重复经颅磁刺激联合等速肌力训练对不完全性脊髓损伤患者神经电生理指标、下肢肌力和脊髓功能独立性的影响

摘要 目的：探讨重复经颅磁刺激（TMS）联合等速肌力训练对不完全性脊髓损伤（SCI）患者神经电生理指标、下肢肌力和脊髓功能独立性的影响。方法：选取2018年3月~2019年12月期间我院收治87例不完全性SCI患者,根据入院奇偶顺序分为观察组（n=44）和对照组（n=43）,两组均给予常规康复训练,对照组在此基础上联合等速肌力训练,观察组在对照组基础上联合TMS,对比两组神经电生理指标[静息运动阈值（RMT）和运动诱发电位（MEP）]、下肢肌力指标[屈、伸肌群的峰力矩（PT）、力矩加速能（TAE）以及胭绳肌与股四头肌肌力比率（H/Q）]、功能独立性评定(FIM)量表、疼痛简化McGill疼痛问卷(SF-MPQ）、Barthel指数评定量表（BI）评分。结果：治疗4周后,观察组RMT较治疗前降低,且低于对照组（P<0.05）;MEP较治疗前升高,且高于对照组（P<0.05）。治疗4周后,两组屈肌群PT、屈肌群TAE、伸肌群PT、伸肌群TAE、H/Q、FIM、BI评分均较治疗前升高,且观察组高于对照组（P<0.05）;两组SF-MPQ评分均较治疗前下降（P<0.05）,且观察组低于对照组（P<0.05）。结论：TMS联合等速肌力训练治疗不完全性SCI患者可刺激患者神经功能恢复,提高患者脊髓功能独立性,改善下肢肌力,减轻患者的神经性疼痛。     

"Effect of transcranial magnetic stimulation to motor cortex on pain perception and nociceptive reflex"

"Noxious stimulation over the foot can evoke a nociceptive flexor reflex (NR) in the lower limb especially for tibialis anterior muscle (TA). Components of NR include the monosynaptic fast latency NRII, and the polysynaptic slow latency NRIII, supposedly a spinal segmental reflex influenced by the supraspinal control. Pain perception is quantified by visual analogous scale (VAS) and has been reported to be related to NRIII. Previous papers have reported the long lasting effect of transcranial magnetic stimulation (TMS), as well as TMS suppressing pain perception. The purpose of this study was to investigate the immediate and prolonged effect of a single-pulse TMS to suppress NR and pain. NRIII was provoked at right TA by a train of electrical stimulation on the right toe in 10 healthy subjects. TMS was delivered over the vertex area to evoke right anterior tibialis muscle activity. A sham TMS from different directions of the coil was performed on the next day. The NRIII amplitude and VAS were measured. As a result, the amplitude of NRIII was significantly decreased than the control 50 ms pre-stimulation (0.20 ± 0.13 mA vs . 0.65 ± 0.42 mV, P = 0.016), 100 ms pre-stimulation (0.10 ± 0.10 mA vs . 0.65 ± 0.42 mV, P = 0.001), 15 min post-stimulation (0.12 ± 0.09 mA vs . 0.65 ± 0.42 mV, P = 0.004), and 30 min post-stimulation (0.41 ± 0.21 mA vs . 0.65 ± 0.42 mV, P = 0.046). VAS was diminished compared with the control 50 ms pre-stimulation (3.3 ± 0.9 vs . 5.4 ± 1.3, P = 0.002), 100 ms pre-stimulation (2.6 ± 0.5 vs . 5.4 ± 1.3, P < 0.001) and 15 min post-stimulation (3.5 ± 0.9 vs . 5.4 ± 1.3, P = 0.046). The NRIII amplitude was well correlated with VAS in reduction during the TMS condition and 15 min after electrical stimulation (P < 0.001). The sham TMS did not suppress NRIII or VAS. In conclusion, our results indicate that NRIII and the nociception can be inhibited by one single pulse TMS and such an effect can last for a period of time."     

Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study

Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient’s left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions.     

Up-Regulation of CX3CL1 via STAT3 Contributes to SMIR-Induced Chronic Postsurgical Pain

Chronic postsurgical pain (CPSP) often occurs after surgery and has a strong impact on patients’ daily lives. However, the underlying mechanism of CPSP remains unknown. Here, we used a skin/muscle incision and retraction (SMIR) model to investigate the role of CX3CL1 in SMIR-induced pain and its underlying mechanism. We found that up-regulation of CX3CL1 in the spinal dorsal horn contributed to SMIR-induced mechanical allodynia. The use of a CX3CL1-neutralizing antibody to block CX3CL1 attenuated mechanical allodynia induced by SMIR surgery. We also found that phospho-STAT3 co-localizes with CX3CL1 in spinal neurons after SMIR surgery and that this contributes to SMIR-induced mechanical allodynia. Intrathecal administration of the STAT3 inhibitor S3I-201 suppressed up-regulation of CX3CL1 at both the protein and mRNA levels after SMIR surgery. Chromatin immunoprecipitation further demonstrated that SMIR promotes the recruitment of STAT3 to the cx3cl1 gene promoter (??1032/??1022). These findings suggest that activation of STAT3 after SMIR mediates the up-regulation of CX3CL1, leading to mechanical allodynia, and that this upregulation may partly be due to the enhanced recruitment of STAT3 to the cx3cl1 gene promoter after SMIR.     

The effect of skilled motor training on corticomotor control of back muscles in different presentations of low back pain

Transcranial magnetic stimulation (TMS) has revealed differences in the motor cortex (M1) between people with and without low back pain (LBP). There is potential to reverse these changes using motor skill training, but it remains unclear whether changes can be induced in people with LBP or whether this differs between LBP presentations. This study (1) compared TMS measures of M1 (single and paired-pulse) and performance of a motor task (lumbopelvic tilting) between individuals with LBP of predominant nociceptive (n = 9) or nociplastic presentation (n = 9) and pain-free individuals (n = 16); (2) compared these measures pre- and post-training; and (3) explored correlations between TMS measures, motor performance, and clinical features. TMS measures did not differ between groups at baseline. The nociplastic group undershot the target in the motor task. Despite improved motor performance for all groups, only MEP amplitudes increased across the recruitment curve and only for the pain-free and nociplastic groups. TMS measures did not correlate with motor performance or clinical features. Some elements of motor task performance and changes in corticomotor excitability differed between LBP groups. Absence of changes in intra-cortical TMS measures suggests regions other than M1 are likely to be involved in skill learning of back muscles.     

经颅磁刺激在大脑皮质研究中的应用和进展

经颅磁刺激（TMS）是一种能够在脑中感应聚焦电流,瞬间调制大脑皮质的无创方法,在临床研究、基础神经学和诊治疾病等方面有许多应用。通过记录运动皮质诱发电位（MEPs),TMS已经或将成为探测脑下运动路径传导、评价皮质兴奋性、皮质映射和研究皮质塑性的常规工具。TMS能够主动干预脑功能,这种特性使它成为研究正常人脑－行为关系的独特技术,可以建立脑活动与任务完成之间的因果关系,探索脑功能连接。近年来的许多实验又表明,TMS在运动紊乱和精神疾病方面有潜在的治疗作用,但达到临床应用还有一定距离。     

Application of transcranial magnetic stimulation for monitoring of the motor cortex condition in dynamics in healthy subjects

Transcranial magnetic stimulation (TMS) is used already for sixteen years for studying human central nervous system. The main objective of this work was to study motor thresholds and their hemispheric asymmetry in healthy subjects during TMS. We examined 31 righthanded healthy students. Their motor thresholds were measured in May (before vacations), September (immediately after vacations), and November (two months after vacations). Magnetic stimulator Neurosoft-MS (Ivanovo, Russia) was used for TNS of the motor cortex. It was shown that in the absence of regular active functional loads on the right hand, the motor thresholds in healthy righthanders significantly increased under the TMS of the left hemisphere, and hemispheric asymmetry disappeared under conditions both of muscle relaxation and voluntary contraction. Motor thresholds under the left-side TMS decreased and hemispheric asymmetry recovered with the restart of the regular active functional loads on the right hand.     

Functionally specific reorganization in human premotor cortex

After unilateral stroke, the dorsal premotor cortex (PMd) in the intact hemisphere is often more active during movement of an affected limb. Whether this contributes to motor recovery is unclear. Functional magnetic resonance imaging (fMRI) was used to investigate short-term reorganization in right PMd after transcranial magnetic stimulation (TMS) disrupted the dominant left PMd, which is specialized for action selection. Even when 1 Hz left PMd TMS had no effect on behavior, there was a compensatory increase in activity in right PMd and connected medial premotor areas. This activity was specific to task periods of action selection as opposed to action execution. Compensatory activation changes were both functionally specific and anatomically specific: the same pattern was not seen after TMS of left sensorimotor cortex. Subsequent TMS of the reorganized right PMd did disrupt performance. Thus, this pattern of functional reorganization has a causal role in preserving behavior after neuronal challenge.     

The Temporal Dynamics of Early Visual Cortex Involvement in Behavioral Priming

Transcranial magnetic stimulation (TMS) allows for non-invasive interference with ongoing neural processing. Applied in a chronometric design over early visual cortex (EVC), TMS has proved valuable in indicating at which particular time point EVC must remain unperturbed for (conscious) vision to be established. In the current study, we set out to examine the effect of EVC TMS across a broad range of time points, both before (pre-stimulus) and after (post-stimulus) the onset of symbolic visual stimuli. Behavioral priming studies have shown that the behavioral impact of a visual stimulus can be independent from its conscious perception, suggesting two independent neural signatures. To assess whether TMS-induced suppression of visual awareness can be dissociated from behavioral priming in the temporal domain, we thus implemented three different measures of visual processing, namely performance on a standard visual discrimination task, a subjective rating of stimulus visibility, and a visual priming task. To control for non-neural TMS effects, we performed electrooculographical recordings, placebo TMS (sham), and control site TMS (vertex). Our results suggest that, when considering the appropriate control data, the temporal pattern of EVC TMS disruption on visual discrimination, subjective awareness and behavioral priming are not dissociable. Instead, TMS to EVC disrupts visual perception holistically, both when applied before and after the onset of a visual stimulus. The current findings are discussed in light of their implications on models of visual awareness and (subliminal) priming.     

Dissociation of motor task-induced cortical excitability and pain perception changes in healthy volunteers

Background

There is evidence that interventions aiming at modulation of the motor cortex activity lead to pain reduction. In order to understand further the role of the motor cortex on pain modulation, we aimed to compare the behavioral (pressure pain threshold) and neurophysiological effects (transcranial magnetic stimulation (TMS) induced cortical excitability) across three different motor tasks.

Methodology/Principal Findings

Fifteen healthy male subjects were enrolled in this randomized, controlled, blinded, cross-over designed study. Three different tasks were tested including motor learning with and without visual feedback, and simple hand movements. Cortical excitability was assessed using single and paired-pulse TMS measures such as resting motor threshold (RMT), motor-evoked potential (MEP), intracortical facilitation (ICF), short intracortical inhibition (SICI), and cortical silent period (CSP). All tasks showed significant reduction in pain perception represented by an increase in pressure pain threshold compared to the control condition (untrained hand). ANOVA indicated a difference among the three tasks regarding motor cortex excitability change. There was a significant increase in motor cortex excitability (as indexed by MEP increase and CSP shortening) for the simple hand movements.

Conclusions/Significance

Although different motor tasks involving motor learning with and without visual feedback and simple hand movements appear to change pain perception similarly, it is likely that the neural mechanisms might not be the same as evidenced by differential effects in motor cortex excitability induced by these tasks. In addition, TMS-indexed motor excitability measures are not likely good markers to index the effects of motor-based tasks on pain perception in healthy subjects as other neural networks besides primary motor cortex might be involved with pain modulation during motor training.     

Pupillary reactions during transcranial magnetic stimulation

Pupillary reactions have been studied in healthy volunteers before, during, and after transcranial magnetic stimulation (TMS) of the primary visual cortex. During TMS in the projection of the primary visual cortex, a significant increase in pupil size was observed. Three minutes after the end of the TMS, a significant decrease in pupil size was recorded. These data point to a role of the primary visual cortex in the mechanisms of correcting pupillary reactions in humans.     

Transcranial magnetic stimulation intensities in cognitive paradigms

Background

Transcranial magnetic stimulation (TMS) has become an important experimental tool for exploring the brain''s functional anatomy. As TMS interferes with neural activity, the hypothetical function of the stimulated area can thus be tested. One unresolved methodological issue in TMS experiments is the question of how to adequately calibrate stimulation intensities. The motor threshold (MT) is often taken as a reference for individually adapted stimulation intensities in TMS experiments, even if they do not involve the motor system. The aim of the present study was to evaluate whether it is reasonable to adjust stimulation intensities in each subject to the individual MT if prefrontal regions are stimulated prior to the performance of a cognitive paradigm.

Methods and Findings

Repetitive TMS (rTMS) was applied prior to a working memory task, either at the ‘fixed’ intensity of 40% maximum stimulator output (MSO), or individually adapted at 90% of the subject''s MT. Stimulation was applied to a target region in the left posterior middle frontal gyrus (pMFG), as indicated by a functional magnetic resonance imaging (fMRI) localizer acquired beforehand, or to a control site (vertex). Results show that MT predicted the effect size after stimulating subjects with the fixed intensity (i.e., subjects with a low MT showed a greater behavioral effect). Nevertheless, the individual adaptation of intensities did not lead to stable effects.

Conclusion

Therefore, we suggest assessing MT and account for it as a measure for general cortical TMS susceptibility, even if TMS is applied outside the motor domain.     

SNAIL NEURON BIOELECTRIC ACTIVITY INDUCED UNDER STATIC OR SINUSOIDAL MAGNETIC FIELDS REPRODUCES MAMMAL NEURON RESPONSES UNDER TRANSCRANIAL MAGNETIC STIMULATION

We have applied static (SMF) or alternating magnetic fields (AMF) to snail (Helix aspersa) single-unit neurons, in the range of those applied in magnetic stimulation (MS)/transcranial magnetic stimulation (TMS). From the experiments we have performed during the past 10 years, we have collected a blind selection of neurons and their responses to either SMF or AMF. Blind selection means that we do not know the nature of neurons. We do not know whether they are sensitive, motor, secretory, pacemaker, or inter-neurons. We have seen that the behavior of single-unit neurons under SMF/AMF exposure (SMF range: 3 mT–0.7 T; AMF range: 1–15 mT) fits well with the electrophysiologic activity described for mammals and human whole brain under MS/TMS (pulsed magnetic field range: 0.3 mT–2.4 T). The neuron experiments shown here have been aleatorily selected from a collection of about 200 neurons studied. Our results could explain some of the effects described induced in mammal neurons under MS/TMS for clinical purposes.     

Reduced short-interval intracortical inhibition after eccentric muscle damage in human elbow flexor muscles

The purpose of this study was to use paired-pulse transcranial magnetic stimulation (TMS) to examine the effect of eccentric exercise on short-interval intracortical inhibition (SICI) after damage to elbow flexor muscles. Nine young (22.5 ± 0.6 yr; mean ± SD) male subjects performed maximal eccentric exercise of the elbow flexor muscles until maximal voluntary contraction (MVC) force was reduced by ～40%. TMS was performed before, 2 h after, and 2 days after exercise under Rest and Active (5% MVC) conditions with motor-evoked potentials (MEPs) recorded from the biceps brachii (BB) muscle. Peripheral electrical stimulation of the brachial plexus was used to assess maximal M-waves, and paired-pulse TMS with a 3-ms interstimulus interval was used to assess changes in SICI at each time point. The eccentric exercise resulted in a 34% decline in strength (P < 0.001), a 41% decline in resting M-wave (P = 0.01), changes in resting elbow joint angle (10°, P < 0.001), and a shift in the optimal elbow joint angle for force production (18°, P < 0.05) 2 h after exercise. This was accompanied by impaired muscle strength (27%, P < 0.001) and increased muscle soreness (P < 0.001) 2 days after exercise, which is indicative of muscle damage. When the test MEP amplitudes were matched between sessions, we found that SICI was reduced by 27% in resting and 23% in active BB muscle 2 h after exercise. SICI recovered 2 days after exercise when muscle pain and soreness were present, suggesting that delayed onset muscle soreness from eccentric exercise does not influence SICI. The change in SICI observed 2 h after exercise suggests that eccentric muscle damage has widespread effects throughout the motor system that likely includes changes in motor cortex.     

Effects of Sensory Behavioral Tasks on Pain Threshold and Cortical Excitability

Background/Objective

Transcutaneous electrical stimulation has been proven to modulate nervous system activity, leading to changes in pain perception, via the peripheral sensory system, in a bottom up approach. We tested whether different sensory behavioral tasks induce significant effects in pain processing and whether these changes correlate with cortical plasticity.

Methodology/Principal Findings

This randomized parallel designed experiment included forty healthy right-handed males. Three different somatosensory tasks, including learning tasks with and without visual feedback and simple somatosensory input, were tested on pressure pain threshold and motor cortex excitability using transcranial magnetic stimulation (TMS). Sensory tasks induced hand-specific pain modulation effects. They increased pain thresholds of the left hand (which was the target to the sensory tasks) and decreased them in the right hand. TMS showed that somatosensory input decreased cortical excitability, as indexed by reduced MEP amplitudes and increased SICI. Although somatosensory tasks similarly altered pain thresholds and cortical excitability, there was no significant correlation between these variables and only the visual feedback task showed significant somatosensory learning.

Conclusions/Significance

Lack of correlation between cortical excitability and pain thresholds and lack of differential effects across tasks, but significant changes in pain thresholds suggest that analgesic effects of somatosensory tasks are not primarily associated with motor cortical neural mechanisms, thus, suggesting that subcortical neural circuits and/or spinal cord are involved with the observed effects. Identifying the neural mechanisms of somatosensory stimulation on pain may open novel possibilities for combining different targeted therapies for pain control.     

舍曲林联合经颅磁刺激对青少年首发抑郁症认知功能的影响

目的:探讨舍曲林联合经颅磁刺激(TMS)对青少年首发抑郁症认知功能的影响。方法:选取2018年10月~2020年2月我院青少年首发抑郁症患者94例作为研究对象,简单随机化分为2组,各47例。对照组予以舍曲林治疗,观察组予以TMS联合舍曲林治疗,2组均连续治疗6周。比较2组疗效、不良反应发生率、随访12个月复发率及治疗前后血清微小核糖核酸(miR)-18a、miR-124水平、汉密尔顿抑郁量表(HAMD-17)评分、重复性成套神经心理状态测试(RBANS)中文版评分。结果:观察组总有效率(93.62%)高于对照组(78.72%),差异有统计学意义(P<0.05)。治疗3、6周后观察组血清miR-18a、miR-124水平低于对照组(P<0.05)。治疗3、6周后观察组焦虑/躯体化、睡眠障碍、抑郁迟滞及认知障碍评分低于对照组(P<0.05)。治疗3、6周后观察组即刻记忆、言语功能、视觉广度、注意力及延时记忆评分高于对照组(P<0.05)。2组不良反应发生率比较,差异无统计学意义(P>0.05)。观察组随访12个月复发率低于对照组(P<0.05)。结论:舍曲林联合TMS首次治疗青少年首发抑郁症,效果显著,能有效调节血清miR-18a、miR-124水平,减轻抑郁症状,从而提高认知功能,降低复发率,保证安全性。     

Therapeutic application of rTMS in neurodegenerative and movement disorders: A review

Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that makes use of the magnetic field generated when an electric current passes through a magnetic coil placed over the scalp. It can be applied as a single stimulus at a time, in pairs of stimuli, or repetitively in trains of stimuli (repetitive TMS, rTMS). RTMS can induce changes in brain activity, whose after-effects reflect the processes of long-term potentiation and long-term depression, as certain protocols, namely those using low frequencies (≤1 Hz) seem to suppress cortical excitability, while those using high frequencies (>1 Hz) seem to enhance it. It is a technique with very few and mostly mild side-effects, whose effects can persist for long time periods, and as such, it has been studied as a potential treatment option in a multitude of neurodegenerative diseases, including those affecting movement. Although rTMS has received approval as a treatment strategy of only a few aspects in movement disorders in the latest guidelines, its further use seems to also be promising in their context. In this review, we gathered the available literature on the therapeutic application of rTMS in movement disorders, namely Parkinson’s disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Dystonia, Tic disorders and Essential Tremor.     

Whole-Body Water Flow Stimulation to the Lower Limbs Modulates Excitability of Primary Motor Cortical Regions Innervating the Hands: A Transcranial Magnetic Stimulation Study

Whole-body water immersion (WI) has been reported to change sensorimotor integration. However, primary motor cortical excitability is not affected by low-intensity afferent input. Here we explored the effects of whole-body WI and water flow stimulation (WF) on corticospinal excitability and intracortical circuits. Eight healthy subjects participated in this study. We measured the amplitude of motor-evoked potentials (MEPs) produced by single transcranial magnetic stimulation (TMS) pulses and examined conditioned MEP amplitudes by paired-pulse TMS. We evaluated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) using the paired-TMS technique before and after 15-min intervention periods. Two interventions used were whole-body WI with water flow to the lower limbs (whole-body WF) and whole-body WI without water flow to the lower limbs (whole-body WI). The experimental sequence included a baseline TMS assessment (T0), intervention for 15 min, a second TMS assessment immediately after intervention (T1), a 10 min resting period, a third TMS assessment (T2), a 10 min resting period, a fourth TMS assessment (T3), a 10 min resting period, and the final TMS assessment (T4). SICI and ICF were evaluated using a conditioning stimulus of 90% active motor threshold and a test stimulus adjusted to produce MEPs of approximately 1–1.2 mV, and were tested at intrastimulus intervals of 3 and 10 ms, respectively. Whole-body WF significantly increased MEP amplitude by single-pulse TMS and led to a decrease in SICI in the contralateral motor cortex at T1, T2 and T3. Whole-body WF also induced increased corticospinal excitability and decreased SICI. In contrast, whole-body WI did not change corticospinal excitability or intracortical circuits.     

Chlorophyll Photosynthetic Potential in Wheat Stands in Dry and Humid Years

Influence of climatic conditions (total precipitation and sunshine duration) on the dynamics of chlorophyll photosynthetic potential (CPSP) and its relation to productivity of crop stands was studied with long- and short-stalked cultivars of winter wheat (Triticum aestivum L.). The reduction of the total exposure time to solar photosynthetically active radiation by 100 h per growing season (humid year) was shown to decrease CPSP by a factor of 1.3 and 1.5 in long-stalked and short-stalked cultivars, respectively. The decrease was mainly related to the suppression of biomass production, one of the main constituents of photosynthetic potential. Retardation of growth processes was manifested in a twofold decrease in the shoot number per m² on average; furthermore, morphological stages were delayed during early development. Suppression of growth processes by the shortened sunshine time was not compensated for by a 30% increase in specific chlorophyll content (as distinct from shade leaves), the other component of CPSP. It was shown that growth conditions have an effect on the correlation coefficient between CPSP and productivity.