right M1 consistently evoked a transcallosal response in left M1 with a consistent negative peak (N1) that sometimes was preceded by a smaller positive peak (P1). Higher stimulation intensity or longer stimulation duration gradually increased N1 amplitude and reduced N1 variability across trials. A combination of stimulation intensities of 5–10 mW with stimulus durations of 1–10 ms were generally sufficient to elicit a robust transcallosal response in most animal, with our optic fiber setup. Optogenetically stimulated excitatory neurons in M1 can reliably evoke a transcallosal response in anesthetized rats. Characterizing the relationship between “stimulation dose” and “response magnitude” (i.e., the gain function) of transcallosal M1-to-M1 excitatory connections can be used to optimize the variables of optogenetic stimulation and ensure stimulation efficacy.

Neural Mechanism Underlying Task-Specific Enhancement of Motor Learning by Concurrent Transcranial Direct Current Stimulation.

The optimal protocol for neuromodulation by transcranial direct current stimulation (tDCS) remains unclear. Using the rotarod paradigm, we found that mouse motor learning was enhanced by anodal tDCS (3.2 mA/cm2) during but not before or after the performance of a task. Dual-task experiments showed that motor learning enhancement was specific to the task accompanied by anodal tDCS. Studies using a mouse model of stroke induced by middle cerebral artery occlusion showed that concurrent anodal tDCS restored motor learning capability in a task-specific manner. Transcranial in vivo Ca2+ imaging further showed that anodal tDCS elevated and cathodal tDCS suppressed neuronal activity in the primary motor cortex (M1). Anodal tDCS specifically promoted the activity of task-related M1 neurons during task performance, suggesting that elevated Hebbian synaptic potentiation in task-activated circuits accounts for the motor learning enhancement. Thus, application of tDCS concurrent with the targeted behavioral dysfunction could be an effective approach to treating brain disorders.

Functional Interactions Between the Parafascicular Thalamic Nucleus and Motor Cortex Are Altered in Hemiparkinsonian Rat.

Parkinson’s disease (PD) is characterized by aberrant discharge patterns and exaggerated oscillatory activity within basal ganglia-thalamocortical circuits. We have previously observed substantial alterations in spike and local field potential (LFP) activities recorded in the thalamic parafascicular nucleus (PF) and motor cortex (M1), respectively, of hemiparkinsonian rats during rest or catching movements. This study explored whether the mutual effects of the PF and M1 depended on the amplitude and phase relationship in their identified neuron spikes or group rhythmic activities. Microwire electrode arrays were paired and implanted in the PF and M1 of rats with unilateral dopaminergic cell lesions. The results showed that the identified PF neurons exhibited aberrant cell type-selective firing rates and preferential and excessive phase-locked firing to cortical LFP oscillations mainly at 12–35 Hz (beta frequencies), consistent with the observation of identified M1 neurons with ongoing PF LFP oscillations. Experimental evidence also showed a decrease in phase-locking at 0.7–12 Hz and 35–70 Hz in the PF and M1 circuits in the hemiparkinsonian rats. Furthermore, anatomical evidence was provided for the existence of afferent and efferent bidirectional reciprocal connectivity pathways between the PF and M1 using an anterograde and retrograde neuroanatomical tracing virus. Collectively, our results suggested that multiple alterations may be present in regional anatomical and functional modes with which the PF and M1 interact, and that parkinsonism-associated changes in PF integrate M1 activity in a manner that varies with frequency, behavioral state, and integrity of the dopaminergic system.

Fluoxetine exposure throughout neurodevelopment differentially influences basilar dendritic morphology in the motor and prefrontal cortices

The significance of serotonin (5HT) in mental health is underscored by the serotonergic action of many classes of psychiatric medication. 5HT is known to have a significant role in neurodevelopment, thus 5HT disruption during development may have a long term impact on brain structure and circuits. We previously generated a model of 5HT alteration throughout neurodevelopment by maternal administration of the selective serotonin reuptake inhibitor fluoxetine. We found resulting social behavior alterations in the offspring during both postnatal and adult ages. Previous work by others has indicated that early 5HT disruption influences neuronal morphology. Therefore, in the current study we sought to determine if dendritic morphological changes occur in areas involved in the social behavior deficits we previously observed, specifically the primary motor (M1) and medial prefrontal (mPFC) cortices. We quantified dendritic morphology of projection neurons in M1 and mPFC at postnatal day (P)10 and P79 in mice exposed to fluoxetine. Basilar dendritic complexity and spine density were persistently decreased in M1 fluoxetine-exposed neurons while in the mPFC, similar reductions were observed at P79 but were not present at P10. Our findings underscore that the developing brain, specifically the projection cortex, is vulnerable to 5HT system perturbation, which may be related to later behavioral disruptions.

Cerebellar noninvasive neuromodulation influences the reactivity of the contralateral primary motor cortex and surrounding areas: a TMS-EMG-EEG study.

Understanding cerebellar-cortical physiological interactions is of fundamental importance to advance the efficacy of neurorehabilitation strategies for patients with cerebellar damage. Previous works have aimed to modulate this pathway by applying transcranial electrical or magnetic stimulation (TMS) over the cerebellum and probing the resulting changes in the primary motor cortex (M1) excitability with motor-evoked potentials (MEPs). While these protocols produce changes in cerebellar excitability, their ability to modulate MEPs has produced inconsistent results, mainly due to the MEP being a highly variable outcome measure that is susceptible to fluctuations in the excitability of M1 neurons and spinal interneurons. To overcome this limitation, we combined TMS with electroencephalography (EEG) to directly record TMS-evoked potentials (TEPs) and oscillations from the scalp. In three sessions, we applied intermittent theta-burst stimulation (iTBS), cathodal direct current stimulation (c-DC) or sham stimulation to modulate cerebellar activity. To assess the effects on M1 and nearby cortex, we recorded TMS-EEG and MEPs before, immediately after (T1) and 15min (T2) following cerebellar neuromodulation. We found that cerebellar iTBS immediately increased TMS-induced alpha oscillations and produced lasting facilitatory effects on TEPs, whereas c-DC immediately decreased TMS-induced alpha oscillations and reduced TEPs. We also found increased MEP following iTBS but not after c-DC. All of the TMS-EEG measures showed high test-retest repeatability. Overall, this work importantly shows that cerebellar neuromodulation influences both cortical and corticospinal physiological measures; however, they are more pronounced and detailed when utilizing TMS-EEG outcome measures. These findings highlight the advantage of using TMS-EEG over MEPs when assessing the effects of neuromodulation.

Neural representation in M1 and S1 cortex of bilateral hand actions during prehension.

Bimanual movements that require coordinated actions of the two hands may be coordinated by synchronous bilateral activation of somatosensory and motor cortical areas in both hemispheres, by enhanced activation of individual neurons specialized for bimanual actions, or by both mechanisms. To investigate cortical neural mechanisms that mediate unimanual and bimanual prehension, we compared actions of the left and right hands in a reach to grasp-and-pull instructed-delay task. Spike trains were recorded with multiple electrode arrays placed in the hand area of primary motor (M1) and somatosensory (S1) cortex of the right hemisphere in macaques, allowing us to measure and compare the relative timing, amplitude, and synchronization of cortical activity in these areas as animals grasped and manipulated objects that differed in shape and location. We report that neurons in the right hemisphere show common task-related firing patterns for the two hands but actions of the ipsilateral hand elicited weaker and shorter-duration responses than those of the contralateral hand. We report significant bimanual activation of neurons in M1 but not in S1 cortex when animals have free choice of hand use in prehension tasks. Population ensemble responses in M1 thereby provide an accurate depiction of hand actions during skilled manual tasks. These studies also demonstrate that somatosensory cortical areas serve important cognitive and motor functions in skilled hand actions. Bilateral representation of hand actions may serve an important role in "motor equivalence" when the same movements are performed by either hand and in transfer of skill learning between the hands.NEW & NOTEWORTHY Humans can manipulate small objects with the right or left hand but typically select the dominant hand to handle them. We trained monkeys to grasp and manipulate objects with either hand, while recording neural activity in primary motor (M1) and somatosensory (S1) cortex. Actions of both hands activate M1 neurons, but S1 neurons respond only to the contralateral hand. Bilateral sensitivity in M1 may aid skill transfer between hands after stroke or head injury.

A behavioral paradigm for cortical control of a robotic actuator by freely moving rats in a one-dimensional two-target reaching task

BackgroundControlling the trajectory of a neuroprosthesis to reach distant targets is a commonly used brain-machine interface (BMI) task in primates and has not been available for rodents yet. New methodHere, we describe a novel, fine-tuned behavioral paradigm and setup which enables this task for rats in one-dimensional space for reaching two distant targets depending on their limited cognitive and visual capabilities compared to those of primates. An online transform was used to convert the activity of a pair of primary motor cortex (M1) units into two robotic actions. The rats were shaped to adapt to the transform and direct the robotic actuator toward the selected target by modulating the activity of the M1 neurons. ResultsAll three rats involved in the study were capable of achieving randomly selected targets with at least 78% accuracy. A total of 9 out of 16 pairs of units examined were eligible for exceeding this success criterion. Two out of three rats were capable of reversal learning, where the mapping between the activity of the M1 units and the robotic actions were reversed. Comparison with existing methodsThe present work is the first demonstration of trajectory-based control of a neuroprosthetic device by rodents to reach two distant targets using visual feedback. ConclusionThe behavioral paradigm and setup introduced here can be used as a cost-effective platform for elucidating the information processing principles in the neural circuits related to neuroprosthetic control and for studying the performance of novel BMI technologies using freely moving rats.

Timescales of Local and Cross-Area Interactions during Neuroprosthetic Learning.

How does the brain integrate signals with different timescales to drive purposeful actions? Brain-machine interfaces (BMIs) offer a powerful tool to causally test how distributed neural networks achieve specific neural patterns. During neuroprosthetic learning, actuator movements are causally linked to primary motor cortex (M1) neurons, i.e., "direct" neurons that project to the decoder and whose firing is required to successfully perform the task. However, it is unknown how such direct M1 neurons interact with both "indirect" local (in M1 but not part of the decoder) and across area neural populations (e.g., in premotor cortex/M2), all of which are embedded in complex biological recurrent networks. Here, we trained male rats to perform a M1-BMI task and simultaneously recorded the activity of indirect neurons in both M2 and M1. We found that both M2 and M1 indirect neuron populations could be used to predict the activity of the direct neurons (i.e., "BMI-potent activity"). Interestingly, compared with M1 indirect activity, M2 neural activity was correlated with BMI-potent activity across a longer set of time lags, and the timescale of population activity patterns evolved more slowly. M2 units also predicted the activity of both M1 direct and indirect neural populations, suggesting that M2 population dynamics provide a continuous modulatory influence on M1 activity as a whole, rather than a moment-by-moment influence solely on neurons most relevant to a task. Together, our results indicate that longer timescale M2 activity provides modulatory influence over extended time lags on shorter-timescale control signals in M1.SIGNIFICANCE STATEMENT A central question in the study of motor control is whether primary motor cortex (M1) and premotor cortex (M2) interact through task-specific subpopulations of neurons, or whether tasks engage broader correlated networks. Brain-machine interfaces (BMIs) are powerful tools to study cross-area interactions. Here, we performed simultaneous recordings of M1 and M2 in a BMI task using a subpopulation of M1 neurons (direct neurons). We found that activity outside of direct neurons in M1 and M2 was predictive of M1-BMI task activity, and that M2 activity evolved at slower timescales than M1. These findings suggest that M2 provides a continuous modulatory influence on M1 as a whole, supporting a model of interactions through broad correlated networks rather than task-specific neural subpopulations.

Reduced Dopamine Signaling Impacts Pyramidal Neuron Excitability in Mouse Motor Cortex.

Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined whether chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson’s disease, was sufficient to shift M1 neuron excitability. We show that D1 receptor (D1R) and D2R antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and origin of the manipulation. Our study highlights the broad influence of dopamine on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.

Epidural cerebellar stimulation drives widespread neural synchrony in the intact and stroke perilesional cortex

BackgroundCerebellar electrical stimulation has shown promise in improving motor recovery post-stroke in both rodent and human studies. Past studies have used motor evoked potentials (MEPs) to evaluate how cerebellar stimulation modulates ongoing activity in the cortex, but the underlying mechanisms are incompletely understood. Here we used invasive electrophysiological recordings from the intact and stroke-injured rodent primary motor cortex (M1) to assess how epidural cerebellar stimulation modulates neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics.MethodsWe recorded single unit spiking and local field potentials (LFPs) in both the intact and acutely stroke-injured M1 contralateral to the stimulated cerebellum in adult Long-Evans rats under anesthesia. We analyzed changes in the firing rates of single units, the extent of synchronous spiking and power spectral density (PSD) changes in LFPs during and post-stimulation.ResultsOur results show that post-stimulation, the firing rates of a majority of M1 neurons changed significantly with respect to their baseline rates. These firing rate changes were diverse in character, as the firing rate of some neurons increased while others decreased. Additionally, these changes started to set in during stimulation. Furthermore, cross-correlation analysis showed a significant increase in coincident firing amongst neuronal pairs. Interestingly, this increase in synchrony was unrelated to the direction of firing rate change. We also found that neuronal ensembles derived through principal component analysis were more active post-stimulation. Lastly, these changes occurred without a significant change in the overall spectral power of LFPs post-stimulation.ConclusionsOur results show that cerebellar stimulation caused significant, long-lasting changes in the activity patterns of M1 neurons by altering firing rates, boosting neural synchrony and increasing neuronal assemblies’ activation strength. Our study provides evidence that cerebellar stimulation can directly modulate cortical dynamics. Since these results are present in the perilesional cortex, our data might also help explain the facilitatory effects of cerebellar stimulation post-stroke.

Roles of Motor Cortex Neuron Classes in Reach-Related Modulation for Hemiparkinsonian Rats.

Disruption of the function of the primary motor cortex (M1) is thought to play a critical role in motor dysfunction in Parkinson’s disease (PD). Detailed information regarding the specific aspects of M1 circuits that become abnormal is lacking. We recorded single units and local field potentials (LFPs) of M1 neurons in unilateral 6-hydroxydopamine (6-OHDA) lesion rats and control rats to assess the impact of dopamine (DA) cell loss during rest and a forelimb reaching task. Our results indicated that M1 neurons can be classified into two groups (putative pyramidal neurons and putative interneurons) and that 6-OHDA could modify the activity of different M1 subpopulations to a large extent. Reduced activation of putative pyramidal neurons during inattentive rest and reaching was observed. In addition, 6-OHDA intoxication was associated with an increase in certain LFP frequencies, especially those in the beta range (broadly defined here as any frequency between 12 and 35 Hz), which become pathologically exaggerated throughout cortico-basal ganglia circuits after dopamine depletion. Furthermore, assessment of different spike-LFP coupling parameters revealed that the putative pyramidal neurons were particularly prone to being phase-locked to ongoing cortical oscillations at 12–35 Hz during reaching. Conversely, putative interneurons were neither hypoactive nor synchronized to ongoing cortical oscillations. These data collectively demonstrate a neuron type-selective alteration in the M1 in hemiparkinsonian rats. These alterations hamper the ability of the M1 to contribute to motor conduction and are likely some of the main contributors to motor impairments in PD.

Determinants of Neural Plastic Changes Induced by Motor Practice.

Short-term motor practice leads to plasticity in the primary motor cortex (M1). The purpose of this study is to investigate the factors that determine the increase in corticospinal tract (CST) excitability after motor practice, with special focus on two factors; “the level of muscle activity” and “the presence/absence of a goal of keeping the activity level constant.” Fifteen healthy subjects performed four types of rapid thumb adduction in separate sessions. In the “comfortable task” (C) and “forceful task” (F), the subjects adducted their thumb using comfortable and strong forces. In the “comfortable with a goal task” (CG) and “forceful with a goal task” (FG), subjects controlled the muscle activity at the same level as in the C and F, respectively, by adjusting the peak electromyographic amplitude within the target ranges. Paired associative stimulation (PAS), which combines peripheral nerve (median nerve) stimulation and transcranial magnetic stimulation (TMS), with an inter-stimulus interval of 25 ms (PAS25) was also done. Before and after the motor tasks and PAS25, TMS was applied to the M1. None of the four tasks showed any temporary changes in behavior, meaning no learning occurred. Motor-evoked potential (MEP) amplitude increased only after the FG and it exhibited a positive correlation with the MEP increase after PAS25, suggesting that FG and PAS25 share at least similar plasticity mechanisms in the M1. Resting motor threshold (RMT) decreased only after FG, suggesting that FG would also be associated with the membrane depolarization of M1 neurons. These results suggest task-dependent plasticity from the synergistic effect of forceful muscle activity and of setting a goal of keeping the activity level constant.

Microscopic assessments of the effect of phoenix dactylifera L. in a rat model of mercury-triggered cerebral M1 changes

Context: Mercury is a widespread environmental and industrial pollutant that exerts toxic effects on vital organs. The cerebrum, composed of cortical areas such as the primary motor cortex (M1), is a vulnerable target of mercury toxicity within the central nervous system. Phoenix dactylifera is used in folk medicine to treat diverse disorders, such as loss of consciousness, memory disturbances, and nervous disorders. Aim: This study microscopically evaluated the neuroprotective effect of aqueous fruit pulp extract of P. dactylifera (AFPD) on mercury-triggered M1 changes in Wistar rats. Materials and Methods: Twenty-four Wistar rats were divided into six groups (I–VI; n = 4). Group I was administered distilled water (2 ml/kg); Group II administered mercuric chloride (MCL, 5 mg/kg); Group III administered Vitamin C (100 mg/kg) + MCL (5 mg/kg); Groups IV, V, and VI were administered AFPD (250 mg/kg, 500 mg/kg, and 1000 mg/kg, respectively) followed by MCL (5 mg/kg). Neuroprotective property was evaluated by microscopic assessment of M1 region applying histological techniques and analysis of histometric features of M1 neurons. Statistical Analysis Used: One-way ANOVA and paired sample t-test were used. Results: Microscopic examination of MCL-treated cerebral sections revealed M1 histoarchitectural distortion and neurodegenerative changes such as pyknosis, neuronal shrinkage, chromatolysis, loss of pyramidal neurites, and altered Nissl substance reactivity, relative to the control. Administration of AFPD remarkably ameliorated MCL-triggered M1 changes, especially at dose 500 mg/kg with neuroprotective property comparable to the reference drug, Vitamin C. Conclusion: AFPD is potentially efficacious in ameliorating mercury-triggered microscopic alterations in M1 region of Wistar rats. The neuroprotective property of AFPD could be attributed to antioxidant properties of constituent phytochemicals.

The motor cortex uses active suppression to sculpt movement.

Even the simplest movements are generated by a remarkably complex pattern of muscle activity. Fast, accurate movements at a single joint are produced by a stereotyped pattern that includes a decrease in any preexisting activity in antagonist muscles. This premovement suppression is necessary to prevent the antagonist muscle from opposing movement generated by the agonist muscle. Here, we provide evidence that the primary motor cortex (M1) sends a command signal that generates this premovement suppression. Thus, output neurons in M1 sculpt complex spatiotemporal patterns of motor output not only by actively turning on muscles but also by actively turning them off.

Adenosine A2A receptor blockade improves neuroprosthetic learning by volitional control of population calcium signal in M1 cortical neurons

Volitional control is at the core of brain-machine interfaces (BMI) adaptation and neuroprosthetic-driven learning to restore motor function for disabled patients, but neuroplasticity changes and neuromodulation underlying volitional control of neuroprosthetic learning are largely unexplored. To better study volitional control at annotated neural population, we have developed an operant neuroprosthetic task with closed-loop feedback system by volitional conditioning of population calcium signal in the M1 cortex using fiber photometry recording. Importantly, volitional conditioning of the population calcium signal in M1 neurons did not improve within-session adaptation, but specifically enhanced across-session neuroprosthetic skill learning with reduced time-to-target and the time to complete 50 successful trials. With brain-behavior causality of the neuroprosthetic paradigm, we revealed that proficiency of neuroprosthetic learning by volitional conditioning of calcium signal was associated with the stable representational (plasticity) mapping in M1 neurons with the reduced calcium peak. Furthermore, pharmacological blockade of adenosine A2A receptors facilitated volitional conditioning of neuroprosthetic learning and converted an ineffective volitional conditioning protocol to be the effective for neuroprosthetic learning. These findings may help to harness neuroplasticity for better volitional control of neuroprosthetic training and suggest a novel pharmacological strategy to improve neuroprosthetic learning in BMI adaptation by targeting striatal A2A receptors.

Movement initiation and grasp representation in premotor and primary motor cortex mirror neurons.

Pyramidal tract neurons (PTNs) within macaque rostral ventral premotor cortex (F5) and (M1) provide direct input to spinal circuitry and are critical for skilled movement control. Contrary to initial hypotheses, they can also be active during action observation, in the absence of any movement. A population-level understanding of this phenomenon is currently lacking. We recorded from single neurons, including identified PTNs, in (M1) (n = 187), and F5 (n = 115) as two adult male macaques executed, observed, or withheld (NoGo) reach-to-grasp actions. F5 maintained a similar representation of grasping actions during both execution and observation. In contrast, although many individual M1 neurons were active during observation, M1 population activity was distinct from execution, and more closely aligned to NoGo activity, suggesting this activity contributes to withholding of self-movement. M1 and its outputs may dissociate initiation of movement from representation of grasp in order to flexibly guide behaviour.

Enhancing Gamma Oscillations Restores Primary Motor Cortex Plasticity in Parkinson's Disease.

In humans, γ oscillations in cortical motor areas reflect asynchronous synaptic activity and contribute to plasticity processes. In Parkinson's disease (PD), γ oscillatory activity in the basal ganglia-thalamo-cortical network is altered and the LTP-like plasticity elicited by intermittent theta burst stimulation (iTBS) is reduced in the primary motor cortex (M1). In this study, we tested whether transcranial alternating current stimulation (tACS) delivered at γ frequency promotes iTBS-induced LTP-like plasticity in M1 in PD patients. Sixteen patients (OFF condition) and 16 healthy subjects (HSs) underwent iTBS during γ-tACS (iTBS-γ tACS) and during sham-tACS (iTBS-sham tACS) in two sessions. Motor-evoked potentials (MEPs) evoked by single-pulse transcranial magnetic stimulation and short-interval intracortical inhibition (SICI) were recorded before and after the costimulation. A subgroup of patients also underwent iTBS during β tACS. iTBS-sham tACS facilitated single-pulse MEPs in HSs, but not in patients. iTBS-γ tACS induced a larger MEP facilitation than iTBS-sham tACS in both groups, with similar values in patients and HSs. In patients, SICI improved after iTBS-γ tACS. The effect produced by iTBS-γ tACS on single-pulse MEPs correlated with disease duration, while changes in SICI correlated with Unified Parkinson's Disease Rating Scale Part III scores. The effect of iTBS-β tACS on both single-pulse MEPs and SICI was similar to that obtained in the iTBS-sham tACS session. Our data suggest that γ oscillations have a role in the pathophysiology of the abnormal LTP-like plasticity in PD. Entraining M1 neurons at the γ rhythm through tACS may be an effective method to restore impaired plasticity.SIGNIFICANCE STATEMENT In Parkinson's disease, the LTP-like plasticity of the primary motor cortex is impaired, and γ oscillations are altered in the basal ganglia-thalamo-cortical network. Using a combined transcranial magnetic stimulation-transcranial alternating current stimulation approach (iTBS-γ tACS costimulation), we demonstrate that driving γ oscillations restores the LTP-like plasticity in patients with Parkinson's disease. The effects correlate with clinical characteristics of patients, being more evident in less affected patients and weaker in patients with longer disease duration. These findings suggest that cortical γ oscillations play a beneficial role in modulating the LTP-like plasticity of M1 in Parkinson's disease. The iTBS-γ tACS approach may be potentially useful in rehabilitative settings in patients.

Cerebellar outputs contribute to spontaneous and movement-related activity in the motor cortex of monkeys

Cerebellar outputs originate from the dentate nucleus (DN), project to the primary motor cortex (M1) via the motor thalamus, control M1 activity, and play an essential role in coordinated movements. However, it is unclear when and how the cerebellar outputs contribute to M1 activity. To address this question, we examined the response of M1 neurons to electrical stimulation of the DN and M1 activity during performance of arm-reaching tasks. Based on response patterns to DN stimulation, M1 neurons were classified into facilitation-, suppression-, and no-response-types. During tasks, not only facilitation- and suppression-type M1 neurons, but also no response-type M1 neurons increased or decreased their firing rates in relation to arm reaching movements. However, the firing rates of facilitation- and suppression-type neurons were higher than those of no-response-type neurons during both inter-trial intervals and arm reaching movements. These results imply that cerebellar outputs contribute to both spontaneous and movement-related activity in the M1, which help to maintain muscle tones and execute coordinated movements, although other inputs also contribute to movement-related activity. Pharmacological inactivation of the DN supports this notion, in that DN inactivation reduced both spontaneous firing rates and movement-related activity in the M1.