Targeting the motor cortex to restore walking after incomplete spinal cord injury

Spinal cord injury(SCI),second only to stroke,is the leading cause of paralysis.The ability to walk is often lost after SCI,reducing independence and quality of life.Restoration of walking is cited as a priority among persons with SCI of all degrees of severity,chronicity,or age at injury.As 70%of SCIs are anatomically incomplete,some neural connections relaying information to and from the brain are spared.     

Modulation of single motor unit discharges using magnetic stimulation of the motor cortex in incomplete spinal cord injury

OBJECTIVES: Motor evoked potentials (MEPs) and inhibition of voluntary contraction to transcranial magnetic stimulation (TMS) of the motor cortex have longer latencies than normal in patients with incomplete spinal cord injury (iSCI) when assessed using surface EMG. This study now examines the modulation of single motor unit discharges to TMS with the aim of improving resolution of the excitatory and inhibitory responses seen previously in surface EMG recordings. METHODS: A group of five patients with iSCI (motor level C4-C7) was compared with a group of five healthy control subjects. Single motor unit discharges were recorded with concentric needle electrodes from the first dorsal interosseus muscle during weak voluntary contraction (2%-5% maximum). TMS was applied with a 9 cm circular stimulating coil centred over the vertex. Modulation of single motor unit discharges was assessed using peristimulus time histograms (PSTHs). RESULTS: Mean (SEM) threshold (expressed as percentage of maximum stimulator output (%MSO)) for the excitatory peak (excitation) or inhibitory trough (inhibition) in the PSTHs was higher (p<0.05) in the patients (excitation = 47.1 (5.9) %MSO; inhibition = 44.3 (3.2) %MSO) than in controls (excitation=31.6 (1.2) %MSO; inhibition = 27.4 (1.0) %MSO). Mean latencies of excitation and inhibition were longer (p<0.05) in the patients (excitation=35 (1.8) ms; inhibition = 47.1 (1.8) ms) than in the controls (excitation = 21.1 (1.6) ms; inhibition = 27 (0.4) ms). Furthermore, the latency difference (inhibition-excitation) was longer (p<0.05) in the patients (10.4 (2.1) ms) than in the controls (6.2 (0.6) ms). CONCLUSION: Increased thresholds and latencies of excitation and inhibition may reflect degraded corticospinal transmission in the spinal cord. However, the relatively greater increase in the latency of inhibition compared with excitation in the patients with iSCI may reflect a weak or absent early component of cortical inhibition. Such a change in cortical inhibition may relate to the restoration of useful motor function after iSCI.     

Enhanced motor cortex excitability after spinal cord injury

<正>Transcranial magnetic stimulation(TMS)represents a useful non-invasive approach to studying cortical physiology,in addition to the descending motor pathways(Hallett,2000),and may also be used to investigate the intracortical facilitatory and inhibitory mechanisms.     

From cortex to cord: motor circuit plasticity after spinal cord injury

Spinal cord injury is associated with chronic sensorimotor deficits due to the interruption of ascending and descending tracts between the brain and spinal cord. Functional recovery after anatomically complete spinal cord injury is limited due to the lack of long-distance axonal regeneration of severed fibers in the adult central nervous system. Most spinal cord injuries in humans, however, are anatomically incomplete.Although restorative treatment options for spinal cord injury remain currently limited, research from experimental models of spinal cord injury have revealed a tremendous capability for both spontaneous and treatment-induced plasticity of the corticospinal system that supports functional recovery. We review recent advances in the understanding of corticospinal circuit plasticity after spinal cord injury and concentrate mainly on the hindlimb motor cortex, its corticospinal projections, and the role of spinal mechanisms that support locomotor recovery. First, we discuss plasticity that occurs at the level of motor cortex and the reorganization of cortical movement representations. Next, we explore downstream plasticity in corticospinal projections. We then review the role of spinal mechanisms in locomotor recovery. We conclude with a perspective on harnessing neuroplasticity with therapeutic interventions to promote functional recovery.     

Vestibulospinal responses in motor incomplete spinal cord injury

ObjectivePostural instability limits ambulatory capacity in patients with spinal cord injury (SCI). Galvanic vestibular stimulation (GVS) was used to investigate the integrity of vestibulospinal pathways and related changes in postural responses in SCI.MethodsBinaural bipolar galvanic stimuli of 400 ms duration and 3 mA intensity were applied in 8 motor incomplete SCI and 8 control subjects who stood facing towards the left. EMG responses were recorded from the right soleus muscle and the trajectory of the centre of pressure (CoP) was measured with a force plate.ResultsThere was no difference in excitability and amplitude of the responses between the groups. However, the latency and duration of the medium latency EMG response and all CoP responses were significantly longer in the SCI group. Additionally, postural stability was reduced in the SCI group, as shown by a greater tendency to fall due to GVS.ConclusionsDespite early EMG responses proving the basic connectivity of the direct vestibulospinal pathways, the delayed GVS responses suggest a vestibulospinal deficit in the SCI subjects.SignificanceGVS can be applied in incomplete SCI to supplement the neurological examination by revealing changes in vestibulospinal responses and impairment of postural stability.     

Synaptic remodeling in mouse motor cortex after spinal cord injury

Spinal cord injury dramatically blocks information exchange between the central nervous system and the peripheral nervous system. The resulting fate of synapses in the motor cortex has not been well studied. To explore synaptic reorganization in the motor cortex after spinal cord injury, we established mouse models of T12 spinal cord hemi-section and then monitored the postsynaptic dendritic spines and presynaptic axonal boutons of pyramidal neurons in the hindlimb area of the motor cortex in vivo. Our results showed that spinal cord hemisection led to the remodeling of dendritic spines bilaterally in the motor cortex and the main remodeling regions changed over time. It made previously stable spines unstable and eliminated spines more unlikely to be re-emerged. There was a significant increase in new spines in the contralateral motor cortex. However, the low survival rate of the new spines demonstrated that new spines were still fragile. Observation of presynaptic axonal boutons found no significant change. These results suggest the existence of synapse remodeling in motor cortex after spinal cord hemi-section and that spinal cord hemi-section affected postsynaptic dendritic spines rather than presynaptic axonal boutons. This study was approved by the Ethics Committee of Chinese PLA General Hospital, China(approval No. 201504168 S) on April 16, 2015.     

Responses of thenar muscles to transcranial magnetic stimulation of the motor cortex in patients with incomplete spinal cord injury

OBJECTIVE—Toinvestigate changes in electromyographic (EMG) responses totranscranial magnetic stimulation (TMS) of the motor cortex afterincomplete spinal cord injury in humans.
METHODS—A group of 10 patients with incomplete spinal cord injury (motor level C3-C8) wascompared with a group of 10 healthy control subjects. Surface EMGrecordings were made from the thenar muscles. TMS was applied with a 9 cm circular stimulating coil centred over the vertex. The EMG responsesto up to 50 magnetic stimuli were rectified and averaged.
RESULTS—Thresholds forcompound motor evoked potentials (cMEPs) and suppression of voluntarycontraction (SVC) elicited by TMS were higher (p<0.05) in the patientgroup. Latency of cMEPs was longer (p<0.05) in the patient group inboth relaxed (controls 21.3 (SEM 0.5) ms; patients 27.7 (SEM 1.3) ms)and voluntarily contracted (controls 19.8 (SEM 0.5) ms; patients 27.6 (SEM 1.3) ms) muscles. The latency of SVCwas longer (p<0.05) in the patients (51.8 (SEM 1.8) ms) than in the controls (33.4 (SEM 1.9) ms). The latency difference(SVC−cMEP) was longer in the patients (25.3 (SEM 2.4) ms) than in the controls (13.4 (SEM 1.6) ms).
CONCLUSION—The longerlatency difference between cMEPs and SVC in the patients may reflect aweak or absent early component of cortical inhibition. Such a changemay contribute to the restoration of useful motor function afterincomplete spinal cord injury.

     

Metabolic changes in rabbit spinal cord after trauma: magnetic resonance spectroscopy studies

Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface coils, was used to monitor certain metabolic changes in the L-3 spinal segment of anesthetized rabbits prior to and following experimental spinal cord trauma. Following severe trauma, resulting in spastic paraplegia, there was a delayed and progressive accumulation of lactic acid, a decline in intracellular pH, and a loss of high-energy phosphates. Maximal alterations occurred between 2 and 3 hours after the trauma, with little further change by 4 hours. Histological examination 2 weeks after trauma showed tissue necrosis and cavitation. These findings support the concept of secondary tissue injury after spinal cord trauma and suggest that early changes in metabolism, as shown by MRS, may predict irreversible tissue damage.     

Prediction of cognitive decline after stroke using proton magnetic resonance spectroscopy

Structural MRI measures have been used to predict cognitive decline in elderly subjects, but few studies have used proton magnetic resonance spectroscopy ((1)H-MRS) for this purpose, particularly after stroke. We studied the potential of (1)H-MRS to predict cognitive decline in patients with stroke or TIA and healthy ageing controls over 12 months and 3 years. Structural MRI and single-voxel (1)H-MRS in the frontal white matter and the occipito-parietal gray matter were performed at the index assessment (3-6 months post-stroke) in 49 stroke/TIA patients and 60 controls. Neuropsychological testing was performed at the index assessment and repeated at 12 months in 30 stroke/TIA patients and 49 controls, and at 3 years in 25 patients and 48 controls. In stroke/TIA patients, frontal NAA/Cr predicted cognitive decline over 12 months and 3 years, and in elderly control subjects frontal NAA predicted cognitive decline over 12 months only. In stroke/TIA patients, the (1)H-MRS measures were better predictors of cognitive decline than structural measures. (1)H-MRS may be useful in assessing early cognitive impairment after stroke/TIA and in normal ageing.     

Treadmill step training promotes spinal cord neural plasticity after incomplete spinal cord injury

A large body of evidence shows that spinal circuits are significantly affected by training,and that intrinsic circuits that drive locomotor tasks are located in lumbosacral spinal segments in rats with complete spinal cord transection.However,after incomplete lesions,the effect of treadmill training has been debated,which is likely because of the difficulty of separating spontaneous stepping from specific training-induced effects.In this study,rats with moderate spinal cord contusion were subjected to either step training on a treadmill or used in the model(control) group.The treadmill training began at day 7 post-injury and lasted 20 ± 10 minutes per day,5 days per week for 10 weeks.The speed of the treadmill was set to 3 m/min and was increased on a daily basis according to the tolerance of each rat.After 3 weeks of step training,the step training group exhibited a significantly greater improvement in the Basso,Beattie and Bresnahan score than the model group.The expression of growth-associated protein-43 in the spinal cord lesion site and the number of tyrosine hydroxylase-positive ventral neurons in the second lumbar spinal segment were greater in the step training group than in the model group at 11 weeks post-injury,while the levels of brain-derived neurotrophic factor protein in the spinal cord lesion site showed no difference between the two groups.These results suggest that treadmill training significantly improves functional recovery and neural plasticity after incomplete spinal cord injury.     

Impaired facilitation of motor evoked potentials in incomplete spinal cord injury

Objectives To improve the diagnosis of damaged spinal motor pathways in incomplete spinal cord injury (iSCI) by assessing the facilitation of lower limbs motor evoked potentials (MEP). Methods Control subjects (n = 12) and iSCI patients (n = 21) performed static and dynamic isometric foot dorsiflexions. MEPs induced by transcranial magnetic stimulation and EMG background of tibialis anterior muscle (TA) were analyzed. Static and dynamic muscle activation was performed at comparable levels of maximal voluntary contraction (MVC). The influence of the motor tasks on the excitability and facilitation of MEPs was compared between controls and iSCI patients. Results In the controls an increased facilitation of TA MEP at lower levels of dynamic compared with static activation (10–20% MVC) could be shown. At matched EMG background level the MEP responses were significantly increased. In the iSCI patients at a comparable level of TA activation the MEP responses were significantly reduced and 3 different patterns of MEP responses could be distinguished: i) preserved increment of TA MEP in the dynamic motor task, ii) unchanged MEP size in the dynamic and static motor task, and iii) elicitable MEPs in the dynamic motor task,which were abolished in the static motor task. Conclusions Static and dynamic motor tasks have different effects on TA MEP facilitation. The task–dependent modulation of TA MEPs is comparable to that described for upper limb muscles. Complementary to the MEP delay this approach allows for an estimation of the severity of spinal tract damage. The task–dependent modulation of TA MEPs is an additional diagnostic tool to improve the assessment and monitoring of motor function in iSCI.     

Adaptation in the motor cortex following cervical spinal cord injury

BACKGROUND: The nature of the adaptive changes that occur in the cerebral cortex following injury to the cervical spinal cord are largely unknown. OBJECTIVE: To investigate these adaptive changes by examining the relationship between the motor cortical representation of the paretic right upper extremity compared with that of the tongue. The tongue was selected because the spinal cord injury (SCI) does not affect its movement and the cortical representation of the tongue is adjacent to that of the paretic upper extremity. METHODS: FMRI was used to map cortical representations associated with simple motor tasks of the right upper extremity and tongue in 14 control subjects and 9 patients with remote (>5.5 months) cervical SCI. RESULTS: The mean value for the site of maximum cortical activation during upper limb movement was identical between the two groups. The site of maximum left hemispheric cortical activation during tongue movement was 12.8 mm (p < 0.01) medial and superior to that of control subjects, indicating the presence of a shift in cortical activation. CONCLUSION: The findings indicate that the adult motor cortex does indeed adapt following cervical SCI. The nature of the adaptation and the underlying biological mechanisms responsible for this change require further investigation.     

氢质子MR波谱对弥漫性轴索损伤的评估

景：目前在弥漫性轴索损伤的临床诊断和伤情评估上,CT和常规MRI的作用非常有限。 目的：验证氢质子MR波谱技术在弥漫性轴索损伤临床诊断及预后评估中的价值。 设计、时间及地点：前瞻性临床对照观察,于2002-10/2007-09在重庆医科大学附属第一医院神经外科及放射科完成。 对象：纳入63例颅脑损伤患者,根据MRI检查结果分为2组,弥漫性轴索损伤组27例,非弥漫性轴索损伤组36例;再利用单纯随机抽样法选择20名健康成年人作为正常对照。 方法：患者入院后,按常规进行治疗,一旦生命体征和意识情况允许,立即行包括液体衰减反转恢复序列在内的磁共振影像学检查,并在此同时行氢质子MR波谱检查,氢质子MR波谱检查数据进行后期工作站分析,并结合临床情况进行分析。 主要观察指标：胼胝体膝部、压部和基底核N-乙酰天冬氨酸/肌酸和磷酸肌酸、胆碱复合物/肌酸和磷酸肌酸、肌醇/肌酸和磷酸肌酸以及谷氨酸和谷氨酰胺/肌酸和磷酸肌酸等指标。 结果：与对照组和非弥漫性轴索损伤组相比,弥漫性轴索损伤组胼胝体膝部、压部和基底核出现N-乙酰天冬氨酸/肌酸和磷酸肌酸降低及胆碱复合物/肌酸和磷酸肌酸升高(P < 0.05~0.01),胼胝体膝部和压部出现肌醇/肌酸和磷酸肌酸及谷氨酰胺/肌酸和磷酸肌酸升高(P < 0.05)。与对照组相比,非弥漫性轴索损伤组出现胼胝体膝部胆碱复合物/肌酸和磷酸肌酸升高和压部N-乙酰天冬氨酸/肌酸和磷酸肌酸降低(P < 0.01),但变化程度比弥漫性轴索损伤组低。弥漫性轴索损伤组胼胝体膝部的胆碱复合物/肌酸和磷酸肌酸和伤后原发昏迷时间呈正相关(r=0.824,P < 0.01)。 结论：胼胝体膝部、压部和基底核各氢质子MR波谱指标可作为弥漫性轴索损伤有效的诊断指标。氢质子MR波谱中的胆碱复合物/肌酸和磷酸肌酸等指标可以很好地反映伤后组织学的改变,是临床伤情预测的灵敏指标。     

Quantitative proton magnetic resonance spectroscopy detects abnormalities in dorsolateral prefrontal cortex and motor cortex of patients with frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease of the frontal and temporal neocortex. The single most common pathology underlying FTLD is neuronal degeneration with ubiquitin-positive but tau-negative inclusions consisting of Tar DNA binding proteins (TDP-43). Inclusions containing TDP-43 in neurons are also the most common pathology underlying motor neuron disease (MND). The present study tested the hypothesis that abnormal metabolite patterns within the dorsolateral prefrontal cortex (DLPFC) as well as the motor cortex (MC) may be observed in FTLD patients without motor disorders, using proton magnetic resonance spectroscopy (¹H MRS). Twenty-six FTLD patients with cognitive damage and ten controls underwent multivoxel ¹H MRS. Absolute concentrations of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) were measured from the DLPFC, the MC and the parietal cortex (PC, an internal control). Statistical analyses were performed for group differences between FTLD patients and controls. Comparisons were also made across brain regions (PC and DLPFC; PC and MC) within FTLD patients. Significant reductions in NAA and Cr along with increased Cho and mI were observed in the DLPFC of FTLD patients compared to controls. Significantly lower NAA and higher Cho were also observed in the MCs of patients as compared to controls. Within the FTLD patients, both the MC and the DLPFC exhibited significantly decreased NAA and elevated Cho compared to the PC. However, only the DLPFC had significantly lower Cr and higher mI. Abnormal metabolite pattern from the MC supports the hypothesis that FTLD and MND may be closely linked.     

氢质子磁共振波谱成像技术在创伤性脑损伤后认知障碍中的应用

创伤性脑损伤(TBI)可引起一系列复杂的病理生理过程变化,这些变化包括脑内物质代谢异常,导致机体出现包括头痛、认知、运动和情感障碍等在内的长、短期症状,而认知障碍是阻碍TBI患者日常生活质量恢复和延缓其回归社会的重要因素。氢质子磁共振波谱成像技术(1H-MRS)可对急、慢性脑部损伤患者的脑组织代谢进行非侵入性检测,具有辅助诊断和预测长期功能预后的价值。该文将近年来1H-MRS在TBI后认知障碍中的应用进行总结和展望。[国际神经病学神经外科学杂志, 2021, 48(2):197-201]     

Estimate of motor conduction in human spinal cord: slowed conduction in spinal cord injury

By using motor evoked potential (MEP) created by transcranial electric stimulation over the motor cortex and F-wave measurement from the peripheral nerve stimulation, it is possible to estimate the spinal cord motor conduction velocity (SCMCV) in the diseased state. Twenty-four patients with spinal cord injury (SCI) between T1 and T11 neurological levels participated in this study. MEP in leg muscle was absent in all neurologically complete paraplegics. In 16 patients with neurologically incomplete SCI, MEP was obtained in 13 patients. The SCMCV estimated from C7 to T12 spinal levels was 32.1 (SD = 9.4) m/s. This was significantly slower than 63.3 (SD = 8.6) m/s in 40 normal controls. This noninvasive, indirect method is measurable, and can provide valuable electrophysiological data in the assessment of motor function in patients with SCI.     

Assessment of GABA concentration in human brain using two-dimensional proton magnetic resonance spectroscopy

A quantitative method to assess in vivo brain gamma-aminobutyric acid (GABA) levels is proposed using a J-resolved, two-dimensional (2D) magnetic resonance spectroscopy (MRS) technique. Localized, J-resolved 2D MR spectra were obtained from a 12-cm(3) voxel in the occipital lobe of 36 healthy volunteers (18 male and 18 female, age: 25.1+/-4.8 years). Based on phantom measurements, a GABA resonance peak located at 2.94 ppm, 7.45 Hz, in J-resolved 2D MRS overlaps the least with other resonance peaks which arise from N-acetylaspartate, choline, creatine, glutamate and glutamine. Measurements of this resonance peak yield in vivo GABA concentrations of 1.01+/-0.36 micromol/cm(3) for male and 1.16+/-0.43 micromol/cm(3) for female volunteers, without correction for T1 and T2 relaxation effects. These results are in good agreement with previously reported data and suggest that, with further development, 2D MRS may provide a practical means to estimate the concentration of this important neurotransmitter.     

Assessment of GABA concentration in human brain using two-dimensional proton magnetic resonance spectroscopy

A quantitative method to assess in vivo brain gamma-aminobutyric acid (GABA) levels is proposed using a J-resolved, two-dimensional (2D) magnetic resonance spectroscopy (MRS) technique. Localized, J-resolved 2D MR spectra were obtained from a 12-cm³ voxel in the occipital lobe of 36 healthy volunteers (18 male and 18 female, age: 25.1±4.8 years). Based on phantom measurements, a GABA resonance peak located at 2.94 ppm, 7.45 Hz, in J-resolved 2D MRS overlaps the least with other resonance peaks which arise from N-acetylaspartate, choline, creatine, glutamate and glutamine. Measurements of this resonance peak yield in vivo GABA concentrations of 1.01±0.36 μmol/cm³ for male and 1.16±0.43 μmol/cm³ for female volunteers, without correction for T1 and T2 relaxation effects. These results are in good agreement with previously reported data and suggest that, with further development, 2D MRS may provide a practical means to estimate the concentration of this important neurotransmitter.     

Fatigue-induced motor cortex excitability changes in subjects with spinal cord injury

To further investigate the mechanisms of exercise-induced cortical plasticity after spinal cord injury (SCI), the cortical silent period (CoSP) evoked by transcranial magnetic stimulation (TMS) during a fatiguing muscle contraction was evaluated in 5 patients with incomplete cervical SCI and in 5 healthy subjects.The physiological lengthening of CoSP end latency during fatigue was not observed in the SCI patients.This reduced intracortical inhibition, probably secondary to decreased activity of the GABAergic inhibitory interneurons that modulate the corticomotoneuronal output, could represent a ‘positive’ neuroplastic response in an attempt to compensate for the loss of corticospinal axons.The investigation of motor cortex excitability during fatiguing exercise may shed light on the role of exercise therapy in promoting brain reorganization and functional recovery in humans.