Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Effect of sonification types in upper-limb movement: a quantitative and qualitative study in hemiparetic and healthy participants.

BACKGROUND: Movement sonification, the use of real-time auditory feedback linked to movement parameters, have been proposed to support rehabilitation. Nevertheless, if promising results have been reported, the effect of the type of sound used has not been studied systematically. The aim of this study was to investigate in a single session the effect of different types of sonification both quantitatively and qualitatively on patients with acquired brain lesions and healthy participants. METHODS: An experimental setup enabling arm sonification was developed using three different categories of sonification (direct sound modulation, musical interaction, and soundscape). Simple moving forward movements performed while sliding on a table with both arms were investigated with all participants. Quantitative analysis on the movement timing were performed considering various parameters (sound condition, affected arm and dominance, sonification categories). Qualitative analysis of semi-structured interviews were also conducted, as well as neuropsychological evaluation of music perception. RESULTS: For both the patient and healthy groups (15 participants each), average duration for performing the arm movement is significantly longer with sonification compared to the no-sound condition (p < 0.001). Qualitative analysis of semi-structured interviews revealed different aspects of motivational and affective aspects of sonification. Most participants of both groups preferred to complete the task with sound (29 of 30 participants), and described the experience as playful (22 of 30 participants). More precisely, the soundscape (nature sounds) was the most constantly preferred (selected first by 14 of 30 participants). CONCLUSION: Overall, our results confirm that the sonification has an effect on the temporal execution of the movement during a single-session. Globally, sonification is welcomed by the participants, and we found convergent and differentiated appreciations of the different sonification types.

Brain-spinal cord interaction in long-term motor sequence learning in human: An fMRI study.

The spinal cord is important for sensory guidance and execution of skilled movements. Yet its role in human motor learning is not well understood. Despite evidence revealing an active involvement of spinal circuits in the early phase of motor learning, whether long-term learning engages similar changes in spinal cord activation and functional connectivity remains unknown. Here, we investigated spinal-cerebral functional plasticity associated with learning of a specific sequence of visually-guided joystick movements (sequence task) over six days of training. On the first and last training days, we acquired high-resolution functional images of the brain and cervical cord simultaneously, while participants practiced the sequence or a random task while electromyography was recorded from wrist muscles. After six days of training, the subjects' motor performance improved in the sequence compared to the control condition. These behavioral changes were associated with decreased co-contractions and increased reciprocal activations between antagonist wrist muscles. Importantly, early learning was characterized by activation in the C8 level, whereas a more rostral activation in the C6-C7 was found during the later learning phase. Motor sequence learning was also supported by increased spinal cord functional connectivity with distinct brain networks, including the motor cortex, superior parietal lobule, and the cerebellum at the early stage, and the angular gyrus and cerebellum at a later stage of learning. Our results suggest that the early vs. late shift in spinal activation from caudal to rostral cervical segments synchronized with distinct brain networks, including parietal and cerebellar regions, is related to progressive changes reflecting the increasing fine control of wrist muscles during motor sequence learning.

Transient increase in recurrent inhibition in amyotrophic lateral sclerosis as a putative protection from neurodegeneration.

AIM: Adaptive mechanisms in spinal circuits are likely involved in homeostatic responses to maintain motor output in amyotrophic lateral sclerosis. Given the role of Renshaw cells in regulating the motoneuron input/output gain, we investigated the modulation of heteronymous recurrent inhibition. METHODS: Electrical stimulations were used to activate recurrent collaterals resulting in the Hoffmann reflex depression. Inhibitions from soleus motor axons to quadriceps motoneurons, and vice versa, were tested in 38 patients and matched group of 42 controls. RESULTS: Compared with controls, the mean depression of quadriceps reflex was larger in patients, while that of soleus was smaller, suggesting that heteronymous recurrent inhibition was enhanced in quadriceps but reduced in soleus. The modulation of recurrent inhibition was linked to the size of maximal direct motor response and lower limb dysfunctions, suggesting a significant relationship with the integrity of the target motoneuron pool and functional abilities. No significant link was found between the integrity of motor axons activating Renshaw cells and the level of inhibition. Enhanced inhibition was particularly observed in patients within the first year after symptom onset and with slow progression of lower limb dysfunctions. Normal or reduced inhibitions were mainly observed in patients with motor weakness first in lower limbs and greater dysfunctions in lower limbs. CONCLUSION: We provide the first evidence for enhanced recurrent inhibition and speculate that Renshaw cells might have transient protective role on motoneuron by counteracting hyperexcitability at early stages. Several mechanisms likely participate including cortical influence on Renshaw cell and reinnervation by slow motoneurons.

Investigating the human spinal sensorimotor pathways through functional magnetic resonance imaging.

Most of our knowledge about the human spinal ascending (sensory) and descending (motor) pathways comes from non-invasive electrophysiological investigations. However, recent methodological advances in acquisition and analyses of functional magnetic resonance imaging (fMRI) data from the spinal cord, either alone or in combination with the brain, have allowed us to gain further insights into the organization of this structure. In the current review, we conducted a systematic search to produced somatotopic maps of the spinal fMRI activity observed through different somatosensory, motor and resting-state paradigms. By cross-referencing these human neuroimaging findings with knowledge acquired through neurophysiological recordings, our review demonstrates that spinal fMRI is a powerful tool for exploring, in vivo, the human spinal cord pathways. We report strong cross-validation between task-related and resting-state fMRI in accordance with well-known hemicord, postero-anterior and rostro-caudal organization of these pathways. We also highlight the specific advantages of using spinal fMRI in clinical settings to characterize better spinal-related impairments, predict disease progression, and guide the implementation of therapeutic interventions.

Development of new outcome measures for adult SMA type III and IV: a multimodal longitudinal study.

OBJECTIVE: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials. METHODS: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables. RESULTS: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials. CONCLUSIONS: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.

Resting-state brain and spinal cord networks in humans are functionally integrated.

In the absence of any task, both the brain and spinal cord exhibit spontaneous intrinsic activity organised in a set of functionally relevant neural networks. However, whether such resting-state networks (RSNs) are interconnected across the brain and spinal cord is unclear. Here, we used a unique scanning protocol to acquire functional images of both brain and cervical spinal cord (CSC) simultaneously and examined their spatiotemporal correspondence in humans. We show that the brain and spinal cord activities are strongly correlated during rest periods, and specific spinal cord regions are functionally linked to consistently reported brain sensorimotor RSNs. The functional organisation of these networks follows well-established anatomical principles, including the contralateral correspondence between the spinal hemicords and brain hemispheres as well as sensory versus motor segregation of neural pathways along the brain-spinal cord axis. Thus, our findings reveal a unified functional organisation of sensorimotor networks in the entire central nervous system (CNS) at rest.

Music Restores Propriospinal Excitation During Stroke Locomotion.

Music-based therapy for rehabilitation induces neuromodulation at the brain level and improves the functional recovery. In line with this, musical rhythmicity improves post-stroke gait. Moreover, an external distractor also helps stroke patients to improve locomotion. We raised the question whether music with irregular tempo (arrhythmic music), and its possible influence on attention would induce neuromodulation and improve the post-stroke gait. We tested music-induced neuromodulation at the level of a propriospinal reflex, known to be particularly involved in the control of stabilized locomotion; after stroke, the reflex is enhanced on the hemiparetic side. The study was conducted in 12 post-stroke patients and 12 controls. Quadriceps EMG was conditioned by electrical stimulation of the common peroneal nerve, which produces a biphasic facilitation on EMG, reflecting the level of activity of the propriospinal reflex between ankle dorsiflexors and quadriceps (CPQ reflex). The CPQ reflex was tested during treadmill locomotion at the preferred speed of each individual, in 3 conditions randomly alternated: without music vs. 2 arrhythmic music tracks, including a pleasant melody and unpleasant aleatory electronic sounds (AES); biomechanical and physiological parameters were also investigated. The CPQ reflex was significantly larger in patients during walking without sound, compared to controls. During walking with music, irrespective of the theme, there was no more difference between groups. In controls, music had no influence on the size of CPQ reflex. In patients, CPQ reflex was significantly larger during walking without sound than when listening to the melody or AES. No significant differences have been revealed concerning the biomechanical and the physiological parameters in both groups. Arrhythmic music listening modulates the spinal excitability during post-stroke walking, restoring the CPQ reflex activity to normality. The plasticity was not accompanied by any clear improvement of gait parameters, but the patients reported to prefer walking with music than without. The role of music as external focus of attention is discussed. This study has shown that music can modulate propriospinal neural network particularly involved in the gait control during the first training session. It is speculated that repetition may help to consolidate plasticity and would contribute to gait recovery after stroke.

Interrogating interneurone function using threshold tracking of the H reflex in healthy subjects and patients with motor neurone disease.

OBJECTIVE: The excitability of the lower motoneurone pool is traditionally tested using the H reflex and a constant-stimulus paradigm, which measures changes in the amplitude of the reflex response. This technique has limitations because reflex responses of different size must involve the recruitment or inhibition of different motoneurones. The threshold-tracking technique ensures that the changes in excitability occur for an identical population of motoneurones. We aimed to assess this technique and then apply it in patients with motor neurone disease (MND). METHODS: The threshold-tracking approach was assessed in 17 healthy subjects and 11 patients with MND. The soleus H reflex was conditioned by deep peroneal nerve stimulation producing reciprocal Ia and so-called D1 and D2 inhibitions, which are believed to reflect presynaptic inhibition of soleus Ia afferents. RESULTS: Threshold tracking was quicker than the constant-stimulus technique and reliable, properties that may be advantageous for clinical studies. D1 inhibition was significantly reduced in patients with MND. CONCLUSIONS: Threshold tracking is useful and may be preferable under some conditions for studying the excitability of the motoneurone pool. The decreased D1 inhibition in the patients suggests that presynaptic inhibition may be reduced in MND. SIGNIFICANCE: Reduced presynaptic inhibition could be evidence of an interneuronopathy in MND. It is possible that the hyperreflexia is a spinal pre-motoneuronal disorder, and not definitive evidence of corticospinal involvement in MND.

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis.

KEY POINTS: •Amyotrophic lateral sclerosis (ALS) motoneurons become hypoexcitable with disease progression in experimental models, raising questions about the neural hyperexcitability supported by clinical observations. •A variant of the ∆F method, based on motor unit discharge frequency modulations during recruitment and derecruitment, has been developed to investigate the motoneuron capacity to self-sustained discharge in patients. •The modulation of motor unit firing rate during ramp contraction and vibration-induced recruitment are modified in ALS, suggesting lower motoneuron capacity to self-sustained discharge, which is a sign of hypoexcitability. •∆F-D decreases with functional impairment and its reduction is more pronounced in fast progressors. •In patients with ALS, motoneurons exhibit hypoexcitability, which increases with disease progression. ABSTRACT: Experimental models have primarily revealed spinal motoneuron hypoexcitability in amyotrophic lateral sclerosis (ALS), which is contentious considering the role of glutamate-induced excitotoxicity in neurodegeneration and clinical features rather supporting hyperexcitability. This phenomenon was evaluated in human patients by investigating changes in motor unit firing during contraction and relaxation. Twenty-two ALS patients with subtle motor deficits and 28 controls performed tonic contractions of extensor carpi radialis, triceps brachialis, tibialis anterior and quadriceps, aiming to isolate a low-threshold unit (U1) on the electromyogram (EMG). Subsequently, they performed a stronger contraction or tendon vibration was delivered, to recruit higher threshold unit (U2) for 10 s before they relaxed progressively. EMG and motor unit potential analyses suggest altered neuromuscular function in all muscles, including those with normal strength (Medical Research Council score at 5). During the preconditioning tonic phase, U1 discharge frequency did not differ significantly between groups. During recruitment, the increase in U1 frequency (∆F-R) was comparable between groups both during contraction and tendon vibration. During derecruitment, the decrease in U1 frequency (∆F-D) was reduced in ALS regardless of the recruitment mode, particularly for ∆F-R <8 Hz in the upper limbs, consistent with the muscle weakness profile of the group. ∆F-D was associated with functional disability and its reduction was more pronounced in patients with more rapid disease progression rate. This in vivo study has demonstrated reduced motoneuron capacity for self-sustained discharge, and further supports that motoneurons are normo- to hypoexcitable in ALS patients, similar to observations in experimental models.

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study.

OBJECTIVE: C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers. METHODS: Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age. RESULTS: At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline. INTERPRETATION: Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.

Effects of Hand Configuration on the Grasping, Holding, and Placement of an Instrumented Object in Patients With Hemiparesis.

Objective: Limitations with manual dexterity are an important problem for patients suffering from hemiparesis post stroke. Sensorimotor deficits, compensatory strategies and the use of alternative grasping configurations may influence the efficiency of prehensile motor behavior. The aim of the present study is to examine how different grasp configurations affect patient ability to regulate both grip forces and object orientation when lifting, holding and placing an object. Methods: Twelve stroke patients with mild to moderate hemiparesis were recruited. Each was required to lift, hold and replace an instrumented object. Four different grasp configurations were tested on both the hemiparetic and less affected arms. Load cells from each of the 6 faces of the instrumented object and an integrated inertial measurement unit were used to extract data regarding the timing of unloading/loading phases, regulation of grip forces, and object orientation throughout the task. Results: Grip forces were greatest when using a palmar-digital grasp and lowest when using a top grasp. The time delay between peak acceleration and maximum grip force was also greatest for palmar-digital grasp and lowest for the top grasp. Use of the hemiparetic arm was associated with increased duration of the unloading phase and greater difficulty with maintaining the vertical orientation of the object at the transitions to object lifting and object placement. The occurrence of touch and push errors at the onset of grasp varied according to both grasp configuration and use of the hemiparetic arm. Conclusion: Stroke patients exhibit impairments in the scale and temporal precision of grip force adjustments and reduced ability to maintain object orientation with various grasp configurations using the hemiparetic arm. Nonetheless, the timing and magnitude of grip force adjustments may be facilitated using a top grasp configuration. Conversely, whole hand prehension strategies compound difficulties with grip force scaling and inhibit the synchrony of grasp onset and object release.

Closed-Loop Control of the Centre of Pressure in Post-Stroke Patients With Balance Impairments.

When a lightly touched surface is moved according to a closed-loop control law, it has been shown in young adults that the centre of pressure (CoP) can be displaced in a controllable way without the conscious cooperation of participants. In this closed-loop paradigm, the surface velocity was continuously adjusted according to the CoP position. Since the closed-loop control of the CoP does not require the participant's voluntary cooperation, it could be of interest for the development of innovative biofeedback devices in balance rehabilitation. Before anticipating the implementation of this closed-loop control paradigm with patients, it is necessary to establish its effects on people suffering from balance impairments. The aim of this paper was to assess the effects of this CoP closed-loop control in post-stroke (PS) patients and aged-matched healthy controls. Efficacy of the closed-loop control for driving the patients' CoP was assessed using the saturation time and two scores computing the error between the predefined and the current CoP trajectories. 68% and 83% of the trials were considered as successful in patients and controls, respectively. The global tracking error of the closed-loop score was similar between the two groups. However, when examining the real CoP displacement from the starting position to the desired one, PS patients responded to the closed-loop control to a lesser extent than controls. These results, obtained in the same conditions for healthy and PS individuals could be improved by tuning the closed-loop parameters according to individual characteristics. This paper paves the road towards the development of involuntary/automatic biofeedback techniques in more ecological conditions.

The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. METHODS: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. RESULTS: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. CONCLUSIONS: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.

Biomarkers of Spinal and Bulbar Muscle Atrophy (SBMA): A Comprehensive Review.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, X-linked, late onset neuromuscular disorder. The disease is caused by a CAG trinucleotide repeat expansion in the first exon of the androgen receptor gene. It is characterized by slowly progressive lower motor neurons degeneration, primary myopathy and widespread multisystem involvement. Respiratory involvement is rare, and the condition is associated with a normal life expectancy. Despite a plethora of therapeutic studies in mouse models, no effective disease-modifying therapy has been licensed for clinical use to date. The development of sensitive monitoring markers for the particularly slowly progressing pathology of SBMA is urgently required to aid future clinical trials. A small number of outcome measures have been proposed recently, including promising biochemical markers, which show correlation with clinical disability and disease-stage and progression. Nevertheless, a paucity of SBMA-specific biomarker studies persists, delaying the development of monitoring markers for pharmaceutical trials. Collaborative efforts through international consortia and multicenter registries are likely to contribute to the characterization of the natural history of the condition, the establishment of disease-specific biomarker panels and ultimately contribute to the development of disease-modifying drugs.

The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy.

OBJECTIVE: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX). METHODS: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated. RESULTS: SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis. CONCLUSIONS: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability. SIGNIFICANCE: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.

Evidence for a Supraspinal Contribution to the Human Crossed Reflex Response During Human Walking.

In humans, an ipsilateral tibial nerve (iTN) stimulation elicits short-latency-crossed-responses (SLCR) comprised of two bursts in the contralateral gastrocnemius lateralis (cGL) muscle. The average onset latency has been reported to be 57-69 ms with a duration of 30.4 ± 6.6 ms. The aim of this study was to elucidate if a transcortical pathway contributes to the SLCR. In Experiment 1 (n = 9), single pulse supra-threshold transcranial magnetic stimulation (supraTMS) was applied alone or in combination with iTN stimulation (85% of the maximum M-wave) while participants walked on a treadmill (delay between the SLCR and the motor evoked potentials (MEP) varied between -30 and 200 ms). In Experiment 2 (n = 6), single pulse sub-threshold TMS (subTMS) was performed and the interstimulus interval (ISI) varied between 0-30 ms. In Experiment 3, somatosensory evoked potentials (SEPs) were recorded during the iTN stimulation to quantify the latency of the resulting afferent volley at the cortical level. SLCRs and MEPs in cGL occurred at 63 ± 6 ms and 29 ± 2 ms, respectively. The mean SEP latency was 30 ± 3 ms. Thus, a transcortical pathway could contribute no earlier than 62-69 ms (SEP+MEP+central-processing-delay) after iTN stimulation. Combined iTN stimulation and supraTMS resulted in a significant MEP extra-facilitation when supraTMS was timed so that the MEP would coincide with the late component of the SLCR, while subTMS significantly depressed this component. This is the first study that demonstrates the existence of a strong cortical control on spinal pathways mediating the SLCR. This likely serves to enhance flexibility, ensuring that the appropriate output is produced in accord with the functional demand.

Abnormal cortical brain integration of somatosensory afferents in ALS.

OBJECTIVES: Infraclinical sensory alterations have been reported at early stages of amyotrophic lateral sclerosis (ALS). While previous studies mainly focused on early somatosensory evoked potentials (SEPs), late SEPs, which reflect on cortical pathways involved in cognitive-motor functions, are relatively underinvestigated. Early and late SEPs were compared to assess their alterations in ALS. METHODS: Median and ulnar nerves were electrically stimulated at the wrist, at 9 times the perceptual threshold, in 21 ALS patients without clinical evidence of sensory deficits, and 21 age- and gender-matched controls. SEPs were recorded at the Erb point using surface electrodes and using a needle inserted in the scalp, in front of the primary somatosensory area (with reference electrode on the ear lobe). RESULTS: Compared to controls, ALS patients showed comparable peripheral (N9) and early cortical component (N20, P25, N30) reductions, while the late cortical components (N60, P100) were more depressed than the early ones. CONCLUSIONS: The peripheral sensory alteration likely contributed to late SEP depression to a lesser extent than that of early SEPs. SIGNIFICANCE: Late SEPs may provide new insights on abnormal cortical excitability affecting brain areas involved in cognitive-motor functions.

Corticospinal control from M1 and PMv areas on inhibitory cervical propriospinal neurons in humans.

Inhibitory propriospinal neurons with diffuse projections onto upper limb motoneurons have been revealed in humans using peripheral nerve stimulation. This system is supposed to mediate descending inhibition to motoneurons, to prevent unwilling muscle activity. However, the corticospinal control onto inhibitory propriospinal neurons has never been investigated so far in humans. We addressed the question whether inhibitory cervical propriospinal neurons receive corticospinal inputs from primary motor (M1) and ventral premotor areas (PMv) using spatial facilitation method. We have stimulated M1 or PMv using transcranial magnetic stimulation (TMS) and/or median nerve whose afferents are known to activate inhibitory propriospinal neurons. Potential input convergence was evaluated by studying the change in monosynaptic reflexes produced in wrist extensor electromyogram (EMG) after isolated and combined stimuli in 17 healthy subjects. Then, to determine whether PMv controlled propriospinal neurons directly or through PMv-M1 interaction, we tested the connectivity between PMv and propriospinal neurons after a functional disruption of M1 produced by paired continuous theta burst stimulation (cTBS). TMS over M1 or PMv produced reflex inhibition significantly stronger on combined stimulations, compared to the algebraic sum of effects induced by isolated stimuli. The extra-inhibition induced by PMv stimulation remained even after cTBS which depressed M1 excitability. The extra-inhibition suggests the existence of input convergence between peripheral afferents and corticospinal inputs onto inhibitory propriospinal neurons. Our results support the existence of direct descending influence from M1 and PMv onto inhibitory propriospinal neurons in humans, possibly though direct corticospinal or via reticulospinal inputs.