Synaptic correlates of the corticocortical circuit in motor learning.

Rodents actively learn new motor skills for survival in reaction to changing environments. Despite the classic view of the primary motor cortex (M1) as a simple muscle relay region, it is now known to play a significant role in motor skill acquisition. The secondary motor cortex (M2) is reported to be a crucial region for motor learning as well as for its role in motor execution and planning. Although these two regions are known for the part they play in motor learning, the role of direct connection and synaptic correlates between these two regions remains elusive. Here, we confirm M2 to M1 connectivity with a series of tracing experiments. We also show that the accelerating rotarod task successfully induces motor skill acquisition in mice. For mice that underwent rotarod training, learner mice showed increased synaptic density and spine head size for synapses between activated cell populations of M2 and M1. Non-learner mice did not show these synaptic changes. Collectively, these data suggest the potential importance of synaptic plasticity between activated cell populations as a potential mechanism of motor learning. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Ultra-early navigated transcranial magnetic stimulation for perioperative stroke: anatomo-functional report.

Navigated repetitive transmagnetic stimulation is a non-invasive and safe brain activity modulation technique. When combined with the classical rehabilitation process in stroke patients it has the potential to enhance the overall neurologic recovery. We present a case of a peri-operative stroke, treated with ultra-early low frequency navigated repetitive transmagnetic stimulation over the contralesional hemisphere. The patient received low frequency navigated repetitive transmagnetic stimulation within 12 hours of stroke onset for seven consecutive days and a significant improvement in his right sided weakness was noticed and he was discharge with normal power. This was accompanied by an increase in the number of positive responses evoked by navigated repetitive transmagnetic stimulation and a decrease of the resting motor thresholds at a cortical level. Subcortically, a decrease in the radial, axial, and mean diffusivity were recorded in the ipsilateral corticospinal tract and an increase in fractional anisotropy, axial diffusivity, and mean diffusivity was observed in the interhemispheric fibers of the corpus callosum responsible for the interhemispheric connectivity between motor areas. Our case demonstrates clearly that ultra-early low frequency navigated repetitive transmagnetic stimulation applied to the contralateral motor cortex can lead to significant clinical motor improvement in patients with subcortical stroke.

Reorganization of motor network in patients with Parkinson's disease after deep brain stimulation.

AIMS: Parkinson's disease (PD) patients experience improvement in motor symptoms after deep brain stimulation (DBS) and before initiating stimulation. This is called the microlesion effect. However, the mechanism remains unclear. The study aims to comprehensively explore the changes in functional connectivity (FC) patterns in movement-related brain regions in PD patients during the microlesion phase through seed-based FC analysis. METHODS: The study collected the resting functional magnetic resonance imaging data of 49 PD patients before and after DBS surgery (off stimulation). The cortical and subcortical areas related to motor function were selected for seed-based FC analysis. Meanwhile, their relationship with the motor scale was investigated. RESULTS: The motor-related brain regions were selected as the seed point, and we observed various FC declines within the motor network brain regions. These declines were primarily in the left middle temporal gyrus, bilateral middle frontal gyrus, right supplementary motor area, left precentral gyrus, left postcentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus after DBS. CONCLUSION: The movement-related network was extensively reorganized during the microlesion period. The study provided new information on enhancing motor function from the network level post-DBS.

Phylogenetic differences in the morphology and shape of the central sulcus in great apes and humans: implications for the evolution of motor functions.

The central sulcus divides the primary motor and somatosensory cortices in many anthropoid primate brains. Differences exist in the surface area and depth of the central sulcus along the dorso-ventral plane in great apes and humans compared to other primate species. Within hominid species, there are variations in the depth and aspect of their hand motor area, or knob, within the precentral gyrus. In this study, we used post-image analyses on magnetic resonance images to characterize the central sulcus shape of humans, chimpanzees (Pan troglodytes), gorillas (Gorilla gorilla), and orangutans (Pongo pygmaeus and Pongo abelii). Using these data, we examined the morphological variability of central sulcus in hominids, focusing on the hand region, a significant change in human evolution. We show that the central sulcus shape differs between great ape species, but all show similar variations in the location of their hand knob. However, the prevalence of the knob location along the dorso-ventral plane and lateralization differs between species and the presence of a second ventral motor knob seems to be unique to humans. Humans and orangutans exhibit the most similar and complex central sulcus shapes. However, their similarities may reflect divergent evolutionary processes related to selection for different positional and habitual locomotor functions.

Anodal M1 tDCS enhances online learning of rhythmic timing videogame skill.

Transcranial direct current stimulation (tDCS) has been shown to modify excitability of the primary motor cortex (M1) and influence online motor learning. However, research on the effects of tDCS on motor learning has focused predominantly on simplified motor tasks. The purpose of the present study was to investigate whether anodal stimulation of M1 over a single session of practice influences online learning of a relatively complex rhythmic timing video game. Fifty-eight healthy young adults were randomized to either a-tDCS or SHAM conditions and performed 2 familiarization blocks, a 20-minute 5 block practice period while receiving their assigned stimulation, and a post-test block with their non-dominant hand. To assess performance, a performance index was calculated that incorporated timing accuracy elements and incorrect key inputs. The results showed that M1 a-tDCS enhanced the learning of the video game based skill more than SHAM stimulation during practice, as well as overall learning at the post-test. These results provide evidence that M1 a-tDCS can enhance acquisition of skills where quality or success of performance depends on optimized timing between component motions of the skill, which could have implications for the application of tDCS in many real-world contexts.

Enhancement of Motor Learning and Corticospinal Excitability: The Role of Electroacupuncture and Motor Training in Healthy Volunteers.

BACKGROUND This study embarked on an innovative exploration to elucidate the effects of integrating electroacupuncture (EA) with motor training (MT) on enhancing corticospinal excitability and motor learning. Central to this investigation is the interplay between homeostatic and non-homeostatic metaplasticity processes, providing insights into how these combined interventions may influence neural plasticity and motor skill acquisition. MATERIAL AND METHODS The investigation enrolled 20 healthy volunteers, subjecting them to 4 distinct interventions to parse out the individual and combined effects of EA and MT. These interventions were EA alone, MT alone, EA-priming followed by MT, and MT-priming followed by EA. The assessment of changes in primary motor cortex (M1) excitability was conducted through motor-evoked potentials (MEPs), while the grooved pegboard test (GPT) was used to evaluate alterations in motor performance. RESULTS The findings revealed that EA and MT independently contributed to enhanced M1 excitability and motor performance. However, the additional priming with EA or MT did not yield further modulation in MEPs amplitudes. Notably, EA-priming was associated with improved GPT completion times, underscoring its potential in facilitating motor learning. CONCLUSIONS The study underscores that while EA and MT individually augment motor cortex excitability and performance, their synergistic application does not further enhance or inhibit cortical excitability. This points to the involvement of non-homeostatic metaplasticity mechanisms. Nonetheless, EA emerges as a critical tool in preventing M1 overstimulation, thereby continuously fostering motor learning. The findings call for further research into the strategic application of EA, whether in isolation or with MT, within clinical settings to optimize rehabilitation outcomes.

A prefrontal motor circuit initiates persistent movement.

Persistence reinforces continuous action, which benefits animals in many aspects. Diverse external or internal signals may trigger animals to start a persistent movement. However, it is unclear how the brain decides to persist with current actions by selecting specific information. Using single-unit extracellular recordings and opto-tagging in awake mice, we demonstrated that a group of dorsal mPFC (dmPFC) motor cortex projecting (MP) neurons initiate a persistent movement by selectively encoding contextual information rather than natural valence. Inactivation of dmPFC MP neurons impairs the initiation and reduces neuronal activity in the insular and motor cortex. After the persistent movement is initiated, the dmPFC MP neurons are not required to maintain it. Finally, a computational model suggests that a successive sensory stimulus acts as an input signal for the dmPFC MP neurons to initiate a persistent movement. These results reveal a neural initiation mechanism on the persistent movement.

Neuromodulatory Responses Elicited by Intermittent versus Continuous Transcranial Focused Ultrasound Stimulation of the Motor Cortex in Rats.

Transcranial focused ultrasound stimulation (tFUS) has emerged as a promising neuromodulation technique that delivers acoustic energy with high spatial resolution for inducing long-term potentiation (LTP)- or depression (LTD)-like plasticity. The variability in the primary effects of tFUS-induced plasticity could be due to different stimulation patterns, such as intermittent versus continuous, and is an aspect that requires further detailed exploration. In this study, we developed a platform to evaluate the neuromodulatory effects of intermittent and continuous tFUS on motor cortical plasticity before and after tFUS application. Three groups of rats were exposed to either intermittent, continuous, or sham tFUS. We analyzed the neuromodulatory effects on motor cortical excitability by examining changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). We also investigated the effects of different stimulation patterns on excitatory and inhibitory neural biomarkers, examining c-Fos and glutamic acid decarboxylase (GAD-65) expression using immunohistochemistry staining. Additionally, we evaluated the safety of tFUS by analyzing glial fibrillary acidic protein (GFAP) expression. The current results indicated that intermittent tFUS produced a facilitation effect on motor excitability, while continuous tFUS significantly inhibited motor excitability. Furthermore, neither tFUS approach caused injury to the stimulation sites in rats. Immunohistochemistry staining revealed increased c-Fos and decreased GAD-65 expression following intermittent tFUS. Conversely, continuous tFUS downregulated c-Fos and upregulated GAD-65 expression. In conclusion, our findings demonstrate that both intermittent and continuous tFUS effectively modulate cortical excitability. The neuromodulatory effects may result from the activation or deactivation of cortical neurons following tFUS intervention. These effects are considered safe and well-tolerated, highlighting the potential for using different patterns of tFUS in future clinical neuromodulatory applications.

Rule-based modulation of a sensorimotor transformation across cortical areas.

Flexible responses to sensory stimuli based on changing rules are critical for adapting to a dynamic environment. However, it remains unclear how the brain encodes and uses rule information to guide behavior. Here, we made single-unit recordings while head-fixed mice performed a cross-modal sensory selection task where they switched between two rules: licking in response to tactile stimuli while rejecting visual stimuli, or vice versa. Along a cortical sensorimotor processing stream including the primary (S1) and secondary (S2) somatosensory areas, and the medial (MM) and anterolateral (ALM) motor areas, single-neuron activity distinguished between the two rules both prior to and in response to the tactile stimulus. We hypothesized that neural populations in these areas would show rule-dependent preparatory states, which would shape the subsequent sensory processing and behavior. This hypothesis was supported for the motor cortical areas (MM and ALM) by findings that (1) the current task rule could be decoded from pre-stimulus population activity; (2) neural subspaces containing the population activity differed between the two rules; and (3) optogenetic disruption of pre-stimulus states impaired task performance. Our findings indicate that flexible action selection in response to sensory input can occur via configuration of preparatory states in the motor cortex.

Structural changes in eloquent cortex secondary to glioma in sensorimotor area.

This study aims to investigate the structural reorganization in the sensorimotor area of the brain in patients with gliomas, distinguishing between those with impaired and unimpaired strength. Using voxel-based morphometry (VBM) and region of interest (ROI) analysis, gray matter volumes (GMV) were compared in the contralesional primary motor gyrus, primary sensory gyrus, premotor area, bilateral supplementary motor area, and medial Brodmann area 8 (BA8). The results revealed that in patients with right hemisphere gliomas, the right medial BA8 volume was significantly larger in the impaired group than in the unimpaired group, with both groups exceeding the volume in 16 healthy controls (HCs). In patients with left hemisphere gliomas, the right supplementary motor area (SMA) was more pronounced in the impaired group compared to the unimpaired group, and both groups were greater than HCs. Additionally, the volumes of the right medial BA8 in both the impaired group were greater than HCs. Contralateral expansions in the gray matter of hand- and trunk-related cortices of the premotor area, precentral gyrus, and postcentral gyrus were observed compared to HCs. Furthermore, a negative correlation was found between hand Medical Research Council (MRC) score and volumes of the contralateral SMA and bilateral medial BA8. Notably, our findings reveal consistent results across both analytical approaches in identifying significant structural reorganizations within the sensorimotor cortex. These consistent findings underscore the adaptive neuroplastic responses to glioma presence, highlighting potential areas of interest for further neurosurgical planning and rehabilitation strategies.

Hebbian priming of human motor learning.

Motor learning relies on experience-dependent plasticity in relevant neural circuits. In four experiments, we provide initial evidence and a double-blinded, sham-controlled replication (Experiment I-II) demonstrating that motor learning involving ballistic index finger movements is improved by preceding paired corticospinal-motoneuronal stimulation (PCMS), a human model for exogenous induction of spike-timing-dependent plasticity. Behavioral effects of PCMS targeting corticomotoneuronal (CM) synapses are order- and timing-specific and partially bidirectional (Experiment III). PCMS with a 2 ms inter-arrival interval at CM-synapses enhances learning and increases corticospinal excitability compared to control protocols. Unpaired stimulations did not increase corticospinal excitability (Experiment IV). Our findings demonstrate that non-invasively induced plasticity interacts positively with experience-dependent plasticity to promote motor learning. The effects of PCMS on motor learning approximate Hebbian learning rules, while the effects on corticospinal excitability demonstrate timing-specificity but not bidirectionality. These findings offer a mechanistic rationale to enhance motor practice effects by priming sensorimotor training with individualized PCMS.

Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10-5. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.

Time synchronization between parietal-frontocentral connectivity with MRCP and gait in post-stroke bipedal tasks.

BACKGROUND: In post-stroke rehabilitation, functional connectivity (FC), motor-related cortical potential (MRCP), and gait activities are common measures related to recovery outcomes. However, the interrelationship between FC, MRCP, gait activities, and bipedal distinguishability have yet to be investigated. METHODS: Ten participants were equipped with EEG devices and inertial measurement units (IMUs) while performing lower limb motor preparation (MP) and motor execution (ME) tasks. MRCP, FCs, and bipedal distinguishability were extracted from the EEG signals, while the change in knee degree during the ME phase was calculated from the gait data. FCs were analyzed with pairwise Pearson's correlation, and the brain-wide FC was fed into support vector machine (SVM) for bipedal classification. RESULTS: Parietal-frontocentral connectivity (PFCC) dysconnection and MRCP desynchronization were related to the MP and ME phases, respectively. Hemiplegic limb movement exhibited higher PFCC strength than nonhemiplegic limb movement. Bipedal classification had a short-lived peak of 75.1% in the pre-movement phase. These results contribute to a better understanding of the neurophysiological functions during motor tasks, with respect to localized MRCP and nonlocalized FC activities. The difference in PFCCs between both limbs could be a marker to understand the motor function of the brain of post-stroke patients. CONCLUSIONS: In this study, we discovered that PFCCs are temporally dependent on lower limb gait movement and MRCP. The PFCCs are also related to the lower limb motor performance of post-stroke patients. The detection of motor intentions allows the development of bipedal brain-controlled exoskeletons for lower limb active rehabilitation.

Cross-Frequency Coupling as a Biomarker for Early Stroke Recovery.

BACKGROUND: The application of neuroimaging-based biomarkers in stroke has enriched our understanding of post-stroke recovery mechanisms, including alterations in functional connectivity based on synchronous oscillatory activity across various cortical regions. Phase-amplitude coupling, a type of cross-frequency coupling, may provide additional mechanistic insight. OBJECTIVE: To determine how the phase of prefrontal cortex delta (1-3 Hz) oscillatory activity mediates the amplitude of motor cortex beta (13-20 Hz) oscillations in individual's early post-stroke. METHODS: Participants admitted to an inpatient rehabilitation facility completed resting and task-based EEG recordings and motor assessments around the time of admission and discharge along with structural neuroimaging. Unimpaired controls completed EEG procedures during a single visit. Mixed-effects linear models were performed to assess within- and between-group differences in delta-beta prefrontomotor coupling. Associations between coupling and motor status and injury were also determined. RESULTS: Thirty individuals with stroke and 17 unimpaired controls participated. Coupling was greater during task versus rest conditions for all participants. Though coupling during affected extremity task performance decreased during hospitalization, coupling remained elevated at discharge compared to controls. Greater baseline coupling was associated with better motor status at admission and discharge and positively related to motor recovery. Coupling demonstrated both positive and negative associations with injury involving measures of lesion volume and overlap injury to anterior thalamic radiation, respectively. CONCLUSIONS: This work highlights the utility of prefrontomotor cross-frequency coupling as a potential motor status and recovery biomarker in stroke. The frequency- and region-specific neurocircuitry featured in this work may also facilitate novel treatment strategies in stroke.

Motor imagery drives the effects of combined action observation and motor imagery on corticospinal excitability for coordinative lower-limb actions.

Combined action observation and motor imagery (AOMI) facilitates corticospinal excitability (CSE) and may potentially induce plastic-like changes in the brain in a similar manner to physical practice. This study used transcranial magnetic stimulation (TMS) to explore changes in CSE for AOMI of coordinative lower-limb actions. Twenty-four healthy adults completed two baseline (BLH, BLNH) and three AOMI conditions, where they observed a knee extension while simultaneously imagining the same action (AOMICONG), plantarflexion (AOMICOOR-FUNC), or dorsiflexion (AOMICOOR-MOVE). Motor evoked potential (MEP) amplitudes were recorded as a marker of CSE for all conditions from two knee extensor, one dorsi flexor, and two plantar flexor muscles following TMS to the right leg representation of the left primary motor cortex. A main effect for experimental condition was reported for all three muscle groups. MEP amplitudes were significantly greater in the AOMICONG condition compared to the BLNH condition (p = .04) for the knee extensors, AOMICOOR-FUNC condition compared to the BLH condition (p = .03) for the plantar flexors, and AOMICOOR-MOVE condition compared to the two baseline conditions for the dorsi flexors (ps ≤ .01). The study findings support the notion that changes in CSE are driven by the imagined actions during coordinative AOMI.

Cerebral hemodynamics underlying ankle force sense modulated by high-definition transcranial direct current stimulation.

This study aimed to investigate the effects of high-definition transcranial direct current stimulation on ankle force sense and underlying cerebral hemodynamics. Sixteen healthy adults (8 males and 8 females) were recruited in the study. Each participant received either real or sham high-definition transcranial direct current stimulation interventions in a randomly assigned order on 2 visits. An isokinetic dynamometer was used to assess the force sense of the dominant ankle; while the functional near-infrared spectroscopy was employed to monitor the hemodynamics of the sensorimotor cortex. Two-way analyses of variance with repeated measures and Pearson correlation analyses were performed. The results showed that the absolute error and root mean square error of ankle force sense dropped more after real stimulation than after sham stimulation (dropped by 23.4% vs. 14.9% for absolute error, and 20.0% vs. 10.2% for root mean square error). The supplementary motor area activation significantly increased after real high-definition transcranial direct current stimulation. The decrease in interhemispheric functional connectivity within the Brodmann's areas 6 was significantly correlated with ankle force sense improvement after real high-definition transcranial direct current stimulation. In conclusion, high-definition transcranial direct current stimulation can be used as a potential intervention for improving ankle force sense. Changes in cerebral hemodynamics could be one of the explanations for the energetic effect of high-definition transcranial direct current stimulation.

Spatiotemporal dynamics of cortical somatosensory network in typically developing children.

Sense of touch is essential for our interactions with external objects and fine control of hand actions. Despite extensive research on human somatosensory processing, it is still elusive how involved brain regions interact as a dynamic network in processing tactile information. Few studies probed temporal dynamics of somatosensory information flow and reported inconsistent results. Here, we examined cortical somatosensory processing through magnetic source imaging and cortico-cortical coupling dynamics. We recorded magnetoencephalography signals from typically developing children during unilateral pneumatic stimulation. Neural activities underlying somatosensory evoked fields were mapped with dynamic statistical parametric mapping, assessed with spatiotemporal activation analysis, and modeled by Granger causality. Unilateral pneumatic stimulation evoked prominent and consistent activations in the contralateral primary and secondary somatosensory areas but weaker and less consistent activations in the ipsilateral primary and secondary somatosensory areas. Activations in the contralateral primary motor cortex and supramarginal gyrus were also consistently observed. Spatiotemporal activation and Granger causality analysis revealed initial serial information flow from contralateral primary to supramarginal gyrus, contralateral primary motor cortex, and contralateral secondary and later dynamic and parallel information flows between the consistently activated contralateral cortical areas. Our study reveals the spatiotemporal dynamics of cortical somatosensory processing in the normal developing brain.

Central imaging based on near-infrared functional imaging technology can be useful to plan management in patients with chronic lateral ankle instability.

BACKGROUND: Near infrared brain functional imaging (FNIRS) has been used for the evaluation of brain functional areas, the imaging differences of central activation of cognitive-motor dual tasks between patients with chronic lateral ankle instability (CLAI) and healthy population remain unclear. This study aimed to evaluated the role of central imaging based on FNIRS technology on the plan management in patients with CLAI, to provide insights to the clinical treatment of CLAI. METHODS: CLAI patients treated in our hospital from January 1, 2021 to June 31, 2022 were selected. Both CLAI patients and health controls were intervened with simple task and cognitive-motor dual task under sitting and walking conditions, and the changes of oxygenated hemoglobin concentration in bilateral prefrontal cortex (PFC), premotor cortex (PMC) and auxiliary motor area (SMA) were collected and compared. RESULTS: A total of 23 participants were enrolled. There were significant differences in the fNIRS ΔHbO2 of barefoot subtractive walking PFC-R and barefoot subtractive walking SMA-R between experimental and control group (all P < 0.05). There was no significant difference in ΔHbO2 between the experimental group and the control group in other states (P > 0.05). There was no significant difference in ΔHbO2 between the experimental group and the control group in each state of the brain PMC region. CONCLUSION: Adaptive alterations may occur within the relevant brain functional regions of individuals with CLAI. The differential activation observed between the PFC and the SMA could represent a compensatory mechanism emerging from proprioceptive afferent disruptions following an initial ankle sprain.