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Vasoactive intestinal polypeptide (VIP) is known to be present in a subclass of cortical interneurons. Here, using three different antibodies, we demonstrate that VIP is also present in the giant layer 5 pyramidal (Betz) neurons which are characteristic of the limb and axial representations of the marmoset primary motor cortex (cytoarchitectural area 4ab). No VIP staining was observed in smaller layer 5 pyramidal cells present in the primary motor facial representation (cytoarchitectural area 4c), or in the premotor cortex (e.g. the caudal subdivision of the dorsal premotor cortex, A6DC), indicating the selective expression of VIP in Betz cells. VIP in Betz cells was colocalized with neuronal specific marker (NeuN) and a calcium-binding protein parvalbumin (PV). PV also intensely labelled axon terminals surrounding Betz cell somata. VIP-positive interneurons were more abundant in the superficial cortical layers and constituted about 5–7% of total cortical neurons, with the highest density observed in area 4c. Our results demonstrate the expression of VIP in the largest excitatory neurons of the primate cortex, which may offer new functional insights into the role of VIP in the brain, and provide opportunities for genetic manipulation of Betz cells. [ABSTRACT FROM AUTHOR]

BACKGROUND: The recovery of function after spinal cord injury depends on the functional remodeling of the motor cortex. However, the anatomical evidence underlying the functional remodeling of the motor cortex is still illusive. Analyzing the anatomical changes in the motor cortex after spinal cord injury can provide new ideas and research directions for regulating functional recovery and rehabilitation after spinal cord injury. OBJECTIVE: To analyze the neural circuit structural basis of functional remodeling of the primary motor cortex after spinal cord injury. METHODS: C57BL/6J mice were randomly divided into a sham operation group and a spinal cord injury group. The adeno-associated virus vectors expressing the fusion protein of Cre recombinase were injected into C4 of mice of both groups. The adeno-associated virus vectors with Cre recombinase-inducible expression of avian sarcoma/leukosis envelope glycoprotein receptor TVA and rabies glycoprotein were injected into the primary motor cortex. Fourteen days later, a C6 dorsal hemisection mice model was established in the spinal cord injury group. The pseudotyped rabies virus was injected into the primary motor cortex of mice of both groups. After 7 days, brain samples were collected and frozen sections were made. The distribution of input neurons innervating corticospinal motor neurons in the brain was observed and analyzed quantitatively. RESULTS AND CONCLUSION: Fluorescence microscopy observation and quantitative analysis found that input neurons innervating corticospinal motor neurons of the primary motor cortex in mice of both groups were distributed in the cerebral cortex, thalamus and midbrain. Among them, in the sham operation group, the number of input neurons in the mouse cerebral cortex accounted for (84.0±3.6)% of total brain input neurons; that in the thalamus accounted for (10.6±2.3)%, and that in the midbrain accounted for (0.7±0.4)%. Direct synaptic input neurons in the spinal cord injury group accounted for (81.7±1.0)%, (13.1±0.5)%, and (1.6±0.8)% in the cerebral cortex, thalamus and midbrain, respectively. The proportion and number of primary motor cortex input neurons in the three regions of the spinal cord injury group did not differ significantly from that of the sham operation group. After spinal cord injury, the number of input neurons innervating corticospinal pyramidal motor neurons in various brain regions did not change significantly, suggesting that functional remodeling of the motor cortex after spinal cord injury may not only depend on changes in synaptic input related to injured corticospinal motor neurons, but also on transcriptional regulation changes within the injured neurons themselves. [ABSTRACT FROM AUTHOR]

Key points Primary motor cortex (M1) network stability depends on activity of inhibitory interneurons, for which susceptibility to stress was previously demonstrated in limbic regions. Hyperexcitability in M1 following changes in the excitatory/inhibitory balance is a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Using electrophysiological approaches, we assessed the impact of acute restraint stress on inhibitory interneurons excitability and global synaptic plasticity in M1 of the SOD1G93A ALS mouse model at a late pre‐symptomatic stage (10–12.5 weeks). Based on their firing type (continuous, discontinuous, with accommodation or not) and electrophysiological characteristics (resting potential, rheobase, firing frequency), interneurons from M1 slices were separated into four clusters, labelled from 1 to 4. Among them, only interneurons from the first cluster, presenting continuous firing with few accommodations, tended to show increased excitability in wild‐type (WT) and decreased excitability in SOD1G93A animals following stress. In vivo analyses of evoked field potentials showed that stress suppressed the theta burst‐induced plasticity of an excitatory component (N1) recorded in the superficial layers of M1 in WT, with no impact on an inhibitory complex (N2–P1) from the deeper layers. In SOD1G93A mice, stress did not affect N1 but suppressed the N2–P1 plasticity. These data suggest that stress can alter M1 network functioning in a different manner in WT and SOD1G93A mice, possibly through changes of inhibitory interneurons excitability and synaptic plasticity. This suggests that stress‐induced activity changes in M1 may therefore influence ALS outcomes. Disruption of the excitatory/inhibitory balance in the primary motor cortex (M1) has been linked to cortical hyperexcitability development, a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Psychological stress was reported to influence excitatory/inhibitory balance in limbic regions, but very little is known about its influence on the M1 functioning under physiological or pathological conditions. Our study revealed that acute stress influences the excitatory/inhibitory balance within the M1, through changes in interneurons excitability along with network plasticity. Such changes were different in pathological (SOD1G93A ALS mouse model) vs. physiological (wild‐type) conditions. The results of our study help us to better understand how stress modulates the M1 and highlight the need to further characterize stress‐induced motor cortex changes because it may be of importance when evaluating ALS outcomes. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying central fatigue (CF) induced by high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are still not fully understood. Methods: In order to explore the effects of these exercises on the functioning of cortical and subcortical neural networks, this study investigated the effects of HIIT and MICT on local field potential (LFP) and neuronal firing in the mouse primary motor cortex (M1) and hippocampal CA1 areas. HIIT and MICT were performed on C57BL/6 mice, and simultaneous multichannel recordings were conducted in the M1 motor cortex and CA1 hippocampal region. Results: A range of responses were elicited, including a decrease in coherence values of LFP rhythms in both areas, and an increase in slow and a decrease in fast power spectral density (PSD, n = 7-9) respectively. HIIT/MICT also decreased the gravity frequency (GF, n = 7-9) in M1 and CA1. Both exercises decreased overall firing rates, increased time lag of firing, declined burst firing rates and the number of spikes in burst, and reduced burst duration (BD) in M1 and CA1 (n = 7-9). While several neuronal firing properties showed a recovery tendency, the alterations of LFP parameters were more sustained during the 10-min post-HIIT/MICT period. MICT appeared to be more effective than HIIT in affecting LFP parameters, neuronal firing rate, and burst firing properties, particularly in CA1. Both exercises significantly affected neural network activities and local neuronal firing in M1 and CA1, with MICT associated with a more substantial and consistent suppression of functional integration between M1 and CA1. Conclusion: Our study provides valuable insights into the neural mechanisms involved in exercise-induced central fatigue by examining the changes in functional connectivity and coordination between the M1 and CA1 regions. These findings may assist individuals engaged in exercise in optimizing their exercise intensity and timing to enhance performance and prevent excessive fatigue. Additionally, the findings may have clinical implications for the development of interventions aimed at managing conditions related to exercise-induced fatigue. [ABSTRACT FROM AUTHOR]

Ageing induces a decline in GABAergic intracortical inhibition, which seems to be associated not only with decremental changes in well‐being, sleep quality, cognition and pain management but also with impaired motor control. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. Therefore, the present study investigated whether age‐related cortical dis‐inhibition could be reversed after 6 months of balance learning and whether improvements in postural control correlated with the extent of reversed dis‐inhibition. The results demonstrated that intracortical inhibition can be upregulated in elderly subjects after long‐term balance learning and revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity‐related upregulation of GABAergic inhibition in a population with chronic dis‐inhibition and may therefore be seminal for many pathologies in which the equilibrium between inhibitory and excitatory neurotransmitters is disturbed. Key points: Ageing induces a decline in GABAergic intracortical inhibition.So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly.After 6 months of balance learning, intracortical inhibition can be upregulated in elderly subjects.The results of this study also revealed a correlation between changes in balance performance and intracortical inhibition.This is the first study to show physical activity‐related upregulation of GABAergic inhibition in a population with chronic dis‐inhibition. [ABSTRACT FROM AUTHOR]

• A tDCS homeostatic plasticity protocol was applied over the motor cortex (M1). • The homeostatic plasticity response of the sensory cortex (S1) was evaluated. • The somatosensory evoked potentials N20-P25, P45, and N33-P45 were facilitated. • No homeostatic response was observed through this methodology. • Homeostatic plasticity over M1 directly modulates S1, but not homeostatically. Homeostatic plasticity is a mechanism that stabilizes cortical excitability within a physiological range. Most homeostatic plasticity protocols have primed and tested the homeostatic response of the primary motor cortex (M1). This study investigated if a homeostatic response could be recorded from the primary sensory cortex (S1) after inducing homeostatic plasticity in M1. In 31 healthy participants, homeostatic plasticity was induced over M1 with a priming and testing block of transcranial direct current stimulation (tDCS) in two different sessions (anodal and cathodal). S1 excitability was assessed by early (N20, P25) and middle-latency (N33-P45) somatosensory evoked potentials (SEP) extracted from 4 electrodes (CP5, CP3, P5, P3). Baseline and post-measures (post-priming, 0-min, 10-min, and 20-min after homeostatic induction) were taken. Anodal M1 homeostatic plasticity induction significantly facilitated the N20-P25, P45 peak, and N33-P45 early SEP components up to 20-min post-induction, without any indication of a homeostatic response (i.e., reduced SEP). Cathodal homeostatic induction did not induce any significant effect on early or middle latency SEPs. M1 homeostatic plasticity induction by anodal stimulation protocol to the primary motor cortex did not induce a homeostatic response in SEPs. [ABSTRACT FROM AUTHOR]

Introduction: The conventional method of placing transcranial direct current stimulation (tDCS) electrodes is just above the target brain area. However, this strategy for electrode placement often fails to improve motor function and modulate cortical excitability. We investigated the effects of optimized electrode placement to induce maximum electrical fields in the leg regions of both M1 and SMA, estimated by electric field simulations in the T1 and T2-weighted MRIbased anatomical models, on motor performance and cortical excitability in healthy individuals. Methods: A total of 36 healthy volunteers participated in this randomized, triple-blind, sham-controlled experiment. They were stratified by sex and were randomly assigned to one of three groups according to the stimulation paradigm, including tDCS with (1) anodal and cathodal electrodes positioned over FCz and POz, respectively, (A-P tDCS), (2) anodal and cathodal electrodes positioned over POz and FCz, respectively, (P-A tDCS), and (3) sham tDCS. The sit-to-stand training following tDCS (2 mA, 10 min) was conducted every 3 or 4 days over 3 weeks (5 sessions total). Results: Compared to sham tDCS, A-P tDCS led to significant increases in the number of sit-to-stands after 3 weeks training, whereas P-A tDCS significantly increased knee flexor peak torques after 3 weeks training, and decreased shortinterval intracortical inhibition (SICI) immediately after the first session of training and maintained it post-training. Discussion: These results suggest that optimized electrode placement of the maximal EF estimated by electric field simulation enhances motor performance and modulates cortical excitability depending on the direction of current flow. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of temporal interference electrical fields (TI) on motor cortical excitability and motor learning abilities in healthy adults, in order to provide evidence for the application of TI stimulation in human. Method: A randomized crossover double-blind design was used with healthy adults participants. Experiment 1: twenty subjects completed transcranial magnetic stimulation (TMS) testing to assess changes in cortical excitability indicators before and after stimulation, including motor evoked potentials (MEP), resting motor threshold (RMT), short- interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Experiment 2: sixteen subjects completed the random reaction time task (RRTT) and the serial reaction time task (SRTT), with performance indicators including average reaction time (RT), first implicit learning (FIL), and second implicit learning (SIL). The effects of TI stimulation on cortical excitability and motor learning abilities were evaluated using a two-factor repeated measures analysis of variance. Result: Experiment 1: there were significant interactions between stimulation condition and time on MEP (F= 28.787, P<0.001, ηP²=0.602) and RMT (F=23.524, P<0.001, ηP²=0.580), while SICI and ICF showed no significant interaction effects. Experiment 2: compared to sham stimulation, FIL in SRTT was significantly improved after TI stimulation (F=4.601, P=0.049, ηP²=0.235), while there was no significant interaction effect in the RRTT task. Conclusion: Variable frequency TI stimulation can significantly increase cortical excitability in the primary motor cortex, and this regulatory effect may contribute to enhancing motor learning performance in healthy adults. [ABSTRACT FROM AUTHOR]

After musculoskeletal injuries, there is often a loss of corticospinal control. Current tendon rehabilitation may not adequately address the corticospinal control of the muscle which may contribute to the recalcitrance of symptom recurrence. This review provides a summary of the current literature regarding the effectiveness of tempo-controlled resistance training (TCRT) in (1) promoting corticospinal plasticity, (2) improving physical performance, and (3) improving strength outcomes in healthy adults. A comprehensive literature search was conducted using electronic databases (PubMed, CINAHL, Embase, and Google Scholar) to identify relevant studies published between 2010 and 2023. Randomized control (RCT) studies that included recreationally trained and untrained healthy adults between 18 and 60 years of age and that compared a TCRT intervention to a control condition were included. Twelve of the 1255 studies identified in the initial search were included in the final analysis. Throughout all included studies, TCRT was shown to elicit greater neural adaptations compared to traditional resistance training methods (i.e., self-paced strength training). These results indicate that TCRT holds promise as an effective method for modulating corticospinal plasticity in healthy adults and may enhance neuromuscular adaptations, including improvements in CSE, decreased SICI, enhanced motor unit synchronization, and voluntary muscle activation. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) has emerged as a potential intervention to improve physical performance. This study investigates the effects of tDCS applied to the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) on performance in a maximal effort task, specifically the No-Jump Burpee exercise. Twenty healthy male subjects (26.0 ± 4.91 years) completed three experimental conditions (a-DLPFC, a-M1, and SHAM) in a double-blind crossover design. Prior to the performance of burpees to exhaustion, tDCS (2 mA, 20 min) was administered. The total number of repetitions, vastus lateralis muscle oxygen saturation, heart rate, and subjective perception of exertion (RPE) during exercise were measured. Repeated ANOVAs showed a significant effect of condition on the number of repetitions (p < 0.001). Subjects performed more repetitions under the M1 condition (68 ± 19.5) compared to DLPFC (63 ± 17.9) and SHAM (58 ± 18.0), with significant differences between all conditions. This study demonstrates that tDCS can improve performance in a physical endurance task such as the No-Jump Burpee. The findings suggest that tDCS may be a viable ergogenic tool for improving athletic performance. Future research should explore the underlying mechanisms and the practical application of these results in long-term physical training programs (NCT06472882). [ABSTRACT FROM AUTHOR]

Abstract Vasoactive intestinal polypeptide (VIP) is known to be present in a subclass of cortical interneurons. Here, using three different antibodies, we demonstrate that VIP is also present in the giant layer 5 pyramidal (Betz) neurons which are characteristic of the limb and axial representations of the marmoset primary motor cortex (cytoarchitectural area 4ab). No VIP staining was observed in smaller layer 5 pyramidal cells present in the primary motor facial representation (cytoarchitectural area 4c), or in the premotor cortex (e.g. the caudal subdivision of the dorsal premotor cortex, A6DC), indicating the selective expression of VIP in Betz cells. VIP in Betz cells was colocalized with neuronal specific marker (NeuN) and a calcium-binding protein parvalbumin (PV). PV also intensely labelled axon terminals surrounding Betz cell somata. VIP-positive interneurons were more abundant in the superficial cortical layers and constituted about 5–7% of total cortical neurons, with the highest density observed in area 4c. Our results demonstrate the expression of VIP in the largest excitatory neurons of the primate cortex, which may offer new functional insights into the role of VIP in the brain, and provide opportunities for genetic manipulation of Betz cells.

Background: The clinical application of 10 Hz repetitive transcranil magnetic stimulation (rTMS) remains limited despite its demonstrated effectiveness in enhancing cortical excitability and improving cognitive function. The present study used a novel stimulus target [left dorsolateral prefrontal cortex + primary motor cortex] to facilitate the enhancement of cognitive function through the bidirectional promotion of cognitive and motor functions; Methods: Post-stroke cognitive impairment patients (n = 48) were randomly assigned to receive either dual-target, single-target, or sham rTMS for 4 weeks. Before and after 4 weeks of treatment, participants were asked to complete the Montreal Cognitive Assessment (MoCA) test, the Modified Barthel Index (MBI), the Trail-making Test (TMT), and the Digital Span Test (DST). In addition, the levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in serum were also measured. Results: After adjusting for pre-intervention (baseline) MoCA scores, the post-intervention MoCA scores varied significantly. After post-hoc analysis, differences existed between the post-treatment scores of the dual-target rTMS group and the sham rTMS group (the experimental group scores were significantly higher), and between those of the dual-target rTMS group and the single-target rTMS group (the dual-target rTMS scores were significantly higher). The serum VEGF levels of the dual-target rTMS group were significantly higher those that of the sham rTMS group. Conclusions: The present study presented data showing that a dual-target rTMS therapy is effective for Post-stroke cognitive impairment (PSCI). The stimulation exhibited remarkable efficacy, suggesting that dual-target stimulation (left dorsolateral prefrontal cortex+motor cortex (L-DLPFC+M1)) holds promise as a potential target for TMS therapy in individuals with cognitive impairment after stroke. [ABSTRACT FROM AUTHOR]

Context: In athletes, postural control impairment and knee muscle dysfunction are the most common disorders following anterior cruciate ligament (ACL) injury. Because of functional changes in the motor cortex following ACL injury, physiotherapy (PT) is not enough for treatment and using neuromodulators, such as trans-cranial direct current stimulation (tDCS) may be necessary. The present study focused on the effects of anodal tDCS (a-tDCS) over the primary motor cortex (M1) concurrent with PT on postural control and muscular performance in the athletes with ACL injury. Design: In this study, 34 athletes with ACL injury were randomly assigned in 2 groups of intervention group (active M1 a-tDCS concurrent with PT, n = 16) and control group (sham M1 a-tDCS concurrent with PT, n = 16). Methods: The participants of all groups received 20-minute 2 mA M1 a-tDCS with PT during 10 sessions, while tDCS was turned off after 30 seconds in the sham group. Before, immediately following, and 1 month after the interventions, the center of pressure and the average of power of flexor and extensor muscles at 2 velocities of 30°/s and 60°/s were measured by force plate and isokinetic devices, respectively. Results: One month after treatment, the displacement of center of pressure was decreased in the intervention group (P < .05), while there were no changes in the control group. Y-axis of center of pressure decreased in the intervention group relative to the control group, although average of power of flexor and extensor muscles increased immediately in both groups, but the rise in the intervention group was larger than that in the control group (P < .05). Conclusion: The findings indicated that M1 a-tDCS can induce the efficacy of PT, which has a lasting effect on the improvement of the postural control in athletes with ACL injury. [ABSTRACT FROM AUTHOR]

Abstract Background Repeated transcranial magnetic stimulation (rTMS) could induce alterations in cortical excitability and promote neuroplasticity. To precisely quantify these effects, functional near-infrared spectroscopy (fNIRS), an optical neuroimaging modality adept at detecting changes in cortical hemodynamic responses, has been employed concurrently alongside rTMS to measure and tailor the impact of diverse rTMS protocols on the brain cortex. Objective This systematic review and meta-analysis aimed to elucidate the effects of rTMS on cortical hemodynamic responses over the primary motor cortex (M1) as detected by fNIRS. Methods Original articles that utilized rTMS to stimulate the M1 cortex in combination with fNIRS for the assessment of cortical activity were systematically searched across the PubMed, Embase, and Scopus databases. The search encompassed records from the inception of these databases up until April, 2024. The assessment for risk of bias was also conducted. A meta-analysis was also conducted in studies with extractable raw data. Results Among 312 studies, 14 articles were eligible for qualitative review. 7 studies were eligible for meta-analysis. A variety of rTMS protocols was employed on M1 cortex. In inhibitory rTMS, multiple studies observed a reduction in the concentration of oxygenated hemoglobin [HbO] at the ipsilateral M1, contrasted by an elevation at the contralateral M1. Meta-analysis also corroborated this consistent trend. Nevertheless, certain investigations unveiled diminished [HbO] in bilateral M1. Several studies also depicted intricate inhibitory or excitatory interplay among distinct cortical regions. Conclusion Diverse rTMS protocols led to varied patterns of cortical activity detected by fNIRS. Meta-analysis revealed a trend of increasing [HbO] in the contralateral cortices and decreasing [HbO] in the ipsilateral cortices following low frequency inhibitory rTMS. However, due to the heterogeneity between studies, further research is necessary to comprehensively understand rTMS-induced alterations in brain activity.

Background: Repeated transcranial magnetic stimulation (rTMS) could induce alterations in cortical excitability and promote neuroplasticity. To precisely quantify these effects, functional near-infrared spectroscopy (fNIRS), an optical neuroimaging modality adept at detecting changes in cortical hemodynamic responses, has been employed concurrently alongside rTMS to measure and tailor the impact of diverse rTMS protocols on the brain cortex. Objective: This systematic review and meta-analysis aimed to elucidate the effects of rTMS on cortical hemodynamic responses over the primary motor cortex (M1) as detected by fNIRS. Methods: Original articles that utilized rTMS to stimulate the M1 cortex in combination with fNIRS for the assessment of cortical activity were systematically searched across the PubMed, Embase, and Scopus databases. The search encompassed records from the inception of these databases up until April, 2024. The assessment for risk of bias was also conducted. A meta-analysis was also conducted in studies with extractable raw data. Results: Among 312 studies, 14 articles were eligible for qualitative review. 7 studies were eligible for meta-analysis. A variety of rTMS protocols was employed on M1 cortex. In inhibitory rTMS, multiple studies observed a reduction in the concentration of oxygenated hemoglobin [HbO] at the ipsilateral M1, contrasted by an elevation at the contralateral M1. Meta-analysis also corroborated this consistent trend. Nevertheless, certain investigations unveiled diminished [HbO] in bilateral M1. Several studies also depicted intricate inhibitory or excitatory interplay among distinct cortical regions. Conclusion: Diverse rTMS protocols led to varied patterns of cortical activity detected by fNIRS. Meta-analysis revealed a trend of increasing [HbO] in the contralateral cortices and decreasing [HbO] in the ipsilateral cortices following low frequency inhibitory rTMS. However, due to the heterogeneity between studies, further research is necessary to comprehensively understand rTMS-induced alterations in brain activity. [ABSTRACT FROM AUTHOR]

A ponto-cerebello-thalamo-cortical network is the pathophysiological correlate of primary orthostatic tremor. Affected patients often do not respond satisfactorily to pharmacological treatment. Consequently, the objective of the current study was to examine the effects of a non-invasive neuromodulation by theta burst repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex (M1) and dorsal medial frontal cortex (dMFC) on tremor frequency, intensity, sway path and subjective postural stability in primary orthostatic tremor. In a cross-over design, eight patients (mean age 70.2 ± 5.4 years, 4 female) with a primary orthostatic tremor received either rTMS of the left M1 leg area or the dMFC at the first study session, followed by the other condition (dMFC or M1 respectively) at the second study session 30 days later. Tremor frequency and intensity were quantified by surface electromyography of lower leg muscles and total sway path by posturography (foam rubber with eyes open) before and after each rTMS session. Patients subjectively rated postural stability on the posturography platform following each rTMS treatment. We found that tremor frequency did not change significantly with M1- or dMFC-stimulation. However, tremor intensity was lower after M1- but not dMFC-stimulation (p = 0.033/ p = 0.339). The sway path decreased markedly after M1-stimulation (p = 0.0005) and dMFC-stimulation (p = 0.023) compared to baseline. Accordingly, patients indicated a better subjective feeling of postural stability both with M1-rTMS (p = 0.007) and dMFC-rTMS (p = 0.01). In conclusion, non-invasive neuromodulation particularly of the M1 area can improve postural control and tremor intensity in primary orthostatic tremor by interference with the tremor network. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of adult disability that results in motor deficits and reduced independence. Regaining independence relies on motor recovery, particularly regaining function of the hand and arm. This review presents evidence from human studies that have used transcranial magnetic stimulation (TMS) to identify neurophysiological mechanisms underlying upper limb motor recovery early after stroke. TMS studies undertaken at the subacute stage after stroke have identified several neurophysiological factors that can drive motor impairment, including membrane excitability, the recruitment of corticomotor neurons, and glutamatergic and GABAergic neurotransmission. However, the inherent variability and subsequent poor reliability of measures derived from motor evoked potentials (MEPs) limit the use of TMS for prognosis at the individual patient level. Currently, prediction tools that provide the most accurate information about upper limb motor outcomes for individual patients early after stroke combine clinical measures with a simple neurophysiological biomarker based on MEP presence or absence, i.e. MEP status. Here, we propose a new compositional framework to examine MEPs across several upper limb muscles within a threshold matrix. The matrix can provide a more comprehensive view of corticomotor function and recovery after stroke by quantifying the evolution of subthreshold and suprathreshold MEPs through compositional analyses. Our contention is that subthreshold responses might be the most sensitive to reduced output of corticomotor neurons, desynchronized firing of the remaining neurons, and myelination processes that occur early after stroke. Quantifying subthreshold responses might provide new insights into post‐stroke neurophysiology and improve the accuracy of prediction of upper limb motor outcomes. [ABSTRACT FROM AUTHOR]

Cardiac function is under neural regulation; however, brain regions in the cerebral cortex responsible for regulating cardiac function remain elusive. In this study, retrograde trans‐synaptic viral tracing is used from the heart to identify a specific population of the excitatory neurons in the primary motor cortex (M1) that influences cardiac function in mice. Optogenetic activation of M1 glutamatergic neurons increases heart rate, ejection fraction, and blood pressure. By contrast, inhibition of M1 glutamatergic neurons decreased cardiac function and blood pressure as well as tyrosine hydroxylase (TH) expression in the heart. Using viral tracing and optogenetics, the median raphe nucleus (MnR) is identified as one of the key relay brain regions in the circuit from M1 that affect cardiac function. Then, a mouse model of cardiac injury is established caused by myocardial infarction (MI), in which optogenetic activation of M1 glutamatergic neurons impaired cardiac function in MI mice. Moreover, ablation of M1 neurons decreased the levels of norepinephrine and cardiac TH expression, and enhanced cardiac function in MI mice. These findings establish that the M1 neurons involved in the regulation of cardiac function and blood pressure. They also help the understanding of the neural mechanisms underlying cardiovascular regulation. [ABSTRACT FROM AUTHOR]

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, d 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Our findings do not support the use of rTMS as a standalone treatment for CLBP. • Top-down and bottom-up interventions might trigger a distinct priming mechanism. • Our study contributed to optimizing treatment strategies for CLBP. The study aims to explore the effects of combining repetitive transcranial magnetic stimulation (rTMS) with sling exercise (SE) intervention in patients with chronic low back pain (CLBP). This approach aims to directly stimulate brain circuits and indirectly activate trunk muscles to influence motor cortex plasticity. However, the impact of this combined intervention on motor cortex organization and clinical symptom improvement is still unclear, as well as whether it is more effective than either intervention alone. To investigate this, patients with CLBP were randomly assigned to three groups: SE/rTMS, rTMS alone, and SE alone. Motor cortical organization, numerical pain rating scale (NPRS), Oswestry Disability Index (ODI), and postural balance stability were measured before and after a 2-week intervention. The results showed statistically significant differences in the representative location of multifidus on the left hemispheres, as well as in NPRS and ODI scores, in the combined SE/rTMS group after the intervention. When compared to the other two groups, the combined SE/rTMS group demonstrated significantly different motor cortical organization, sway area, and path range from the rTMS alone group, but not from the SE alone group. These findings highlight the potential benefits of a combined SE/rTMS intervention in terms of clinical outcomes and neuroadaptive changes compared to rTMS alone. However, there was no significant difference between the combined intervention and SE alone. Therefore, our research does not support the use of rTMS as a standalone treatment for CLBP. Our study contributed to optimizing treatment strategies for individuals suffering from CLBP. [ABSTRACT FROM AUTHOR]

Humans display automatic action tendencies toward emotional stimuli, showing faster automatic behavior (i.e., approaching a positive stimulus and avoiding a negative stimulus) than regulated behavior (i.e., avoiding a positive stimulus and approaching a negative stimulus). Previous studies have shown that the primary motor cortex is involved in the processing of automatic actions, with higher motor evoked potential amplitudes during automatic behavior elicited by single-pulse transcranial magnetic stimulation. However, it is unknown how intracortical circuits are involved with automatic action tendencies. Here, we measured short-interval intracortical inhibition and intracortical facilitation within the primary motor cortex by using paired-pulse transcranial magnetic stimulation protocols during a manikin task, which has been widely used to explore approaching and avoiding behavior. Results showed that intracortical facilitation was stronger during automatic behavior than during regulated behavior. Moreover, there was a significant negative correlation between reaction times and intracortical facilitation effect during automatic behavior: individuals with short reaction times had stronger faciliatory activity, as shown by higher intracortical facilitation. By contrast, no significant difference was found for short-interval intracortical inhibition between automatic behavior and regulated behavior. The results indicated that the intracortical facilitation circuit, mediated by excitatory glutamatergic neurons, in the primary motor cortex, plays an important role in mediating automatic action tendencies. This finding further supports the link between emotional perception and the action system. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To systematically evaluate the efficacy of transcranial direct current stimulation on the motor function of patients with Parkinson’s disease, and to compare the efficacy of transcranial direct current stimulation at different targets on the motor function of patients with Parkinson’s disease, so as to provide a theoretical basis for the target selection of transcranial direct current stimulation in clinical practice. METHODS: Cochrane Library, PubMed, Web of Science, CNKI, VIP, WanFang Data were retrieved for randomized controlled trials on the improvement of motor function in patients with Parkinson’s disease by transcranial direct current stimulation published from the database inception to January 2023. The keywords were “Parkinson, transcranial direct current stimulation” in English and Chinese. The quality of the included studies was evaluated using the Cochrane 5.1.0 risk of bias assessment tool and the PEDro scale. Meta-analysis of outcome indicators was performed using RevMan 5.4 and Stata 17.0 software. RESULTS: Fifteen randomized controlled trials were finally included, and the PEDro scale showed that all were high-quality or very high-quality studies. Meta-analysis showed that transcranial direct current stimulation significantly improved Unified-Parkinson Disease Rating Scale part III score [mean difference (MD)=-2.49, 95% confidence interval (CI): -4.42 to -0.55, P < 0.05), step frequency score (MD=0.07, 95%CI: 0.03-0.11, P < 0.05) and step speed score (MD=0.02, 95%CI: 0.00-0.05, P < 0.05), but not for Berg Balance Scale scores (MD=2.57, 95%CI:-0.74 to 5.87, P > 0.05). Network Meta-analysis probability ranking: In terms of Unified-Parkinson Disease Rating Scale part III scores, the probability ranking results of target stimulation efficacy were dorsal lateral prefrontal cortex (52.4%) > primary motor cortex (45.8%) > central point of the brain (1.8%) > conventional rehabilitation (0%); in terms of gait frequency scores, the probability probability ranking results of target stimulation efficacy were cerebellum (50.1%) > central point of the brain (45.8%) > dorsal lateral prefrontal cortex (3.9%) > primary motor cortex (0.2%) > conventional rehabilitation (0%); in terms of gait speed scores, the probability ranking results of target stimulation efficacy were cerebellum( 64.8%) > dorsal lateral prefrontal cortex (23.8%) > central point of the brain (9.4%) > primary motor cortex (1.7%) > conventional rehabilitation (0.4%); in terms of Berg Balance Scale scores, the probability ranking results of target stimulation efficacy were cerebellum (77.4%) > dorsal lateral prefrontal cortex (20.7%) > central point of the brain (0.7%) > conventional rehabilitation (0.2%). CONCLUSION: Transcranial direct current stimulation significantly improves motor function of patients with Parkinson’s disease, with better motor coordination in the dorsolateral prefrontal cortex and better walking and balance in the cerebellum. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) is a non‐invasive brain stimulation technique which was found to have a positive modulatory effect on online sequence acquisition or offline motor consolidation, depending on the relative role of the associated brain region. Primary motor regions (M1) and dorsolateral prefrontal cortices (DLPFC) have both been related to sequential learning. However, research so far did not systematically disentangle their differential roles in online and offline learning especially in more complex sequential paradigms. In this study, the influence of anodal M1 leg area‐tDCS and anodal DLPFC‐tDCS applied during complex sequential learning (online and offline) was investigated using a complex whole body serial reaction time task (CWB‐SRTT) in 42 healthy volunteers. TDCS groups did not differ from sham tDCS group regarding their response and reaction time (online) and also not in terms of overnight consolidation (offline). Sequence specific learning and the number of recalled items also did not differ between groups. Results may be related to unspecific parameters such as timing of the stimulation or current intensity but can also be attributed to the relative role of M1 and DLPFC during early complex learning. Taken together, the current study provides preliminary evidence that M1 leg area or DLPFC modulation by means of tDCS does not improve complex sequential skill learning. Significance statement: Understanding motor learning is helpful to deepen our knowledge about the human ability to acquire new skills. Complex sequential learning tasks have only been studied, sparsely, but are particularly mimicking challenges of daily living. The present study studied early motor learning in a complex serial reaction time task while transcranial direct current stimulation (tDCS) was either applied to leg primary motor cortex or bilateral dorsolateral prefrontal cortex. TDCS did not affect sequential learning, neither directly during performance nor in terms of sequence consolidation. Results provide preliminary information that M1 or bilateral DLPFC modulation does not improve early complex motor learning. [ABSTRACT FROM AUTHOR]

Considering the advantages of brain stimulation techniques in detecting the role of different areas of the brain in human sensorimotor behaviors, we used anodal transcranial direct-current stimulation (a-tDCS) over three different brain sites of the frontoparietal cortex (FPC) in healthy participants to elucidate the role of these three brain areas of the FPC on reaction time (RT) during a sequential visual isometric pinch task (SVIPT). We also aimed to assess if the stimulation of these cortical sites affects the transfer of learning during SVIPT. A total of 48 right-handed healthy participants were randomly assigned to one of the four a-tDCS groups: (1) left primary motor cortex (M1), (2) left dorsolateral prefrontal cortex (DLPFC), (3) left posterior parietal cortex (PPC), and (4) sham. A-tDCS (0.3 mA, 20 min) was applied concurrently with the SVIPT, in which the participants precisely controlled their forces to reach seven different target forces from 10 to 40% of the maximum voluntary contraction (MVC) presented on a computer screen with the right dominant hand. Four test blocks were randomly performed at the baseline and 15 min after the intervention, including sequence and random blocks with either hand. Our results showed significant elongations in the ratio of RTs between the M1 and sham groups in the sequence blocks of both the right-trained and left-untrained hands. No significant differences were found between the DLPFC and sham groups and the PPC and sham groups in RT measurements within the SVIPT. Our findings suggest that RT improvement within implicit learning of an SVIPT is not mediated by single-session a-tDCS over M1, DLPFC, or PPC. Further research is needed to understand the optimal characteristics of tDCS and stimulation sites to modulate reaction time in a precision control task such as an SVIPT. [ABSTRACT FROM AUTHOR]

Objectives: Existing applications of non-invasive brain stimulation in the modulation of balance ability are focused on the primary motor cortex (M1). It is conceivable that other brain and spinal cord areas may be comparable or more promising targets in this regard. This study compares transcranial direct current stimulation (tDCS) over (i) the M1, (ii) the cerebellum, and (iii) trans-spinal direct current stimulation (tsDCS) in the modulation of balance ability. Methods: Forty-two sports students were randomized in this placebo-controlled study. Twenty minutes of anodal 1.5 mA t/tsDCS over (i) the M1, (ii) the cerebellum, and (iii) the spinal cord, as well as (iv) sham tDCS were applied to each subject. The Y Balance Test, Single Leg Landing Test, and Single Leg Squat Test were performed prior to and after each intervention. Results: The Y Balance Test showed significant improvement after real stimulation of each region compared to sham stimulation. While tsDCS supported the balance ability of both legs, M1 and cerebellar tDCS supported right leg stand only. No significant differences were found in the Single Leg Landing Test and the Single Leg Squat Test. Conclusions: Our data encourage the application of DCS over the cerebellum and spinal cord (in addition to the M1 region) in supporting balance control. Future research should investigate and compare the effects of different stimulation protocols (anodal or cathodal direct current stimulation (DCS), alternating current stimulation (ACS), high-definition DCS/ACS, closed-loop ACS) over these regions in healthy people and examine the potential of these approaches in the neurorehabilitation. [ABSTRACT FROM AUTHOR]

Using theta burst stimulation (TBS) to induce neural plasticity has played an important role in improving the treatment of neurological disorders. However, the variability of TBS-induced synaptic plasticity in the primary motor cortex prevents its clinical application. Thus, factors associated with this variability should be explored to enable the creation of a predictive model. Statistical approaches, such as regression analysis, have been used to predict the effects of TBS. Machine learning may potentially uncover previously unexplored predictive factors due to its increased capacity for capturing nonlinear changes. In this study, we used our prior dataset (Katagiri et al., 2020) to determine the factors that predict variability in TBS-induced synaptic plasticity in the lower limb motor cortex for both intermittent (iTBS) and continuous (cTBS) TBS using machine learning. Validation of the created model showed an area under the curve (AUC) of 0.85 and 0.69 and positive predictive values of 77.7 and 70.0% for iTBS and cTBS, respectively; the negative predictive value was 75.5% for both patterns. Additionally, the accuracy was 0.76 and 0.72, precision was 0.82 and 0.67, recall was 0.82 and 0.67, and F1 scores were 0.82 and 0.67 for iTBS and cTBS, respectively. The most important predictor of iTBS was the motor evoked potential amplitude, whereas it was the intracortical facilitation for cTBS. Our results provide additional insights into the prediction of the effects of TBS variability according to baseline neurophysiological factors. [ABSTRACT FROM AUTHOR]

Although attentional focus affects motor performance, whether corticospinal excitability and intracortical modulations differ between focus strategies depending on the exercise patterns remains unclear. In the present study, using single- and paired-pulse transcranial magnetic stimulation and peripheral nerve stimulation, we demonstrated changes in the cortical and spinal excitability under external focus (EF) and internal focus (IF) conditions with dynamic or static exercise. Participants performed the ramp-and-hold contraction task of right index finger abduction against an object (sponge or wood) with both exercises. They were asked to concentrate on the pressure on the sponge/wood induced by finger abduction under the EF condition, and on the index finger itself under the IF condition. Motor-evoked potential (MEP) and F-wave in the premotor, phasic, or tonic phase, and short- and long-interval intracortical inhibition (SICI and LICI, respectively), and intracortical facilitation (ICF) in the premotor phase were examined by recording surface electromyographic activity in the right first dorsal interosseous muscle. Increments in the MEP amplitude were larger under the EF condition than under the IF condition in the dynamic, but not static, exercise. The F-wave, SICI, and LICI did not differ between focus conditions in both exercises. In the dynamic exercise, interestingly, ICF was greater under the EF condition than under the IF condition and positively correlated with the MEP amplitude. These results indicate that corticospinal excitability and intracortical modulations to attentional focus differ depending on exercise patterns, suggesting that attentional focus differentially affects the central nervous system responsible for diverse motor behaviors. NEW & NOTEWORTHY: We investigated attentional focus-dependent corticospinal and intracortical modulations in dynamic or static exercise. The corticospinal excitability was modulated differentially depending on the focus of attention during dynamic, but not static exercise. Although the reduction of intracortical GABAergic inhibition was comparable between focus conditions in both exercises, intracortical facilitation was smaller when focusing on the internal environments in the dynamic exercise, resulting in lower activation of the corticospinal tract. [ABSTRACT FROM AUTHOR]

Motor learning is crucial for the survival of many animals. Acquiring a new motor skill involves complex alterations in both local neural circuits in many brain regions and long-range connections between them. Such changes can be observed anatomically and functionally. The primary motor cortex (M1) integrates information from diverse brain regions and plays a pivotal role in the acquisition and refinement of new motor skills. In this review, we discuss how motor learning affects the M1 at synaptic, cellular, and circuit levels. Wherever applicable, we attempt to relate and compare findings in humans, non-human primates, and rodents. Understanding the underlying principles shared by different species will deepen our understanding of the neurobiological and computational basis of motor learning.

Temporal interference (TI) electric field brain stimulation is a novel neuromodulation technique that enables the non-invasive modulation of deep brain regions, but few advances about TI stimulation effectiveness and mechanisms have been reported. Conventional transcranial alternating current stimulation (tACS) can enhance motor skills, whether TI stimulation has an effect on motor skills in mice has not been elucidated. In the present study, TI stimulation was proved to stimulating noninvasively primary motor cortex (M1) of mice, and that TI stimulation with an envelope wave frequency of 20 Hz (Δ f = 20 Hz) once a day for 20 min for 7 consecutive days significantly improved the motor skills of mice. The mechanism of action may be related to regulating of neurotransmitter metabolism, increasing the expression of synapse-related proteins, promoting neurotransmitter release, increasing dendritic spine density, enhancing the number of synaptic vesicles and the thickness of postsynaptic dense material, and ultimately enhance neuronal excitability and plasticity. It is the first report about TI stimulation promoting motor skills of mice and describing its mechanisms.

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory, resistant to antiepileptic drugs, and has a high recurrence rate. The pathogenesis of temporal lobe epilepsy is complex and is not fully understood. Intracellular calcium dynamics have been implicated in temporal lobe epilepsy. However, the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown, and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice. In this study, we used a multi-channel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process. We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes. In particular, cortical spreading depression, which has recently been frequently used to represent the continuously and substantially increased calcium signals, was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from grade II to grade V. However, vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures. Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to grade I episodes. In addition, the latency of cortical spreading depression was prolonged, and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced. Intriguingly, it was possible to rescue the altered intracellular calcium dynamics. Via simultaneous analysis of calcium signals and epileptic behaviors, we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced, and that the end-point behaviors of temporal lobe epilepsy were improved. Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades. Furthermore, the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy, thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.

In healthy people, the brain controls movement with a high amount of feedback from many modes of perception. Disease or injury compromises these sensory pathways, as well as their neural impulse counterparts, in many people, resulting in major deficits and a lower quality of life. The use of kinesthetics feedback can be used as a therapy method for a variety of neurological diseases like Parkinson's disease (PD) and stroke is gaining popularity. One of these therapeutic possibilities is to use a closed-loop feedback model with mental imagery as the self-regulation support to improve volitional control of malfunctioning or damaged brain networks and nodes. BMIs (Brain–Machine Interfaces) promise to restore function to these people by letting them to control a gadget with their thoughts. The majority of present BMI implementations rely on visual feedback for closed-loop control; But it has been argued that adding more sensory modalities could improve control. The paper shows that kinesthetics feedback may be combined with vision to considerably improve control of a primary motor cortex neural activity (MI). These findings imply that in paralysed individuals with residual kinesthetics feeling, BMI control can be greatly enhanced, and they provide the framework for augmenting cortically controlled BMIs with a variety of surrogate or natural sensory feedback.

The subthalamic nucleus (STN) receives cortical inputs via the hyperdirect and indirect pathways, projects to the output nuclei of the basal ganglia, and plays a critical role in the control of voluntary movements and movement disorders. STN neurons change their activity during execution of movements, while recent studies emphasize STN activity specific to cancelation of movements. To address the relationship between execution and cancelation functions, we examined STN activity in two Japanese monkeys (Macaca fuscata, both sexes) who performed a goal-directed reaching task with a delay that included Go, Cancel, and NoGo trials. We first examined responses to the stimulation of the forelimb regions in the primary motor cortex and/or supplementary motor area. STN neurons with motor cortical inputs were found in the dorsal somatomotor region of the STN. All these STN neurons showed activity changes in Go trials, suggesting their involvement in execution of movements. Part of them exhibited activity changes in Cancel trials and sustained activity during delay periods, suggesting their involvement in cancelation of planedmovements and preparation of movements, respectively. The STN neurons rarely showed activity changes in NoGo trials. Go- and Cancel-related activity was selective to the direction of movements, and the selectivity was higher in Cancel trials than in Go trials. Changes in Go- and Cancel-related activity occurred early enough to initiate and cancel movements, respectively. These results suggest that the dorsal somatomotor region of the STN, which receives motor cortical inputs, is involved in preparation and execution of movements and cancelation of planned movements. [ABSTRACT FROM AUTHOR]

Non‐invasive brain stimulation has the potential to boost neuronal plasticity in the primary motor cortex (M1), but it remains unclear whether the stimulation of both superficial and deep layers of the human motor cortex can effectively promote M1 plasticity. Here, we leveraged transcranial ultrasound stimulation (TUS) to precisely target M1 circuits at depths of approximately 5 mm and 16 mm from the cortical surface. Initially, we generated computed tomography images from each participant's individual anatomical magnetic resonance images (MRI), which allowed for the generation of accurate acoustic simulations. This process ensured that personalized TUS was administered exactly to the targeted depths within M1 for each participant. Using long‐term depression and long‐term potentiation (LTD/LTP) theta‐burst stimulation paradigms, we examined whether TUS over distinct depths of M1 could induce LTD/LTP plasticity. Our findings indicated that continuous theta‐burst TUS‐induced LTD‐like plasticity with both superficial and deep M1 stimulation, persisting for at least 30 min. In comparison, sham TUS did not significantly alter M1 excitability. Moreover, intermittent theta‐burst TUS did not result in the induction of LTP‐ or LTD‐like plasticity with either superficial or deep M1 stimulation. These findings suggest that the induction of M1 plasticity can be achieved with ultrasound stimulation targeting distinct depths of M1, which is contingent on the characteristics of TUS. Key points: The study integrated personalized transcranial ultrasound stimulation (TUS) with electrophysiology to determine whether TUS targeting superficial and deep layers of the human motor cortex (M1) could elicit long‐term depression (LTD) or long‐term potentiation (LTP) plastic changes.Utilizing acoustic simulations derived from individualized pseudo‐computed tomography scans, we ensured the precision of TUS delivery to the intended M1 depths for each participant.Continuous theta‐burst TUS targeting both the superficial and deep layers of M1 resulted in the emergence of LTD‐like plasticity, lasting for at least 30 min.Administering intermittent theta‐burst TUS to both the superficial and deep layers of M1 did not lead to the induction of LTP‐ or LTD‐like plastic changes.We suggest that theta‐burst TUS targeting distinct depths of M1 can induce plasticity, but this effect is dependent on specific TUS parameters. [ABSTRACT FROM AUTHOR]

Intracortical Brain-Computer Interfaces (iBCI) use single-unit activity (SUA), multiunit activity (MUA) and local field potentials (LFP) to control neuroprosthetic devices. SUA and MUA are usually extracted from the bandpassed recording through amplitude thresholding, while subthreshold data are ignored. Here, we show that subthreshold data can actually be decoded to determine behavioral variables with test set accuracy of up to 100%. Although the utility of SUA, MUA and LFP for decoding behavioral variables has been explored previously, this study investigates the utility of spike-band subthreshold activity exclusively. We provide evidence suggesting that this activity can be used to keep decoding performance at acceptable levels even when SUA quality is reduced over time. To the best of our knowledge, the signals that we derive from the subthreshold activity may be the weakest neural signals that have ever been extracted from extracellular neural recordings, while still being decodable with test set accuracy of up to 100%. These results are relevant for the development of fully data-driven and automated methods for amplitude thresholding spike-band extracellular neural recordings in iBCIs containing thousands of electrodes. [ABSTRACT FROM AUTHOR]

Background: Post‐stroke dysphagia (PSD), a common and serious disease, affects the quality of life of many patients and their families. Electroacupuncture (EA) has been commonly used effectively in the treatment of PSD, but the therapeutic mechanism is still under exploration at present. We aim to investigate the effect of the nucleus tractus solitarus (NTS) on the treatment of PSD by EA at Lianquan (CV23) through the primary motor cortex (M1). Methods: C57 male mice were used to construct a PSD mouse model using photothrombotic technique, and the swallowing function was evaluated by electromyography (EMG) recording. C‐Fos‐positive neurons and types of neurons in the NTS were detected by immunofluorescence. Optogenetics and chemical genetics were used to regulate the NTS, and the firing rate of neurons was recorded via multichannel recording. Results: The results showed that most of the activated neurons in the NTS were excitatory neurons, and multichannel recording indicated that the activity levels of both pyramidal neurons and interneurons in the NTS were regulated by M1. This process was involved in the EA treatment. Furthermore, while chemogenetic inhibition of the NTS reduced the EMG signal associated with the swallowing response induced by activation of M1 in PSD mice, EA rescued this signal. Conclusion: Overall, the NTS was shown to participate in the regulation of PSD by EA at CV23 through M1. [ABSTRACT FROM AUTHOR]

Temporal interference (TI) electric field brain stimulation is a novel neuromodulation technique that enables the non-invasive modulation of deep brain regions, but few advances about TI stimulation effectiveness and mechanisms have been reported. Conventional transcranial alternating current stimulation (tACS) can enhance motor skills, whether TI stimulation has an effect on motor skills in mice has not been elucidated. In the present study, TI stimulation was proved to stimulating noninvasively primary motor cortex (M1) of mice, and that TI stimulation with an envelope wave frequency of 20 Hz (Δ f = 20 Hz) once a day for 20 min for 7 consecutive days significantly improved the motor skills of mice. The mechanism of action may be related to regulating of neurotransmitter metabolism, increasing the expression of synapse-related proteins, promoting neurotransmitter release, increasing dendritic spine density, enhancing the number of synaptic vesicles and the thickness of postsynaptic dense material, and ultimately enhance neuronal excitability and plasticity. It is the first report about TI stimulation promoting motor skills of mice and describing its mechanisms. • Temporal interference (TI) electric field brain stimulation enhances motor skills in mice. • TI modulates neurotransmitter metabolism and enhances neuronal calcium and neurotransmitter release. • TI enhances synaptic plasticity. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to analyze the changes in connectivity between motor imagery (MI) and motor execution (ME) in the premotor area (PMA) and primary motor cortex (MA) of the brain, aiming to explore suitable forms of treatment and potential therapeutic targets. Methods: Twenty-three inpatients with stroke were selected, and 21 righthanded healthy individuals were recruited. EEG signal during hand MI and ME (synergy and isolated movements) was recorded. Correlations between functional brain areas during MI and ME were compared. Results: PMA and MA were significantly and positively correlated during hand MI in all participants. The power spectral density (PSD) values of PMA EEG signals were greater than those of MA during MI and ME in both groups. The functional connectivity correlation was higher in the stroke group than in healthy people during MI, especially during left-handed MI. During ME, functional connectivity correlation in the brain was more enhanced during synergy movements than during isolated movements. The regions with abnormal functional connectivity were in the 18th lead of the left PMA area. Conclusion: Left-handed MI may be crucial in MI therapy, and the 18th lead may serve as a target for non-invasive neuromodulation to promote further recovery of limb function in patients with stroke. This may provide support for the EEG theory of neuromodulation therapy for hemiplegic patients. [ABSTRACT FROM AUTHOR]

Cerebellar brain inhibition (CBI), a neural connection between the cerebellum and primary motor cortex (M1), has been researched as a target pathway for neuromodulation to improve clinical outcomes in various neurological diseases. However, conflicting results of anodal cerebellar transcranial direct current stimulation (acb-tDCS) on M1 excitability indicate that additional investigation is required to examine its precise effect. This study aimed to gather evidence of the neuromodulatory effect of acb-tDCS on the M1 using functional near-infrared spectroscopy (fNIRS). Sixteen healthy participants were included in this cross-over study. Participants received real and sham acb-tDCS randomly, with a minimum 1-week washout period between them. The anode and cathode were placed on the right cerebellum and the right buccinator muscle, respectively. Stimulation lasted 20 min at an intensity of 2 mA, and fNIRS data were recorded for 42 min (including a 4-min baseline before stimulation and an 18-min post-stimulation duration) using eight channels attached bilaterally on the M1. acb-tDCS induced a significant decrease in oxyhemoglobin (HbO) concentration (inhibitory effect) in the left (contralateral) M1, whereas it induced a significant increase in HbO concentration (excitatory effect) in the right (ipsilateral) M1 compared to sham tDCS during (p < 0.05) and after stimulation (p < 0.01) in a group level analysis. At the individual level, variations in response to acb-tDCS were observed. Our findings demonstrate the neuromodulatory effects of acb-tDCS on the bilateral M1 in terms of neuronal hemodynamics. [ABSTRACT FROM AUTHOR]

Background: Freezing of gait (FOG) is a common and disabling phenomenon in patients with Parkinson's disease (PD), but effective treatment approach remains inconclusive. Dysfunctional emotional factors play a key role in FOG. Since primary motor cortex (M1) connects with prefrontal areas via the frontal longitudinal system, where are responsible for emotional regulation, we hypothesized M1 may be a potential neuromodulation target for FOG therapy. The purpose of this study is to explore whether high-frequency rTMS over bilateral M1 could relieve FOG and emotional dysregulation in patients with PD. Methods: This study is a single-center, randomized double-blind clinical trial. Forty-eight patients with PD and FOG from the Affiliated Hospital of Xuzhou Medical University were randomly assigned to receive 10 sessions of either active (N = 24) or sham (N = 24) 10 Hz rTMS over the bilateral M1. Patients were evaluated at baseline (T0), after the last session of treatment (T1) and 30 days after the last session (T2). The primary outcomes were Freezing of Gait Questionnaire (FOGQ) scores, with Timed Up and Go Test (TUG) time, Standing-Start 180° Turn (SS-180) time, SS-180 steps, United Parkinson Disease Rating Scales (UPDRS) III, Hamilton Depression scale (HAMD)-24 and Hamilton Anxiety scale (HAMA)-14 as secondary outcomes. Results: Two patients in each group dropped out at T2 and no serious adverse events were reported by any subject. Two-way repeated ANOVAs revealed significant group × time interactions in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14. Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14 at T1 and T2. No significant improvement was found in the sham group. The Spearman correlation analysis revealed a significantly positive association between the changes in HAMD-24 and HAMA-14 scores and FOGQ scores at T1. Conclusion: High-frequency rTMS over bilateral M1 can improve FOG and reduce depression and anxiety in patients with PD. [ABSTRACT FROM AUTHOR]

What happens once a cortical territory becomes functionally redundant? We studied changes in brain function and behavior for the remaining hand in humans (male and female) with either a missing hand from birth (one-handers) or due to amputation. Previous studies reported that amputees, but not one-handers, show increased ipsilateral activity in the somatosensory territory of the missing hand (i.e., remapping). We used a complex finger task to explore whether this observed remapping in amputees involves recruiting more neural resources to support the intact hand to meet greater motor control demands. Using basic fMRI analysis, we found that only amputees had more ipsilateral activity when motor demand increased; however, this did not match any noticeable improvement in their behavioral task performance. More advanced multivariate fMRI analyses showed that amputees had stronger and more typical representation--relative to controls' contralateral hand representation--compared with one-handers. This suggests that in amputees, both hand areas work together more collaboratively, potentially reflecting the intact hand's efference copy. One-handers struggled to learn difficult finger configurations, but this did not translate to differences in univariate or multivariate activity relative to controls. Additional white matter analysis provided conclusive evidence that the structural connectivity between the two hand areas did not vary across groups. Together, our results suggest that enhanced activity in the missing hand territory may not reflect intact hand function. Instead, we suggest that plasticity is more restricted than generally assumed and may depend on the availability of homologous pathways acquired early in life. [ABSTRACT FROM AUTHOR]

• The M1 laminar distribution of D1 receptor positive (D1+) cells is similar in young and adult mice. • Most of D1+ cells in M1 also express Satb2. • D1 receptor activation increases the excitability of M1 layer V PNs both in young and adult mice. • Blocking the D1 receptor reduces PN excitability in young mice but increases it in adults. The primary motor cortex (M1) receives dopaminergic (DAergic) projections from the midbrain which play a key role in modulating motor and cognitive processes, such as motor skill learning. However, little is known at the level of individual neurons about how dopamine (DA) and its receptors modulate the intrinsic properties of the different neuronal subpopulations in M1 and if this modulation depends on age. Using immunohistochemistry, we first mapped the cells expressing the DA D1 receptor across the different layers in M1, and quantified the number of pyramidal neurons (PNs) expressing the D1 receptor in the different layers, in young and adult mice. This work reveals that the spatial distribution and the molecular profile of D1 receptor-expressing neurons (D1+) across M1 layers do not change with age. Then, combining whole-cell patch-clamp recordings and pharmacology, we explored ex vivo in young and adult mice the impact of activation or blockade of D1 receptors on D1+ PN intrinsic properties. While the bath application of the D1 receptor agonist induced an increase in the excitability of layer V PNs both in young and adult, we identified a distinct modulation of intrinsic electrical properties of layer V D1+ PNs by D1 receptor antagonist depending on the age of the animal. [ABSTRACT FROM AUTHOR]

Focused Clinical Question: Is there evidence to suggest that transcranial direct current stimulation improves clinical and patient-reported outcomes in patients with chronic ankle instability? Clinical Bottom Line: Evidence from two clinical studies supports the use of transcranial direct current stimulation for improving outcomes in patients with chronic ankle instability. [ABSTRACT FROM AUTHOR]

Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.

Abstract Cardiac function is under neural regulation; however, brain regions in the cerebral cortex responsible for regulating cardiac function remain elusive. In this study, retrograde trans‐synaptic viral tracing is used from the heart to identify a specific population of the excitatory neurons in the primary motor cortex (M1) that influences cardiac function in mice. Optogenetic activation of M1 glutamatergic neurons increases heart rate, ejection fraction, and blood pressure. By contrast, inhibition of M1 glutamatergic neurons decreased cardiac function and blood pressure as well as tyrosine hydroxylase (TH) expression in the heart. Using viral tracing and optogenetics, the median raphe nucleus (MnR) is identified as one of the key relay brain regions in the circuit from M1 that affect cardiac function. Then, a mouse model of cardiac injury is established caused by myocardial infarction (MI), in which optogenetic activation of M1 glutamatergic neurons impaired cardiac function in MI mice. Moreover, ablation of M1 neurons decreased the levels of norepinephrine and cardiac TH expression, and enhanced cardiac function in MI mice. These findings establish that the M1 neurons involved in the regulation of cardiac function and blood pressure. They also help the understanding of the neural mechanisms underlying cardiovascular regulation.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1G93A mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1G93A mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1G93A mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.