The protective effects of repetitive transcranial magnetic stimulation with different high frequencies on motor functions in MPTP/probenecid induced Parkinsonism mouse models.

BACKGROUND: High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS. OBJECTIVE: The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model. METHODS: Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored. RESULTS: We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1ß in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest. CONCLUSIONS: Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.

Conscious but not thinking-Mind-blanks during visuomotor tracking: An fMRI study of endogenous attention lapses.

Attention lapses (ALs) are complete lapses of responsiveness in which performance is briefly but completely disrupted and during which, as opposed to microsleeps, the eyes remain open. Although the phenomenon of ALs has been investigated by behavioural and physiological means, the underlying cause of an AL has largely remained elusive. This study aimed to investigate the underlying physiological substrates of behaviourally identified endogenous ALs during a continuous visuomotor task, primarily to answer the question: Were the ALs during this task due to extreme mind-wandering or mind-blanks? The data from two studies were combined, resulting in data from 40 healthy non-sleep-deprived subjects (20M/20F; mean age 27.1 years, 20-45). Only 17 of the 40 subjects were used in the analysis due to a need for a minimum of two ALs per subject. Subjects performed a random 2-D continuous visuomotor tracking task for 50 and 20 min in Studies 1 and 2, respectively. Tracking performance, eye-video, and functional magnetic resonance imaging (fMRI) were recorded simultaneously. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorise lapses of responsiveness as microsleeps or ALs. Changes in neural activity during 85 ALs (17 subjects) relative to responsive tracking were estimated by whole-brain voxel-wise fMRI and by haemodynamic response (HR) analysis in regions of interest (ROIs) from seven key networks to reveal the neural signature of ALs. Changes in functional connectivity (FC) within and between the key ROIs were also estimated. Networks explored were the default mode network, dorsal attention network, frontoparietal network, sensorimotor network, salience network, visual network, and working memory network. Voxel-wise analysis revealed a significant increase in blood-oxygen-level-dependent activity in the overlapping dorsal anterior cingulate cortex and supplementary motor area region but no significant decreases in activity; the increased activity is considered to represent a recovery-of-responsiveness process following an AL. This increased activity was also seen in the HR of the corresponding ROI. Importantly, HR analysis revealed no trend of increased activity in the posterior cingulate of the default mode network, which has been repeatedly demonstrated to be a strong biomarker of mind-wandering. FC analysis showed decoupling of external attention, which supports the involuntary nature of ALs, in addition to the neural recovery processes. Other findings were a decrease in HR in the frontoparietal network before the onset of ALs, and a decrease in FC between default mode network and working memory network. These findings converge to our conclusion that the ALs observed during our task were involuntary mind-blanks. This is further supported behaviourally by the short duration of the ALs (mean 1.7 s), which is considered too brief to be instances of extreme mind-wandering. This is the first study to demonstrate that at least the majority of complete losses of responsiveness on a continuous visuomotor task are, if not due to microsleeps, due to involuntary mind-blanks.

Repetitive transcranial magnetic stimulation promotes motor function recovery in mice after spinal cord injury via regulation of the Cx43-autophagy loop.

Spinal cord injury (SCI) is a severe condition with an extremely high disability rate. It is mainly manifested as the loss of motor, sensory and autonomic nerve functions below the injury site. High-frequency transcranial magnetic stimulation, a recently developed neuromodulation method, can increase motor function in mice with spinal cord injury. This study aimed to explore the possible mechanism by which transcranial magnetic stimulation (TMS) restores motor function after SCI. A complete T8 transection model of the spinal cord was established in mice, and the mice were treated daily with 15 Hz high-frequency transcranial magnetic stimulation. The BMS was used to evaluate the motor function of the mice after SCI. Western blotting and immunofluorescence were used to detect the expression of Connexin43 (CX43) and autophagy-related proteins in vivo and in vitro, and correlation analysis was performed to study the relationships among autophagy, CX43 and motor function recovery after SCI in mice. Western blotting was used to observe the effect of magnetic stimulation on the expression of mTOR pathway members. In the control group, the expression of CX43 was significantly decreased, and the expression of microtubule-associated protein 1 A/1b light chain 3 (LC3II) and P62 was significantly increased after 4 weeks of spinal cord transection. After high-frequency magnetic stimulation, the level of CX43 decreased, and the levels of LC3II and P62 increased in primary astrocytes. The BMS of the magnetic stimulation group was greater than that of the control group. High-frequency magnetic stimulation can inhibit the expression of CX43, which negatively regulates autophagic flux. HF-rTMS increased the expression levels of mTOR, p-mTOR and p-S6. Our experiments showed that rTMS can restore hindlimb motor function in mice after spinal cord injury via regulation of the Cx43-autophagy loop and activation of the mTOR signalling pathway.

Awareness of embodiment enhances enjoyment and engages sensorimotor cortices.

Whether in performing arts, sporting, or everyday contexts, when we watch others move, we tend to enjoy bodies moving in synchrony. Our enjoyment of body movements is further enhanced by our own prior experience with performing those movements, or our 'embodied experience'. The relationships between movement synchrony and enjoyment, as well as embodied experience and movement enjoyment, are well known. The interaction between enjoyment of movements, synchrony, and embodiment is less well understood, and may be central for developing new approaches for enriching social interaction. To examine the interplay between movement enjoyment, synchrony, and embodiment, we asked participants to copy another person's movements as accurately as possible, thereby gaining embodied experience of movement sequences. Participants then viewed other dyads performing the same or different sequences synchronously, and we assessed participants' recognition of having performed these sequences, as well as their enjoyment of each movement sequence. We used functional near-infrared spectroscopy to measure cortical activation over frontotemporal sensorimotor regions while participants performed and viewed movements. We found that enjoyment was greatest when participants had mirrored the sequence and recognised it, suggesting that awareness of embodiment may be central to enjoyment of synchronous movements. Exploratory analyses of relationships between cortical activation and enjoyment and recognition implicated the sensorimotor cortices, which subserve action observation and aesthetic processing. These findings hold implications for clinical research and therapies seeking to foster successful social interaction.

Utilizing connectome fingerprinting functional MRI models for motor activity prediction in presurgical planning: A feasibility study.

Presurgical planning prior to brain tumor resection is critical for the preservation of neurologic function post-operatively. Neurosurgeons increasingly use advanced brain mapping techniques pre- and intra-operatively to delineate brain regions which are "eloquent" and should be spared during resection. Functional MRI (fMRI) has emerged as a commonly used non-invasive modality for individual patient mapping of critical cortical regions such as motor, language, and visual cortices. To map motor function, patients are scanned using fMRI while they perform various motor tasks to identify brain networks critical for motor performance, but it may be difficult for some patients to perform tasks in the scanner due to pre-existing deficits. Connectome fingerprinting (CF) is a machine-learning approach that learns associations between resting-state functional networks of a brain region and the activations in the region for specific tasks; once a CF model is constructed, individualized predictions of task activation can be generated from resting-state data. Here we utilized CF to train models on high-quality data from 208 subjects in the Human Connectome Project (HCP) and used this to predict task activations in our cohort of healthy control subjects (n = 15) and presurgical patients (n = 16) using resting-state fMRI (rs-fMRI) data. The prediction quality was validated with task fMRI data in the healthy controls and patients. We found that the task predictions for motor areas are on par with actual task activations in most healthy subjects (model accuracy around 90%-100% of task stability) and some patients suggesting the CF models can be reliably substituted where task data is either not possible to collect or hard for subjects to perform. We were also able to make robust predictions in cases in which there were no task-related activations elicited. The findings demonstrate the utility of the CF approach for predicting activations in out-of-sample subjects, across sites and scanners, and in patient populations. This work supports the feasibility of the application of CF models to presurgical planning, while also revealing challenges to be addressed in future developments. PRACTITIONER POINTS: Precision motor network prediction using connectome fingerprinting. Carefully trained models' performance limited by stability of task-fMRI data. Successful cross-scanner predictions and motor network mapping in patients with tumor.

The effect of robot-assisted versus standard training on motor function following subacute rehabilitation after ischemic stroke - protocol for a randomised controlled trial nested in a prospective cohort (RoboRehab).

BACKGROUND: Body weight unloaded treadmill training has shown limited efficacy in further improving functional capacity after subacute rehabilitation of ischemic stroke patients. Dynamic robot assisted bodyweight unloading is a novel technology that may provide superior training stimuli and continued functional improvements in individuals with residual impairments in the chronic phase after the ischemic insult. The aim of the present study is to investigate the effect of dynamic robot-assisted versus standard training, initiated 6 months post-stroke, on motor function, physical function, fatigue, and quality of life in stroke-affected individuals still suffering from moderate-to-severe disabilities after subacute rehabilitation. METHODS: Stroke-affected individuals with moderate to severe disabilities will be recruited into a prospective cohort with measurements at 3-, 6-, 12- and 18-months post-stroke. A randomised controlled trial (RCT) will be nested in the prospective cohort with measurements pre-intervention (Pre), post-intervention (Post) and at follow-up 6 months following post-intervention testing. The present RCT will be conducted as a multicentre parallel-group superiority of intervention study with assessor-blinding and a stratified block randomisation design. Following pre-intervention testing, participants in the RCT study will be randomised into robot-assisted training (intervention) or standard training (active control). Participants in both groups will train 1:1 with a physiotherapist two times a week for 6 months (groups are matched for time allocated to training). The primary outcome is the between-group difference in change score of Fugl-Meyer Lower Extremity Assessment from pre-post intervention on the intention-to-treat population. A per-protocol analysis will be conducted analysing the differences in change scores of the participants demonstrating acceptable adherence. A priori sample size calculation allowing the detection of the minimally clinically important between-group difference of 6 points in the primary outcome (standard deviation 6 point, α = 5% and ß = 80%) resulted in 34 study participants. Allowing for dropout the study will include 40 participants in total. DISCUSSION: For stroke-affected individuals still suffering from moderate to severe disabilities following subacute standard rehabilitation, training interventions based on dynamic robot-assisted body weight unloading may facilitate an appropriate intensity, volume and task-specificity in training leading to superior functional recovery compared to training without the use of body weight unloading. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06273475. TRIAL STATUS: Recruiting. Trial identifier: NCT06273475. Registry name: ClinicalTrials.gov. Date of registration on ClinicalTrials.gov: 22/02/2024.

Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

Making precise movements increases confidence in perceptual decisions.

Perceptual decision-making often lacks explicit feedback, making confidence in our choices pivotal for guiding subsequent actions. Recent studies have highlighted the role of motor responses in modulating decision confidence. Two competing mechanisms have been proposed to elucidate this phenomenon. The "fluency hypothesis" posits that the ease and smoothness of executing a motor response can serve as a cue to enhance retrospective confidence. Conversely, the "monitoring hypothesis" suggests that the extent of action monitoring during response selection may boost retrospective confidence, with heightened monitoring potentially offsetting response fluency. We conducted a pre-registered experiment to directly test these hypotheses. Participants engaged in a perceptual task involving the discrimination of Gabor patch orientation. Perceptual responses required high or low motor precision, manipulated by the size of target circles that participants had to reach with the computer mouse to provide a response. Contrary to the "fluency hypothesis", our results showed that, in trials requiring higher precision (utilizing small circles), participants reported higher confidence levels compared to trials with less demanding responses (involving larger circles). Importantly, this increase in confidence did not coincide with any change in perceptual accuracy. These findings align with the "monitoring hypothesis," suggesting that the degree of action monitoring during response execution can indeed influence retrospective decision confidence.

Mechanosensory bristles mediate avoidance behavior by triggering sustained local motor activity in Drosophila melanogaster.

During locomotion, most vertebrates-and invertebrates such as Drosophila melanogaster-are able to quickly adapt to terrain irregularities or avoid physical threats by integrating sensory information along with motor commands. Key to this adaptability are leg mechanosensory structures, which assist in motor coordination by transmitting external cues and proprioceptive information to motor centers in the central nervous system. Nevertheless, how different mechanosensory structures engage these locomotor centers remains poorly understood. Here, we tested the role of mechanosensory structures in movement initiation by optogenetically stimulating specific classes of leg sensory structures. We found that stimulation of leg mechanosensory bristles (MsBs) and the femoral chordotonal organ (ChO) is sufficient to initiate forward movement in immobile animals. While the stimulation of the ChO required brain centers to induce forward movement, unexpectedly, brief stimulation of leg MsBs triggered a fast response and sustained motor activity dependent only on the ventral nerve cord (VNC). Moreover, this leg-MsB-mediated movement lacked inter- and intra-leg coordination but preserved antagonistic muscle activity within joints. Finally, we show that leg-MsB activation mediates strong avoidance behavior away from the stimulus source, which is preserved even in the absence of a central brain. Overall, our data show that mechanosensory stimulation can elicit a fast motor response, independently of central brain commands, to evade potentially harmful stimuli. In addition, it sheds light on how specific sensory circuits modulate motor control, including initiation of movement, allowing a better understanding of how different levels of coordination are controlled by the VNC and central brain locomotor circuits.

Assessment of EN-RAGE, sRAGE, and its isoforms: cRAGE, esRAGE in obese patients treated by moderate caloric restriction combined with physical activity conducted in hospital condition.

BACKGROUND: AGEs, their receptor (RAGE), and the extracellular newly identified receptor for AGEs product-binding protein (EN-RAGE) are implicated in the pathogenesis of inflammation. AIM: We analyzed serum EN-RAGE, soluble RAGE (sRAGE), and their isoforms: endogenous secretory - esRAGE and cleaved - cRAGE concentrations in lean controls (n = 74) and in patients with obesity (n = 71) treated for three weeks with moderate calorie restriction (CR) combined with physical activity in a hospital condition. METHODS: Using the ELISA method, serum sRAGE, esRAGE, and EN-RAGE were measured before and after CR. RESULTS: The serum level of sRAGE and esRAGE in patients with obesity was lower than that in non-obese individuals, contrary to cRAGE. EN-RAGE concentration was about three times higher in obese patients. Gradually, a rise in BMI resulted in sRAGE, esRAGE reduction, and EN-RAGE increase. The sRAGE concentration was sex-dependent, indicating a higher value in lean men. A moderate negative correlation was observed between BMI and all RAGE isoforms, whereas EN-RAGE displays a positive correlation. CR resulted in an expected decrease in anthropometric, metabolic, and proinflammatory parameters and EN-RAGE, but no RAGE isoforms. The ratio EN-RAGE/sRAGE was higher in obese humans than in control and was not modified by CR. CONCLUSION: Obesity decreases sRAGE and esRAGE and increases EN-RAGE concentration. Moderate CR and physical activity by decreasing inflammation reduces EN-RAGE but is insufficient to increase sRAGE and esRAGE to the extent observed in lean patients. EN-RAGE instead of sRAGE could be helpful to indicate a better outcome of moderate dietary intervention in obese subjects.

The Motor of Time: Coupling Action to Temporally Predictable Events Heightens Perception.

Timing and motor function share neural circuits and dynamics, which underpin their close and synergistic relationship. For instance, the temporal predictability of a sensory event optimizes motor responses to that event. Knowing when an event is likely to occur lowers response thresholds, leading to faster and more efficient motor behavior though in situations of response conflict can induce impulsive and inappropriate responding. In turn, through a process of active sensing, coupling action to temporally predictable sensory input enhances perceptual processing. Action not only hones perception of the event's onset or duration, but also boosts sensory processing of its non-temporal features such as pitch or shape. The effects of temporal predictability on motor behavior and sensory processing involve motor and left parietal cortices and are mediated by changes in delta and beta oscillations in motor areas of the brain.

Reconfigurations of cortical manifold structure during reward-based motor learning.

Adaptive motor behavior depends on the coordinated activity of multiple neural systems distributed across the brain. While the role of sensorimotor cortex in motor learning has been well established, how higher-order brain systems interact with sensorimotor cortex to guide learning is less well understood. Using functional MRI, we examined human brain activity during a reward-based motor task where subjects learned to shape their hand trajectories through reinforcement feedback. We projected patterns of cortical and striatal functional connectivity onto a low-dimensional manifold space and examined how regions expanded and contracted along the manifold during learning. During early learning, we found that several sensorimotor areas in the dorsal attention network exhibited increased covariance with areas of the salience/ventral attention network and reduced covariance with areas of the default mode network (DMN). During late learning, these effects reversed, with sensorimotor areas now exhibiting increased covariance with DMN areas. However, areas in posteromedial cortex showed the opposite pattern across learning phases, with its connectivity suggesting a role in coordinating activity across different networks over time. Our results establish the neural changes that support reward-based motor learning and identify distinct transitions in the functional coupling of sensorimotor to transmodal cortex when adapting behavior.

A multimodal approach integrating cognitive and motor demands into physical activity for optimal mental health: Methodological issues and future directions.

Physical activity is known for its positive effects on cognition and affect, with existing literature suggesting that these mental health benefits may be optimally experienced by incorporating cognitive and motor demands during physical activity (PA). However, the existing body of literature lacks a comprehensive guideline for designing the qualitative characteristics of a PA program. Accordingly, this narrative review aimed to (1) provide a working two-dimension model that operationally defines the cognitive and motor demands involved in PA and the rationale for systematically studying these qualitative aspects of PA, (2) identify methods to assess the cognitive and motor demands of PA and address associated methodological issues, and (3) offer potential future directions for research on the cognitive and motor aspects of PA in support of the development of PA programs designed to maximize PA-induced cognitive and affective benefits. We anticipate this article to inform the need for future research and development on this topic, aiming to create clear, evidence-based guidelines for designing innovative and effective PA interventions.

Representation of rhythmic chunking in striatum of mice executing complex continuous movement sequences.

We used a step-wheel system to examine the activity of striatal projection neurons as mice practiced stepping on complexly arranged foothold pegs in this Ferris-wheel-like device to receive reward. Sets of dorsolateral striatal projection neurons were sensitive to specific parameters of repetitive motor coordination during the runs. They responded to combinations of the parameters of continuous movements (interval, phase, and repetition), forming "chunking responses"-some for combinations of these parameters across multiple body parts. Recordings in sensorimotor cortical areas exhibited notably fewer such responses but were documented for smaller neuron sets whose heterogeneity was significant. Striatal movement encoding via chunking responsivity could provide insight into neural strategies governing effective motor control by the striatum. It is possible that the striking need for external rhythmic cuing to allow movement sequences by Parkinson's patients could, at least in part, reflect dysfunction in such striatal coding.

Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α ). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index (ABI) metric, a transformation of α , and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α . Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical use in a large dataset.

The association between physical activity and neck circumference with cardiovascular disease risk in older wheelchair users.

OBJECTIVE: To examine the association between physical activity, neck circumference, and cardiovascular disease risk in older wheelchair users. DESIGN: A cross-sectional study. SUBJECTS/PATIENTS: Sixty-one Korean wheelchair users aged 50 years and older. METHODS: Physical activity was assessed using a self-administered questionnaire. Neck circumference was measured with a tape ruler. Cardiovascular disease risk was evaluated by calculating the Framingham risk score (FRS) for estimating 10-year cardiovascular disease risk, which was classified as low-moderate (19% or less) or high risk (20% or more). RESULTS: The FRS for 10-year cardiovascular disease risk was inversely related to physical activity (beta [SE] = -0.213 (0.103), p = 0.043) and positively related to neck circumference (beta [SE] = 1.331 ± 0.419, p = 0.003). Binary logistic regression showed that those with low physical activity (odds ratio [95% confidence interval] = 4.256 (1.188~15.243), p = 0.026) or a large neck circumference (odds ratio [95% confidence interval] = 3.645 (1.172~11.338), p = 0.025) had a higher risk for high cardiovascular disease risk compared with those with high physical activity or normal neck circumference. CONCLUSION: The current study findings suggest that an intervention targeting physical inactivity and upper-body obesity should be implemented to reduce cardiovascular disease risk in older wheelchair users.

Phasic Stimulation of Dopaminergic Neurons of the Lateral Substantia Nigra Increases Open Field Exploratory Behaviour and Reduces Habituation Over Time.

Transient nigrostriatal dopaminergic signalling is well known for its role in reinforcement learning and increasingly so for its role in the initiation of voluntary movement. However, how transient bursts of dopamine modulate voluntary movement remains unclear, likely due to the heterogeneity of the nigrostriatal system, the focus of optogenetic studies on locomotion at sub-sec time intervals, and the overlapping roles of phasic dopamine in behaviour and novelty signalling. In this study we investigated how phasic activity in the lateral substantia nigra pars compacta (lateral SNc) over time affects voluntary behaviours during exploration. Using a transgenic mouse model of both sexes expressing channelrhodopsin (ChR2) in dopamine transporter-expressing cells, we stimulated the lateral SNc while mice explored an open field over two consecutive days. We found that phasic activation of the lateral SNc induced an increase in exploratory behaviours including horizontal movement activity, locomotion initiation, and rearing specifically on the first open field exposure, but not on the second day. In addition, stimulated animals did not habituate to the same extent as their ChR2-negative counterparts, as indicated by a lack of decrease in baseline activity. These findings suggest that rather than prompting voluntary movement in general, phasic nigrostriatal dopamine prompts context-appropriate behaviours. In addition, dopamine signalling that modulates movement acts over longer timescales than the transient signal, affecting behaviour even after the signal has ended.

Effects of a novel regimen of repetitive transcranial magnetic stimulation (rTMS) on neural remodeling and motor function in adult male mice with ischemic stroke.

Neuroinflammation caused by excessive microglial activation plays a key role in the pathogenesis of ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulatory technique that has recently been reported to regulate microglial functions and exert anti-inflammatory effects. The intermittent burst stimulation (iTBS) regimen in rTMS improves neuronal excitability. However, whether iTBS exerts its anti-inflammatory effects by stimulating neurons and thereby modulating microglial polarization remains unclear. Motor function was assessed after 1 week of rTMS (iTBS regimen) treatment in adult male mice with occlusion/reperfusion of the middle cerebral artery (MCAO/r) injury. We also investigated the molecular biological alterations associated with microglial polarization using a cell proliferation assay, multiplex cytokine bioassays, and immunofluorescence staining. iTBS regimen can improve balance and motor coordination function, increase spontaneous movement, and improve walking function in mice with early cerebral ischemia injury. Expression levels of IL-1ß, TNF-α, and IL-10 increased significantly in mice with MCAO injury. Especially, rTMS significantly increased the number of proliferating cells in the infarcted cortex. The fluorescence intensity of MAP2 in the peri-infarct area of MCAO injured mice was low, but the signal was broader. Compared with MCAO group, the fluorescence intensity of MAP2 in rTMS group was significantly increased. rTMS inhibited pro-inflammatory M1 activation (Iba1+/CD86+) and improved anti-inflammatory M2 activation (Iba1+/CD206+) in the peri-infarct zone, thus significantly changing the phenotypic ratio M1/M2. rTMS improves motor dysfunction and neuroinflammation after cerebral I/R injury in mice by regulating microglial polarization.

The effects of MEPaL on oxidative stress and motor function in the rats affected by prenatal hypoxia.

BACKGROUND AND OBJECTIVES: Maternal hypoxia disrupts neural development and subsequently leads to cerebral palsy and epilepsy in newborns. Hypoxia plays a role in neurodegeneration by increasing oxidative stress. Pistacia atlantica is known as an important antioxidant, and its anti-inflammatory and antioxidant effects have been shown in various studies. This study aims to investigate the effects of methanolic extract of P. atlantica leaves (MEPaLs) on the oxidative parameters in the serum of rats affected by maternal hypoxia. MATERIAL AND METHODS: In this study, eight pregnant rats were used. The newborns were divided into four groups, including the control and the hypoxia groups, which are affected by maternal hypoxia, hypoxia + MEPaL 100 mg/kg, and hypoxia + MEPaL 150 mg/kg. MEPaL was injected (i.p) for 21 days into the neonatal rats after the lactation period. Hypoxia was induced by keeping pregnant rats in a hypoxic chamber with 7% oxygen and 93% nitrogen intensity for 3 h on the 20th day of pregnancy. Behavioral changes were measured using open-field and rotarod tests. Finally, biomarkers of oxidative stress, nitric oxide (NO), glutathione (GSH), GSSG, TAS, TOS, and oxidative stress index (OSI) were measured in the experimental groups. RESULTS: Behavioral results showed that the anxiety behavior in the hypoxia group increased, but the motor activity (moved distance and movement speed) decreased. Moreover, the amount of time spent maintaining balance on the rotarod rod was significantly decreased in the hypoxia group. The concentration of NO in the group of hypoxia + MEPaL 100 mg/kg showed a significant decrease, and MEPaL 100, and 150 mg/kg + hypoxia also increased the concentration of GSH and decreased GSSG. In addition, MEPaL100 and 150 mg/kg caused a significant increase in the ratio of GSH to GSSG and decreased OSI and total oxidant capacity. CONCLUSIONS: Oxidative stress increased in the rats affected by maternal hypoxia and may be the main mechanism for motor activity impairment and balance disturbance, whereas MELaL improved motor performance by decreasing oxidative stress.

Parental Exposure to Morphine Before Conception Decreases Morphine and Cocaine-Induced Locomotor Sensitization in Male Offspring.

Repeated exposure to abused drugs leads to reorganizing synaptic connections in the brain, playing a pivotal role in the relapse process. Additionally, recent research has highlighted the impact of parental drug exposure before gestation on subsequent generations. This study aimed to explore the influence of parental morphine exposure 10 days prior to pregnancy on drug-induced locomotor sensitization. Adult male and female Wistar rats were categorized into morphine-exposed and control groups. Ten days after their last treatment, they were mated, and their male offspring underwent morphine, methamphetamine, cocaine, and nicotine-induced locomotor sensitization tests. The results indicated increased locomotor activity in both groups after drug exposure, although the changes were attenuated in morphine and cocaine sensitization among the offspring of morphine-exposed parents (MEPs). Western blotting analysis revealed altered levels of D2 dopamine receptors (D2DRs) in the prefrontal cortex and nucleus accumbens of the offspring from MEPs. Remarkably, despite not having direct in utero drug exposure, these offspring exhibited molecular alterations affecting morphine and cocaine-induced sensitization. The diminished sensitization to morphine and cocaine suggested the development of a tolerance phenotype in these offspring. The changes in D2DR levels in the brain might play a role in these adaptations.