Anticipatory postural adjustments stabilise the whole upper-limb prior to a gentle index \ufb01nger tap

Abstract Little is known about anticipatory postural adjustments (APAs) developing when body segments of tiny mass are moved. Thus, APAs in the human upper-limb were investigated during a gentle and small index \ufb01nger tap (35 mm stroke in 50 ms). This task was ful\ufb01lled by ten subjects either with prone or supine hand. EMG was recorded from Flexor Digitorum Super\ufb01cialis (FDS), the prime mover, and from several upper-limb muscles under slight tonic contraction. Regardless of hand posture, EMG was inhibited in Flexor Carpi Radialis and facilitated in Extensor Carpi Radialis well before the FDS burst. With the prone hand, the prime mover activity was preceded by Biceps inhibition and Triceps facilitation; this effect reverted in sign with the supine hand. A postural reversal was also observed in Anterior Deltoid and Trapezius which were both inhibited with the prone hand. The effect in Trapezius was present only with the unsupported forearm. It is thus demonstrated that a gentle small \ufb01nger tap produces well-de\ufb01ned anticipatory natural synergies behaving as the most \u2018\u2018classical\u2019\u2019 APAs: (1) they are distributed to several upper-limb muscles creating a postural chain aiming to prevent the effects of the interaction torques generated by the voluntary movement; (2) they change in amplitude according to the level of postural stability and (3) they revert in sign when movement direction is reverted. These results are also corroborated by data obtained from a simple mechanical model simulating \ufb01nger tapping in a \ufb01ctive upper-limb. A possible role of APAs in controlling movements\u2019 accuracy is also discussed

Mechanical and focal electrical stimuli applied to the skin of the index fingertip induce both inhibition and excitation in low-threshold flexor carpi radialis motor units

It has been observed that mechanical stimulation of the skin of the index fingertip causes a weak short-latency inhibition followed by a strong long-lasting facilitation of the flexor carpi radialis (FCR) H-reflex. Based on threshold and latency, these cutaneous reflexes are thought to be routed to motoneurons by parallel pathways. As recent studies have shown predominant inhibitory potentials in slow motoneurons and predominant excitatory potentials in faster ones, the question arises as to whether or not the two cutaneous pathways converge onto the same motoneuron. The poststimulus time histogram technique was used to investigate the changes in firing frequency of low-threshold FCR motor units (MUs), induced by passive mechanical or focal electrical stimuli to the index skin. After gently tapping the finger pulp a small sharp inhibition appeared in 20 MUs. On average, inhibition started 10.2 +/- 1.6 ms from the homonymous Ia monosynaptic effect, and its central delay was estimated to be 1.2 +/- 1.6 ms. The subsequent facilitation, more consistent, had a mean latency of 13.5 +/- 1.7 ms. Inhibition and excitation were statistically significant (P < 0.05). A similar biphasic effect was observed in seven other FCR-MUs, also after focal electrical stimulation of the same skin area. Comparison with the time course of the H-reflex, representing the whole population of MUs, showed striking similarities in time course and latency to the present MU effect. It is thus suggested that cutaneous spinal pathways may have a homogeneous distribution within the FCR motoneuron pool, and that the skewed distribution of cutaneous afferents onto motoneurons should be not taken as a ruleIt has been observed that mechanical stimulation of the skin of the index fingertip causes a weak short-latency inhibition followed by a strong long-lasting facilitation of the flexor carpi radialis (FCR) H-reflex. Based on threshold and latency, these cutaneous reflexes are thought to be routed to motoneurons by parallel pathways. As recent studies have shown predominant inhibitory potentials in slow motoneurons and predominant excitatory potentials in faster ones, the question arises as to whether or not the two cutaneous pathways converge onto the same motoneuron. The poststimulus time histogram technique was used to investigate the changes in firing frequency of low-threshold FCR motor units (MUs), induced by passive mechanical or focal electrical stimuli to the index skin. After gently tapping the finger pulp a small sharp inhibition appeared in 20 MUs. On average, inhibition started 10.2 \ub1 1.6 ms from the homonymous Ia monosynaptic effect, and its central delay was estimated to be 1.2 \ub1 1.6 ms. The subsequent facilitation, more consistent, had a mean latency of 13.5 \ub1 1.7 ms. Inhibition and excitation were statistically significant (P < 0.05). A similar biphasic effect was observed in seven other FCR-MUs, also after focal electrical stimulation of the same skin area. Comparison with the time course of the H-reflex, representing the whole population of MUs, showed striking similarities in time course and latency to the present MU effect. It is thus suggested that cutaneous spinal pathways may have a homogeneous distribution within the FCR motoneuron pool, and that the skewed distribution of cutaneous afferents onto motoneurons should be not taken as a rule

A randomized controlled trial on the effects induced by robot-assisted and usual-care rehabilitation on upper limb muscle synergies in post-stroke subjects

Muscle synergies are hypothesized to reflect connections among motoneurons in the spinal cord activated by central commands and sensory feedback. Robotic rehabilitation of upper limb in post-stroke subjects has shown promising results in terms of improvement of arm function and motor control achieved by reassembling muscle synergies into a set more similar to that of healthy people. However, in stroke survivors the potentially neurophysiological changes induced by robot-mediated learning versus usual care have not yet been investigated. We quantified upper limb motor deficits and the changes induced by rehabilitation in 32 post-stroke subjects through the movement analysis of two virtual untrained tasks of object placing and pronation. The sample analyzed in this study is part of a larger bi-center study and included all subjects who underwent kinematic analysis and were randomized into robot and usual care groups. Post-stroke subjects who followed robotic rehabilitation showed larger improvements in axial-to-proximal muscle synergies with respect to those who underwent usual care. This was associated to a significant improvement of the proximal kinematics. Both treatments had negative effects in muscle synergies controlling the distal district. This study supports the definition of new rehabilitative treatments for improving the neurophysiological recovery after stroke

Emotional training of facial nerve palsy : a preliminary report

Introduction: Differently from limb muscles, facial muscles motoneurons can be recruited by two descending motor pathways, one arising from the primary motor cortex and the second arising from the midcingulate area (1). Lesions involving the former pathway are associated to voluntary facial paresis, while lesions involving the latter are associated to emotional paresis (2). Patients suffering a voluntary facial paresis cannot voluntary smile, but for example they smile normally in response to jokes. On the contrary, patients suffering an emotional paresis can voluntarily mimic facial expressions, but are unable to produce spontaneous emotional expressions. During rehabilitation after facial nerve lesion, patients are commonly trained to produce symmetric and isolated voluntary movements [e.g. neuromuscular retraining (3)]. In this work we used emotional activation to train facial muscles after peripheral facial nerve palsy, according to the hypothesis that midcingulate area in addition to the primary motor cortex can participate to the motor recovery after facial nerve lesion. Materials: Tue House-Brackmann scale (HBS) was used to evaluate facial symmetry and synkinesis, both before and after the rehabilitation program. Methods: Ten patients (36-76 years) suffering a facial nerve lesion (6 Bell's palsy, 2 Ramsay Hunt syndrome, 2 post-surgery palsy) underwent up to 20 physiotherapy sessions. Each session ( 45 minutes long) was led by a physiotherapist. Consecutive sessions were kept at least 3 days apart. The emotional activation of the paretic facial muscles was obtained by asking patients to recall pleasant memories. Patients were guided by the therapist in increasing their awareness of the emotion-evoked movement by concentrating on kinesthesis. Results: On average, patients started the rehabilitation 80 days after the nerve lesion. At the beginning of the rehabilitation program, patients suffered a moderate facial asymmetry according to the HBS (median HBS score: 3.5; IQR: 3). At the end of the rehabilitation program, HBS score median was reduced to 1 (IQR: 1), indicating a more symmetric face and less severe synkinesis (Wilcoxon test, p = 0.002). Ali patients improved their HBS score. Discussion: Emotional training, a form of repetitive task-specific training, seems beneficial for people receiving rehabilitation following facial nerve lesion. Tue neural network mediating the emotional training effects could include structures of the limbic system such as the amygdala which are known to project to the facial muscle motoneurons via the midcingulate area (1). Conclusion: Emotional training of facial muscles led by a physiotherapist is a promising tool for rehabilitation after facial nerve lesions. References: 1. Morecraft RJ, Louie JL, Herrick JL, Stilwell-Morecraft KS. Cortical innervation of the facial nucleus in the non-human primate: a new interpretation of the effects of stroke and related subtotal brain trauma on the muscles of facial expression. Brain (2001);124:176-208 2. Gothard KM. Tue amygdalo-motor pathways and the control of facial expressions. Front Neurosci. (2014); 19(8):43 3. Nicastri M, Mancini P, De Seta D, Bertoli G, Prosperini L, Toni D, lnghilleri M, Filipo R. Efficacy of early physical therapy in severe Bell's palsy: a randomized controlled trial. Neurorehabil Neural Repair. (2013);27(6):542-5

CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors

Lung tumor-infiltrating neutrophils are known to support growth and dissemination of cancer cells and to suppress T cell responses. However, the precise impact of tissue neutrophils on programming and differentiation of anticancer CD8 T cells in vivo remains poorly understood. Here, we identified cancer cell-autonomous secretion of CXCL5 as sufficient to drive infiltration of mature, protumorigenic neutrophils in a mouse model of non-small cell lung cancer (NSCLC). Consistently, CXCL5 transcripts correlate with neutrophil density and poor prognosis in a large human lung adenocarcinoma compendium. CXCL5 genetic deletion, unlike antibody-mediated depletion, completely and selectively prevented neutrophils accumulation in lung tissues. Depletion of tumor-infiltrating neutrophils promoted expansion of tumor-specific CD8 T cells, differentiation into effector cells and acquisition of cytolytic functions. Transfer of effector CD8 T cells into neutrophil-rich tumors, inhibited IFN-ϒ production, indicating active suppression of effector functions. Importantly, blocking neutrophils infiltration in the lung, overcame resistance to checkpoint blockade. Hence, this study demonstrates that neutrophils curb acquisition of cytolytic functions in lung tumor tissues and suggests targeting of CXCL5 as a strategy to restore anti-tumoral T cell functions

Botulinum Toxin Injections Reduce Associative Plasticity in Patients with Primary Dystonia

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long-term potentiation-like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation-evoked motor evoked potentials before and after paired associative stimulation. We also measured the input-output curve, short-interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. (C) 2011 Movement Disorder Societ

Inhibitory APAs observed in several upper limb muscles prior to index tapping are shaped by supraspinal inhibitory circuits

We previously observed that index tapping is anticipated by inhibitory postural adjustments (iAPA) in the ongoing EMG of several upper limb muscles, including Biceps Brachii (BB) and Superior Trapezius (ST). Aim of the present work is to investigate the spinal and supra-spinal contribution to this effect. This has been tested by probing changes in cortico-spinal excitability, by means of TMS motor evoked potential (MEP) and changes in spinal excitability, by means of T-reflex, during iAPA development. Index tapping was triggered by an acoustic signal, while EMG from the prime mover and from BB or ST was recorded by surface electrodes. MEP or T-reflexes elicited in the relaxed postural muscle (BB or ST), with latency ranging -2000 to +300ms from index flexion, were collected and their peak to peak amplitude measured. In the various subjects (9), with the hand prone and the postural muscle contracted, a clear inhibition of both BB and ST EMG started in average 50+/-23ms before the prime mover onset; in contrast, as expected, when postural muscles were relaxed no inhibitory effect was seen. However, all MEPs falling in the iAPA temporal window were reduced in amplitude, while T-reflexes were unaffected. In each subject, statistical analysis (t-test comparing MEP or T amplitude in the iAPA window versus the responses falling prior to the go-signal) gave significance to this effect (p<0.02). Moreover a high correlation (p<0.01) was found only between the ongoing EMG amplitude and the MEP amplitude in the relaxed muscle. Lastly, on average, MEP inhibition developed 98+/-33ms before the prime mover onset, i.e. about 50ms prior to the iAPA onset. These results show i) that when motoneurons are not firing, iAPAs are still associated to the motor command although under threshold, and ii) that during the iAPA spinal motoneurons are more likely disfacilitated than inhibited. Thus, iAPAs seem to be fully sustained by inhibitory circuits located in the supraspinal centres

Supra-spinal circuits shape inhibitory postural adjustments anticipating voluntary index-finger flexion

We previously observed that index finger flexion, with the prone hand, is preceded by an inhibitory postural adjustment (iAPA) in the Biceps Brachii (BB) electromyogram (EMG). The aim of this work is to locate the iAPA origin by testing the changes in spinal and cortico-spinal excitability during its development. Subjects were asked to flex their index finger, at will after an acoustic signal, while surface EMGs from Flexor Digitorum Superficialis (prime mover) and from BB (postural muscle) were recorded. In each experiment, tendon (T) reflexes in the resting BB and motor-evoked potentials elicited by magnetic cortical stimulation (CMEPs) in the resting, or in the slightly contracted BB, were collected both during the iAPA development and before the go signal. When BB was fully relaxed, T-reflexes falling in the iAPA temporal window were un-modulated, while CMEPs were significantly inhibited; this inhibition occurred, on average, 37 ms before the iAPA onset indicating that iAPA sets up and develops at supraspinal level. Changes in CMEPs' excitability clearly anticipated the iAPA onset (about 50 ms) also when cortico-spinal excitability was probed in the active BB, thus indicating that this effect is likely due to a de-recruitment of spinal motoneurones. Thus, (1) iAPA is associated with voluntary movement even when postural muscles are at rest, (2) during iAPA spinal motoneurones are more likely disfacilitated than inhibited, and (3) the iAPA timing is regulated similarly to prime mover activation. All together these results suggest that iAPAs is fully sustained by inhibitory circuits located in the supra-spinal centres