Spasticity

The elimination of ground reaction force (support withdrawal) vastly affects slow postural muscles in terms of their regulation and structure. One of the effects of support withdrawal in this study was an immediate postural muscle inactivation, followed by the daily gradual development of spontaneous activity of the slow postural soleus muscle in response to rat hindlimb suspension to mimic space flight. The origin of this activity is somewhat akin to muscle spasticity after spinal cord injuries and is the result of KCC2 content decline in the spinal cord’s motor neurons. However, the physiological consequences of unloading-induced spontaneous activity remain unexplored. We have conducted an experiment with the administration of a highly specific KCC2 activator during 7-day unloading. For this experiment, 32 male Wistar rats were divided into 4 groups: C+placebo, C+CLP-290 (100 mg/kg b w), 7HS+placebo, and 7HS+CLP—hindlimb-suspended group with CLP-290 administration (100 mg/kg b w). The soleus muscles of the animals were dissected and analyzed for several proteostasis- and metabolism-related parameters. CLP-290 administration to the unloaded animals led to the upregulation of AMPK downstream (p-ACC) and mTOR targets (p-p70S6k and p-4E-BP) and an enhanced PGC1alpha decrease vs. the 7HS group, but neither prevented nor enhanced atrophy of the soleus muscle or myofiber CSA.

Background Investigating the spatial distribution of muscle activity would facilitate understanding the underlying mechanism of spasticity. The purpose of this study is to investigate the characteristics of spastic muscles during passive stretch and active contraction by high-density surface electromyography (HD-sEMG). Methods Fourteen spastic hemiparetic subjects and ten healthy subjects were recruited. The biceps brachii (BB) muscle activity of each subject was recorded by HD-sEMG during passive stretch at four stretch velocities (10, 60, 120, 180°/s) and active contraction at three submaximal contraction levels (20, 50, 80%MVC). The intensity and spatial distribution of the BB activity were compared by the means of two-way analysis of variance, independent sample t-test, and paired sample t-test. Results Compared with healthy subjects, spastic hemiparetic subjects showed significantly higher intensity with velocity-dependent heterogeneous activation during passive stretch and more lateral and proximal activation distribution during active contraction. In addition, spastic hemiparetic subjects displayed almost non-overlapping activation areas during passive stretch and active contraction. The activation distribution of passive stretch was more distal when compared with the active contraction. Conclusions These alterations of the BB activity could be the consequence of deficits in the descending central control after stroke. The complementary spatial distribution of spastic BB activity reflected their opposite motor units (MUs) recruitment patterns between passive stretch and active contraction. This HD-sEMG study provides new neurophysiological evidence for the spatial relationship of spastic BB activity between passive stretch and active contraction, advancing our knowledge on the mechanism of spasticity.

Purpose: The effective relief of muscle spasticity requires prompt solutions in rehabilitation medicine. This study aimed to reveal that the highest region of muscle spindle abundance is the optimal target of botulinum toxin A (BTX‑A) injections for relieve muscle spasm.

Methods: Sixty adult, male Sprague–Dawley rats with lower limbs spasm caused by stroke after modeling, weighing (200 ± 20) g, were included in this study. The model rats were divided into four groups: muscle spasm model group (group A), model rats treated with BTX‑A injections into the middle of the muscle belly (group B), model rats treated with BTX‑A injections into the center of the intramuscular nerve‑dense region (INDR) (group C), and model rats treated with BTX‑A injection into the center of the highest region of muscle spindle abundance (HRMSA) (group D). Groups B, C, and D were further divided into two subgroups: the 3rd and 6th days after BTX‑A injection. The rats in each group were assigned modified Ashworth scale scores (MAS), and the changes in gastrocnemius muscle tone, wet muscle weight, and cross‑sectional area of muscle fiber were detected.

Results: Muscle spindle abundance was the highest in the upper part of the INDR. Group B experienced no significant changes in MAS, muscle tone, wet muscle weight, or cross‑sectional area of the muscle fiber. Conversely, groups C and D experienced a decrease in these indicators. Group C experienced the most significant decrease in wet muscle weight and cross‑sectional area of muscle fibers. Group D experienced the most notable decrease in MAS and muscle tone. There were no significant differences in the indicators between the 3rd and 6th days after BTX‑A injections in group B and there were significant differences in the improvement in the indicators between the two subgroups in groups C and D, with group D experiencing more notable intersubgroup differences.

Conclusion: The efficacy of BTX‑A injections into the HRMSA is significantly superior to that of conventional BTX‑A injections into the middle of the belly muscle or the INDR in the treatment of muscle spasms. Hence, HRMSA should be the optimal target of BTX‑A to relieve muscle spasms.

Background Investigating the spatial distribution of muscle activity would facilitate understanding the underlying mechanism of spasticity. The purpose of this study is to investigate the characteristics of spastic muscles during passive stretch and active contraction by high-density surface electromyography (HD-sEMG). Methods Fourteen spastic hemiparetic subjects and ten healthy subjects were recruited. The biceps brachii (BB) muscle activity of each subject was recorded by HD-sEMG during passive stretch at four stretch velocities (10, 60, 120, 180°/s) and active contraction at three submaximal contraction levels (20, 50, 80%MVC). The intensity and spatial distribution of the BB activity were compared by the means of two-way analysis of variance, independent sample t-test, and paired sample t-test. Results Compared with healthy subjects, spastic hemiparetic subjects showed significantly higher intensity with velocity-dependent heterogeneous activation during passive stretch and more lateral and proximal activation distribution during active contraction. In addition, spastic hemiparetic subjects displayed almost non-overlapping activation areas during passive stretch and active contraction. The activation distribution of passive stretch was more distal when compared with the active contraction. Conclusions These alterations of the BB activity could be the consequence of deficits in the descending central control after stroke. The complementary spatial distribution of spastic BB activity reflected their opposite motor units (MUs) recruitment patterns between passive stretch and active contraction. This HD-sEMG study provides new neurophysiological evidence for the spatial relationship of spastic BB activity between passive stretch and active contraction, advancing our knowledge on the mechanism of spasticity.

Overt muscle activity and impaired spinal locomotor control hampering coordinated movement is a hallmark of spasticity and movement disorders like dystonia. While botulinum toxin A (BoNT-A) standard therapy alleviates mentioned symptoms presumably due to its peripheral neuromuscular actions alone, the aim of present study was to examine for the first time the toxin’s trans‑synaptic activity within central circuits that govern the skilled movement. The rat hindlimb motor pools were targeted by BoNT‑A intrasciatric bilateral injection (2 U per nerve), while its trans‑synaptic action on premotor inputs was blocked by intrathecal BoNT‑A–neutralising antitoxin (5 i.u.). Effects of BoNT‑A on coordinated and high intensity motor tasks (rotarod, beamwalk swimming), and localised muscle weakness (digit abduction, gait ability) were followed until their substantial recovery by day 56 post BoNT‑A. Later, (day 62–77) the BoNT‑A effects were examined in unilateral calf muscle spasm evoked by tetanus toxin (TeNT, 1.5 ng). In comparison to peripheral effect alone, combined peripheral and central trans‑synaptic BoNT‑A action induced a more prominent and longer impairment of different motor tasks, as well as the localised muscle weakness. After near‑complete recovery of motor functions, the BoNT‑A maintained the ability to reduce the experimental calf spasm evoked by tetanus toxin (TeNT 1.5 ng, day 62) without altering the monosynaptic reflex excitability. These results indicate that, in addition to muscle terminals, BoNT‑A‑mediated control of hyperactive muscle activity in movement disorders and spasticity may involve the spinal premotor inputs and central circuits participating in the skilled locomotor performance.

Botulinum toxin-A (BTX) administration into muscle is an established treatment for conditions with excessive muscle contraction. However, botulinum therapy has short-term effectiveness, and high-dose injection of BTX could induce neutralizing antibodies against BTX. Therefore, prolonging its effects could be beneficial in a clinical situation. Insulin-like growth factor-1 receptor (IGF1R) and its ligands, insulin-like growth factor (IGF) ‑I and II, regulate the physiological and pathological processes of the nervous system. It has been suggested that IGF1R is involved in the process after BTX administration, but the specific regeneration mechanism remains unclear. Therefore, this study aimed to determine how inhibition of IGF1R signaling pathway affects BTX-induced muscle paralysis. The results showed that anti-IGF1R antibody administration inhibited the recovery from BTX-induced neurogenic paralysis, and the synaptic components at the neuromuscular junction (NMJ), mainly post-synaptic components, were significantly affected by the antibody. In addition, the wet weight or frequency distribution of the cross-sectional area of the muscle fibers was regulated by IGF1R, and sequential antibody administration following BTX treatment increased the number of Pax7+ satellite cells in the gastrocnemius (GC) muscle, independent of NMJ recovery. Moreover, BTX treatment upregulated mammalian target of rapamycin (mTOR)/S6 kinase signaling pathway, HDAC4, Myog, Fbxo32/MAFbx/Atrogin-1 pathway, and transcription of synaptic components, but not autophagy. Finally, IGF1R inhibition affected only mTOR/S6 kinase translational signaling in the GC muscle. In conclusion, the IGF1R signaling pathway is critical for NMJ regeneration via specific translational signals. IGF1R inhibition could be highly beneficial in clinical practice by decreasing the number of injections and total dose of BTX due to the prolonged duration of the effect.

Botulinum neurotoxin type-A (BoNT) injections are commonly used as spasticity treatment in cerebral palsy (CP). Despite improved clinical outcomes, concerns regarding harmful effects on muscle morphology have been raised, and the BoNT effect on muscle stem cells remains not well defined. This study aims at clarifying the impact of BoNT on growing muscles (1) by analyzing the in vitro effect of BoNT on satellite cell (SC)-derived myoblasts and fibroblasts obtained from medial gastrocnemius microbiopsies collected in young BoNT-naïve children (t0) compared to age ranged typically developing children; (2) by following the effect of in vivo BoNT administration on these cells obtained from the same children with CP at 3 (t1) and 6 (t2) months post BoNT; (3) by determining the direct effect of a single and repeated in vitro BoNT treatment on neuromuscular junctions (NMJs) differentiated from hiPSCs. In vitro BoNT did not affect myogenic differentiation or collagen production. The fusion index significantly decreased in CP at t2 compared to t0. In NMJ cocultures, BoNT treatment caused axonal swelling and fragmentation. Repeated treatments impaired the autophagic-lysosomal system. Further studies are warranted to understand the long-term and collateral effects of BoNT in the muscles of children with CP.

Purpose: The adductor pollicis muscle is frequently targeted for botulinum neurotoxin injective treatment for spasticity. However, there are no injective guidelines for delivering injection to the muscle.

Materials and Methods: A method known as the modified Sihler’s method was used to stain the adductor pollicis muscle in 16 specimens to reveal intramuscular neural distribution of the muscle.

Results: The most intramuscular neural distribution was located on 1/5 to 3/5 of the muscle regarding midline of 3rd metacarpal bone (0) to the base of the 1st proximal phalanx (5/5). The nerve entry point was mostly located on 0 to 1/5 of the muscle.

Conclusion: The result suggests that botulinum neurotoxin should be delivered at the middle of second metacarpal bone via deep injection.

In this study, using immunohistochemistry with fresh cadavers, deliberate histological profiling was performed to determine which fibers are predominant within each compartment. To verify the fascial compartmentation of the SSC and elucidate its histological components of type I and II fibers using macroscopic, histological observation and cadaveric simulation for providing an anatomical reference of efficient injection of the BoNT into the SSC. Seven fixed and three fresh cadavers (six males and four females; mean age, 82.5 years) were used in this study. The dissected specimens revealed a distinct fascia demarcating the SSC into the superior and inferior compartments. The Sihler’s staining revealed that the upper and lower subscapular nerves (USN and LSN) innervated the SSC, with two territories distributed by each nerve, mostly corresponding to the superior and inferior compartments of the muscle, although there were some tiny communicating twigs between the USN and LSN. The immunohistochemical stain revealed the density of each type of fiber. Compared with the whole muscle area, the densities of the slow-twitch type I fibers were 22.26 ± 3.11% (mean ± SD) in the superior and 81.15 ± 0.76% in the inferior compartments, and the densities of the fast-twitch type II fiber were 77.74% ± 3.11% in the superior and 18.85 ± 0.76% in the inferior compartments. The compartments had different proportions of slow-fast muscle fibers, corresponding to the functional differences between the superior compartment as an early-onset internal rotator and the inferior compartment as a durable stabilizer of the glenohumeral joint.

Background Out-of-hospital cardiac arrest (OHCA) is one of the most dramatic events in pediatric age and, despite advanced neurointensive care, the survival rate remains low. Currently, no effective treatments can restore neuronal loss or produce significant improvement in these patients. Nerve Growth Factor (NGF) is a neurotrophin potentially able to counteract many of the deleterious effects triggered by OHCA. Transcranial Direct Current Stimulation (tDCS) has been reported to be neuroprotective in many neurological diseases, such as motor deficit and cognitive impairment. Children with the diagnosis of chronic vegetative state after OHCA were enrolled. These patients underwent a combined treatment of intranasal administration of human recombinant NGF (hr‑NGF), at a total dose of 50δ/kg, and tDCS, in which current intensity was increased from zero to 2 mA from the first 5 s of stimulation and maintained constant for 20 min. The treatment schedule was performed twice, at one month distance each. Neuroradiological evaluation with Positron Emission Tomography scan (PET), Single Photon Emission Computed Tomography (SPECT), Electroencephalography (EEG) and Power Spectral Density of the brain (PSD) was determined before the treatment and one month after the end. Neurological assessment was deepened by using modified Ashworth Scale, Gross Motor Function Measure, and Disability Rating Scale. Results Three children with a chronic vegetative state secondary to OHCA were treated. The combined treatment with hr‑NGF and tDCS improved functional (PET and SPECT) and electrophysiological (EEG and PSD) assessment. Also clinical conditions improved, mainly for the reduction of spasticity and with the acquisition of voluntary finger movements, improved facial mimicry and reaction to painful stimuli. No side effects were reported.

Intramuscular injections of botulinum toxin A (BTX) are regularly used to treat skeletal muscle spasticity and relieve pain during rehabilitation therapy. However, while numerous preclinical studies have shown dramatic atrophic changes in muscle, little is known about the long‑term effect of toxin on human skeletal muscle. In this study, muscle morphology was analyzed in biopsies taken from spastic upper extremity muscles of 8 cerebral palsy patients treated with BTX 5 months to 4 years prior sampling and was compared to muscles from 7 patients who had not ever received BTX treatment (overall 25 muscle biopsies obtained from 6 different muscles.). The most important (and surprising) finding was that BTX‑treated muscles contained significantly larger fibers compared to untreated muscles. A strong correlation between fiber size and age was observed but the growth rate in the BTX group was larger. Pathological signs such as central nuclei, neonatal myosin heavy chain expression, angular fibers and hybrid fibers (expressing both slow and fast myosin heavy chain fibers) were significantly greater in BTX‑treated muscles compared to untreated muscles. Capillarization was also increased in BTX‑treated muscle compared to untreated muscles and was the best predictor of fiber size. We suggest that, in the context of spasticity, BTX may block negative, atrophy‑inducing pressure of the central nervous system on skeletal muscle or may allow an altered use pattern that should be considered a positive adjuvant to current rehabilitation therapies.

Recent evidence suggests that the vagus nerve and autonomic dysfunction play an important role in the pathogenesis of Parkinson’s disease. Using heart rate variability analysis, the autonomic modulation of cardiac activity can be investigated. This meta-analysis aims to assess if analysis of heart rate variability may indicate decreased parasympathetic tone in patients with Parkinson’s disease. The MEDLINE, EMBASE and Cochrane Central databases were searched on 31 December 2020. Studies were included if they: (1) were published in English, (2) analyzed idiopathic Parkinson’s disease and healthy adult controls, and (3) reported at least one frequency- or time-domain heart rate variability analysis parameter, which represents parasympathetic regulation. We included 47 studies with 2772 subjects. Random-effects meta-analyses revealed significantly decreased effect sizes in Parkinson patients for the high-frequency spectral component (HFms²) and the short-term measurement of the root mean square of successive normal-to-normal interval differences (RMSSD). However, heterogeneity was high, and there was evidence for publication bias regarding HFms². There is some evidence that a more advanced disease leads to an impaired parasympathetic regulation. In conclusion, short-term measurement of RMSSD is a reliable parameter to assess parasympathetically impaired cardiac modulation in Parkinson patients. The measurement should be performed with a predefined respiratory rate.

Partial neurectomy of motor nerves has been shown to reduce spasticity in the target muscles. It is effective only on the spastic component of the deformity, underlining the need for a preliminary thorough clinical examination. Hyperselective neurectomy, which consists in following each motor ramus until its entry point into the target muscle, aims at improving selectivity, widespread partial denervation, and durability of the results.

The aims of this study were to localize the body surface position and depth of nerve entry points, and the center of the intramuscular nerve-dense regions of the pectoralis major and pectoralis minor in order to provide guidance for blocking muscle spasticity.

Aims Impaired autonomic nervous system regulation is frequently observed in patients with stroke. The aim of this prospective study was to evaluate the impact of cardiac autonomic tone on functional outcome after the early post-stroke rehabilitation.

Methods and results One hundred and three consecutive patients (67 ± 11 years, body mass index (BMI) 27.1 ± 5.4 kg/m², 64% men) with ischaemic (84% of patients) and haemorrhagic stroke were studied. Depressed heart rate variability (HRV), as a surrogate marker of increased sympathetic tone, was defined by the standard deviation of NN intervals < 100 ms and HRV triangular index ≤ 20 assessed from a 24 h Holter electrocardiogram at admission to rehabilitation (23 ± 16 days after stroke). Twenty-two per cent of patients had depressed HRV at baseline and were comparable with patients with normal HRV with regard to their functional [Barthel Index (BI), modified Rankin Scale (mRS), and Rivermead Motor Assessment (RMA)] and biochemical status. After a 4-week follow-up, 70% of patients with depressed HRV showed a cumulative functional disability, defined by mRS ≥ 4, BI ≤ 70, and RMA ≤ 5, in contrast to patients with normal HRV (35%, P = 0.003). Patients with depressed HRV showed a worse functional status by BI (−16%, P < 0.001), RMA (−12%, P < 0.05), and mRS (+16%, P < 0.01), compared with patients with normal HRV. Cumulative functional disability was associated with depressed HRV (odds ratio 4.25, 95% confidence interval 1.56–11.54, P < 0.005) after adjustment for age, sex, and body mass index (odds ratio 4.6, 95% confidence interval 1.42–14.97, P < 0.05).

Quantifying neural and non-neural contributions to the joint resistance in spasticity is essential for a better evaluation of different intervention strategies such as botulinum toxin A (BoTN-A). However, direct measurement of muscle mechanical properties and spasticity-related parameters in humans is extremely challenging. The aim of this study was to use a previously developed musculoskeletal model and optimization scheme to evaluate the changes of neural and non-neural related properties of the spastic wrist flexors during passive wrist extension after BoTN-A injection. Data of joint angle and resistant torque were collected from 21 chronic stroke patients before, and 4 and 12 weeks post BoTN-A injection using NeuroFlexor, which is a motorized force measurement device to passively stretch wrist flexors. The model was optimized by tuning the passive and stretch-related parameters to fit the measured torque in each participant. It was found that stroke survivors exhibited decreased neural components at 4 weeks post BoTN-A injection, which returned to baseline levels after 12 weeks. The decreased neural component was mainly due to the increased motoneuron pool threshold, which is interpreted as a net excitatory and inhibitory inputs to the motoneuron pool. Though the linear stiffness and viscosity properties of wrist flexors were similar before and after treatment, increased exponential stiffness was observed over time which may indicate a decreased range of motion of the wrist joint. Using a combination of modeling and experimental measurement, valuable insights into the treatment responses, i.e., transmission of motoneurons, are provided by investigating potential parameter changes along the stretch reflex pathway in persons with chronic stroke.

This study aimed to identify the location and depth of the center of intramuscular nerves dense regions (CINDRs) in anterior brachial muscles. Twelve adult cadavers were used. One side anterior brachial muscles were isolated and subjected to Sihler’s staining to show intramuscular nerve dense regions. Then the data was used to localize CINDRs in situ on the same muscles of the contralateral side. The localization method involved dissection and exposure of CINDRs, barium sulfate labeling, body surface reference line design, spiral computed tomography scan, three-dimensional image reconstruction, and Syngo system measurements. The number of CINDRs in coracobrachialis, biceps brachii and brachialis muscle were 3, 2 and 2, respectively. The body surface coordinates for the three CINDRs in coracobrachialis muscle were at 24.22%, 18.89% and 8.15% on the horizontal reference line and 21.37%, 31.78 and 30.07% on the longitudinal reference line. For biceps brachii muscle, they were at 49.68% and 40.28% on the horizontal reference line and 56.60% and 67.63% on the longitudinal reference line. For brachialis muscle, they were at 48.34% and 52.45% on the horizontal reference line and 71.30% and 81.62% on the longitudinal reference line. On cross-sectional planes, the depths of these CINDRs were at 22.81%, 26.76% and 27.99% (coracobrachialis); 14.79% and 17.45% (biceps); 34.03% and 30.26% (brachialis) of section diameters through CINDRs. These results may help to guide the injection of botulinum toxin A for the treatment of spasticity in the anterior brachial muscles and improve treatment efficacy and efficiency.

Botulin toxin (BTX) is widely used for treating skeletal muscle spasticity. Experimental reports on BTX treatment were mainly focused on the neuromuscular junction, while relatively little is known about toxin effects on the muscle cell itself. We investigated possible impact of BTX type A on skeletal muscle cell transcriptome by microarray analysis in muscle-derived cell cultures (fibroblasts, myoblasts and myotubes) from controls and spastic patients, and results were then validated at transcript and protein level.

BTX-A treatment of control cells induced major changes in the myogenic component of the transcriptome, whereas the same treatment had a negligible effect in the fibrogenic component. BTX-A treatment of cell cultures from spastic patients induced an increased number of genes differentially expressed both in the fibrogenic and myogenic components. Specifically, BTX-A had a major effect on cell cycle-related genes in myoblasts, on muscle contraction-related genes in myotubes, and on extracellular matrix-related genes in fibroblasts from spastic patients.

Our findings show that in vitro BTX-A treatment differentially affects transcript expression in muscle cells from spastic patients compared to those from controls suggesting a direct effect of BTX-A on muscle-specific functional pathways.

Background Spasticity and spastic dystonia are two separate phenomena of the upper motor neuron syndrome. Spasticity is clinically defined by velocity-dependent hypertonia and tendon jerk hyperreflexia due to the hyper-excitability of the stretch reflex. Spastic dystonia is the inability to relax a muscle leading to a spontaneous tonic contraction. Both spasticity and spastic dystonia are present in patients who are at rest; however, only patients with spasticity are actually able to kept their muscles relaxed prior to muscle stretch. The idea that has inspired the present work is that also in patients with spastic dystonia the stretch reflex is likely to be hyper-excitable. Therefore, velocity-dependent hypertonia could be mediated not only by spasticity, but also by spastic dystonia.

Muscle overactivity (spasticity, dystonia or spasm) seen in certain neuromuscular disorders has been effectively treated with intramuscular injection of botulinum neurotoxins (BTXs). Since they act in the nerve terminals, toxins must be transported to the neuromuscular junctions which are generally clustered in one or more restricted areas (innervations zone(s) (IZs)) in a skeletal muscle. Likewise, IZ targeted BTX injections using guidance is highly recommended to achieve an optimal therapeutic goal with lower doses and fewer side effects. Hence, detection of the injection sites should be based on the knowledge about the localization of the IZs and also the transport mechanism of BTX in skeletal muscle is crucial for intramuscular application of BTX. In this paper, IZ(s) of the skeletal muscles, distribution of BTX, proper sites and guidance for the injections are discussed taking into account the muscle structure and architecture.

Objective: To assess the prevalence of pain in adults with spasticity and to assess the association between the subjective experience of pain and spasticity. Design: Cross-sectional study. Setting: outpatient spasticity management clinic of a rehabilitation centre. Patients: Patients with upper motor neuron lesions and spasticity (n=131) were recruited. Methods: We assessed pain intensity and location, relationship between spasticity and pain perception, and perception of pain relief from botulinum toxin type-A (BoNTA) injections. Main outcome measures: Pain perception rated on a 10-point numerical rating scale and pain quality. Results: 65% of the patients with spasticity reported presence of pain and 60% described it as an aching pain. More patients reported pain with movement (34%) compared to rest (21%). There was a statistically poor correlation between the severity of pain and spasticity (r = 0.16; p<0.05). Most patients (80%) believed that their pain was related to spasticity and 62% reported that BoNTA injections decreased their pain. Conclusions: The high incidence of pain noted within our sample suggests that physicians may have to consider pain management as part of spasticity treatment. Participants reported that their pain was related to their spasticity, and that it decreased after BoNTA treatment. Further study is needed to explore the relationships between objective measures of spasticity and pain.

Background: Botulinum toxin type A manages spasticity disorders in neurological central diseases. Some studies have reported that it might induce muscle changes. Methods: We present a literature review abiding by the PRISMA statement guidelines. The purpose was to explore the structural and passive biomechanical muscle properties after botulinum toxin type A injections in healthy and spastic limb muscles, on animals and humans, as well as methods for evaluating these properties. We searched the PubMed and Cochrane Library databases using the following keywords: “Botulinum toxin” AND (“muscle structure” OR “muscle atrophy”) and, “Botulinum toxin” AND “muscle elasticity”. Results: From the 228 initially identified articles, 21 articles were included. Histological analyses were performed, especially on animals. A neurogenic atrophy systematically occurred. In humans, one year after a single injection, the histological recovery remained incomplete. Furthermore, 2D ultrasound analyses showed a reduction of the gastrocnemius thickness and pennation angle. MRI volumetric analysis evidenced muscular atrophy six months or one year after a single injection. Passive muscle stiffness depends on these structural changes. On the short term, the biomechanical analysis showed an elastic modulus increase in animals whereas no change was recorded in humans. On the short term, ultrasound elastography imaging showed a decreased elastic modulus.

Spasticity is one of many consequences after stroke. It is characterized by a velocity‑dependent increase in resistance during passive stretch, resulting from hyperexcitability of the stretch reflex. The underlying mechanism of the hyperexcitable stretch reflex, however, remains poorly understood. Accumulated experimental evidence has supported supraspinal origins of spasticity, likely from an imbalance between descending inhibitory and facilitatory regulation of spinal stretch reflexes secondary to cortical disinhibition after stroke. The excitability of reticulospinal (RST) and vestibulospinal tracts (VSTs) has been assessed in stroke survivors with spasticity using non‑invasive indirect measures. There are strong experimental findings that support the RST hyperexcitability as a prominent underlying mechanism of post‑stroke spasticity. This mechanism can at least partly account for clinical features associated with spasticity and provide insightful guidance for clinical assessment and management of spasticity. However, the possible role of VST hyperexcitability cannot be ruled out from indirect measures. In vivo measure of individual brainstem nuclei in stroke survivors with spasticity using advanced fMRI techniques in the future is probably able to provide direct evidence of pathogenesis of post‑stroke spasticity.

Background. Arm spasticity is a challenge in the care of chronic stroke survivors with motor deficits. In order to advance spasticity treatments, a better understanding of the mechanism of spasticity-related neuroplasticity is needed. Objective. To investigate brain function correlates of spasticity in chronic stroke and to identify specific regional functional brain changes related to rehabilitation-induced mitigation of spasticity. Methods. 23 stroke survivors (>6 months) were treated with an arm motor learning and spasticity therapy (5 d/wk for 12 weeks). Outcome measures included Modified Ashworth scale, sensory tests, and functional magnetic resonance imaging (fMRI) for wrist and hand movement. Results. First, at baseline, greater spasticity correlated with poorer motor function (P = 0.001) and greater sensory deficits (P = 0.003). Second, rehabilitation produced improvement in upper limb spasticity and motor function (P < 0.0001). Third, at baseline, greater spasticity correlated with higher fMRI activation in the ipsilesional thalamus (rho = 0.49, P = 0.03). Fourth, following rehabilitation, greater mitigation of spasticity correlated with enhanced fMRI activation in the contralesional primary motor (r = -00.755, P = 0.003), premotor (r = -0.565, P = 0.04), primary sensory (r = -0.614, P = 0.03), and associative sensory (r = -0.597, P = 0.03) regions while controlling for changes in motor function. Conclusions. Contralesional motor regions may contribute to restoring control of muscle tone in chronic stroke.

Histopathological studies have demonstrated a generalized increase in extracellular connective tissue in spastic muscles. It is known that increased connective tissue in an immobilized and contracted muscle reduces its compliance and could reduce the threshold for stimulation of spindle receptors in the muscle. Various authors have investigated how increased stretch-induced stimulation of spindles in muscles with stiffer connective tissue can contribute to spasticity. In this review, we compile evidence for the idea that the primary injury to the central nervous system that leads to muscle paresis also triggers changes in the viscosity of the extracellular matrix due to abnormal turnover of hyaluronic acid. Hyaluronic acid is a complex molecule that exhibits non-Newtonian behavior at higher concentrations, leading to altered connective tissue viscosity, which begins a vicious circle that exacerbates spasticity through reduced tissue compliance and potentiation of reflex mechanisms and fibrosis, and contributes to abnormal limb posturing, pain symptoms, and decreases in activities of daily living. The rationale for emerging treatments to break this vicious circle are discussed.

Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that produces a sustained yet transitory blockade of transmitter release from peripheral nerve terminals. Local delivery of this neurotoxin is successfully employed in clinical practice to reduce muscle hyperactivity such as in spasticity and dystonia, and to relieve pain with long‑lasting therapeutic effects. However, not all BoNT/A effects can be explained by an action at peripheral nerve terminals. Indeed, it appears that BoNT/A is endowed with trafficking properties similar to the parental tetanus neurotoxin and thus be able to directly affect the CNS. In this review, we present and discuss novel compelling evidence for a direct central effect of BoNT/A in both dorsal and ventral horns of the animal and human spinal cord after peripheral injection of the neurotoxin, with important consequences on pain and motor control. This new knowledge is expected to radically change the approach to the use of BoNT/A in the future. As BoNT/A central action appears to also contribute to functional improvement, for instance in human spastic gait, the challenge will be to develop new subtypes or BoNT derivatives with deliberate, cell‑specific central effects in order to fully exploit the spectrum of BoNT/A therapeutic activity.

Type A Botulinum neurotoxin (BoNT/A), the most potent poison known to mankind, is produced by Clostridium botulinum type A as a complex with neurotoxin-associated proteins (NAPs). Currently BoNT/A in purified and complex forms are both available in therapeutic and cosmetic applications to treat neuromuscular disorders. Whereas Xeomin® (incobotulinumtoxin A, Merz Pharmaceuticals, Germany) is free from complexing proteins, Botox® (onabotulinumtoxin A, Allergan, USA) contains NAPs, which by themselves have no known role in the intracellular biochemical process involved in the blockade of neurotransmitter release. Since the fate and possible interactions of NAPs with patient tissues after intramuscular injection are not known, it was the aim of this study to evaluate the binding of BoNT/A and/or the respective NAPs to cells derived from neuronal and non-neuronal human tissues, and to further explore neuronal cell responses to different components of BoNT/A. BoNT/A alone, the complete BoNT/A complex, and the NAPs alone, all bind to neuronal SH‑S5Y cells. The BoNT/A complex and NAPs additionally bind to RMS13 skeletal muscle cells, TIB‑152 lymphoblasts, Detroit 551 fibroblasts besides the SH‑S5Y cells. However, no binding to these non‑neuronal cells was observed with pure BoNT/A. Although BoNT/A, both in its purified and complex forms, bind to SH‑S5Y, the intracellular responses of the SH‑S5Y cells to these BoNT/A components are not clearly understood. Examination of inflammatory cytokine released from SH‑S5Y cells revealed that BoNT/A did not increase the release of inflammatory cytokines, whereas exposure to NAPs significantly increased release of IL‑6, and MCP‑1, and exposure to BoNT/A complex significantly increased release of IL‑6, MCP‑1, IL‑8, TNF‑α, and RANTES vs. control, suggesting that different components of BoNT/A complex induce significantly differential host response in human neuronal cells. Results suggest that host response to different compositions of BoNT/A based therapeutics may play important role in local and systemic symptoms in patients.

Stroke is the second leading cause of death and the leading cause of disability in Western countries. More than 60% of patients remain disabled, 50% of patients suffer from hemiparesis and 30% remain unable to walk without assistance. The skeletal muscle is the main effector organ accountable for disability in stroke. This disability is primarily attributed to the brain lesion; however less attention is paid to structural, metabolic and functional alterations of muscle tissue after stroke. Hemiparetic stroke leads to various muscle abnormalities: A combination of denervation, disuse, inflammation, remodelling and spasticity accounts for a complex pattern of muscle tissue phenotype change and atrophy. The molecular mechanisms of muscle degradation after stroke are only incompletely understood. Reinnervation, fibre-type shift, disuse atrophy, and local inflammatory activation are only some of the key features yet to be explained. Only limited data is available today on clinical muscle changes after stroke that results from few studies in a mere 500 patients. Despite its importance for optimum post stroke recovery, stroke-related sarcopenia is not considered in current guidelines for stroke therapy or rehabilitation and measurement tools to address sarcopenia are infrequently used. This lack of robust evidence on muscle pathology after stroke and on treatment strategies needs to be addressed in an interdisciplinary integrated approach. This review provides an overview on current pathophysiologic insights and on clinical relevance of sarcopenia in stroke patients and on measurement tools to address the problem in the clinical setting.

Background: Spasticity following a stroke occurs in about 30% of patients. The mechanisms underlying this disorder, however, are not well understood. Method: This review aims to define spasticity, describe hypotheses explaining its development after a stroke, give an overview of related neuroimaging studies as well as a description of the most common scales used to quantify the degree of spasticity and finally explore which treatments are currently being used to treat this disorder. Results: The lack of consensus is highlighted on the basis of spasticity and the associated absence of guidelines for treatment, use of drugs and rehabilitation programmes. Conclusions: Future studies require controlled protocols to determine the efficiency of pharmacological and non‑pharmacological treatments for spasticity. Neuroimaging may help predict the occurrence of spasticity and could provide insight into its neurological basis.

The effects of botulinum neurotoxin A on the passive mechanical properties of skeletal muscle have not been investigated, but may have significant impact in the treatment of neuromuscular disorders including spasticity. Single fiber and fiber bundle passive mechanical testing was performed on rat muscles treated with botulinum neurotoxin A. Myosin heavy chain and titin composition of single fibers was determined by gel electrophoresis. Muscle collagen content was determined using a hydroxyproline assay. Neurotoxin-treated single fiber passive elastic modulus was reduced compared to control fibers (53.00 kPa versus 63.43 kPa). Fiber stiffness and slack sarcomere length were also reduced compared to control fibers and myosin heavy chain composition shifted from faster to slower isoforms. Average titin molecular weight increased 1.77% after treatment. Fiber bundle passive elastic modulus increased following treatment (168.83 kPa versus 75.14 kPa). Bundle stiffness also increased while collagen content per mass of muscle tissue increased 38%. Injection of botulinum neurotoxin A produces an effect on the passive mechanical properties of normal muscle that is opposite to the changes observed in spastic muscles.

Stroke is the third leading cause of death and the leading cause of disability in Western countries. More than 60% of patients remain disabled, 50% of patients suffer from some hemiparesis and 30% remain unable to walk without assistance. The skeletal muscle is the main effector organ accountable for disability in stroke. This disability is, however, traditionally attributed to the brain injury itself and less attention is paid to structural, metabolic and functional aspects of muscle tissue. Hemiparetic stroke leads to various muscle abnormalities. A combination of denervation, disuse, inflammation, remodelling and spasticity account for a complex pattern of muscle tissue phenotype change and atrophy. While the molecular mechanisms of muscle degradation after stroke are only incompletely understood, a stroke-related sarcopenia may be concluded. Reinnervation, fiber‑type shift, disuse atrophy and local inflammatory activation are only some of the key features to be addressed. Despite the importance for optimum post stroke recovery, stroke‑related sarcopenia is not recognised in current guidelines for stroke therapy and rehabilitation. A total of not more than 500 patients forms the basis for all available evidence on clinical muscle changes after stroke. A lack of robust evidence on muscle pathology after stroke and on treatment strategies becomes apparent that needs to be addressed in an interdisciplinary integrated approach.

This review critically examines the definition and mechanisms of spasticity as a consequence of upper‑motor‑neuron lesions, evaluates evidence for reflex hyperexcitability and biomechanical contributions, and proposes an updated terminology and measurement framework.

Intramuscular injections of the paralytic botulinum neurotoxin A (Btx) and physical exercise are used in the treatment of chronic spasticity in children with cerebral palsy. We tested whether Btx‑induced paralysis and/or exercise training would have differential effects on the expression of mechanosensing and signalling genes implicated in the adaptive remodelling of skeletal muscle. Juvenile (29‑day‑old) male rats were injected with Btx or saline (NoBtx) into the right gastrocnemius and housed in standard cages (NoEx) or with running wheels (Ex), for 3 weeks (n= 6 per group). The mRNA expression of nine sarcomere‑associated genes in the medial gastrocnemius was then determined by quantitative reverse transcriptase‑polymerase chain reaction. The Btx‑injected muscles weighed 50% less than NoBtx muscles, but Ex had no effect on the wet mass of Btx or NoBtx muscles. Atrogenic MuRF1, sarcomeric Titin and myogenic MyoD were upregulated (2‑fold) with the elimination of contractile activity in Btx muscle. Expression of CARP, Ankrd2 and MLP was increased with mechanical stimuli associated with Btx (5‑to 10‑fold) or Ex (2‑to 4‑fold). Expression of CARP and Ankrd2 increased synergistically in Btx‑Ex muscle (≥20‑fold), indicating that these genes may be sensitive to passive stretch of the sarcomeric I‑band region of titin to which their proteins bind. Tcap, Myopalladin and Atrogin1 were not, or were no longer responsive to the altered mechanical stimuli after 3 weeks of Btx or Ex. The expression of Ankrd2, CARP and MLP may thus be enhanced by passive stretch within the Btx‑paralysed and/or exercising gastrocnemius and contribute to adaptations, other than muscle mass, in juvenile rats.

Objective To assess the safety and evaluate the effects of repeated treatments with botulinum toxin type A (BTX‑A) on functional disability, quality of life (QOL), and muscle tone of patients with upper‑limb poststroke spasticity, as well as its effect on caregivers. Design Multicenter, open‑label, repeated‑dose study. Setting Thirty‑five clinical sites in North America. Participants Patients (N=279) with upper‑limb poststroke spasticity at 6 months or more poststroke. Intervention Up to 5 intramuscular injections of BTX‑A (200–400U) divided among the wrist, finger, thumb, and elbow flexors, with at least 200U in the wrist and finger flexors. Retreatment was permitted at 12 weeks or more after the last treatment. Main Outcome Measures Investigators rated disability using the Disability Assessment Scale and muscle tone using the Ashworth Scale. Each patient’s health‑related QOL was assessed by using the Stroke Adapted Sickness Impact Profile and the visual analog scale of the European Quality of Life–5 Dimensions questionnaires. Results Patients treated with BTX‑A reported improvements in muscle tone, disability, and ability to function that were statistically significant and clinically meaningful. Significant improvements were observed at week 30 and at subsequent time points in QOL in the overall group and the high‑dose group. Conclusions Up to 5 treatments with BTX‑A every 12 weeks for up to 56 weeks in patients with poststroke spasticity was well tolerated and significantly improved muscle tone, lessened disability, and improved patients’ QOL. Further research is required to examine the effectiveness of repeated injections of BTX‑A in patients with poststroke spasticity.

A randomised, double‑blind, placebo‑controlled study investigated botulinum toxin A injection into the subscapularis muscle for shoulder pain in patients with spastic hemiplegia after stroke. The toxin significantly reduced pain and improved passive shoulder motion compared with placebo.

Spectral analysis of HRV was contemplated in 15 young male subjects during their engagement in PC based Cognitive Tasks [consisting of Auditory Tone Discrimination, Working Memory and Continuous Performance (Vigilance) Tasks, each with two or more levels of memory load/time compression]. Manipulation of cognitive demands in these task variants was objectively defined. Results of the study did establish susceptibility of certain spectral components of HRV to cognition especially when locus of the load was on working memory. The effect was demonstrably independent of possible entrainment of power spectrum of HRV with the stimulus frequency and/or changes in breathing pattern. Nevertheless, a change was demonstrable only between ‘rest’ and ‘task’ conditions and it did not co-vary with a further manipulation of load in the working memory. Modulation of HRV during cognition seemed to be correlational and not causational. Results are discussed in the text.