Non-target Muscles Research Articles

Safety of botulinum toxin injections in children less than one year old: A retrospective chart review.

Infants can have muscle hypertonia due to cerebral palsy, muscle strength imbalances due to brachial plexus palsy, refractory clubfoot, and torticollis. These muscle problems can cause significant development impairments. A child with severe sialorrhea and dysphagia from leukodystrophy can aspirate, causing respiratory problems. Botulinum toxin (BoNT) injections can improve these conditions but may lead to adverse effects from the toxin spreading to non-targeted muscles, potentially impacting breathing, swallowing, and overall strength. This is particularly concerning in infants. This study assessed the safety of BoNT injections in children less than one year of age. This was a retrospective cohort study. Forty-seven patients (22 male, 25 female) received BoNT injections before one year of age (three to 12 months). Thirty-seven received one round of injections and 10 were injected on multiple occasions. Forty-five received onabotulinumtoxinA (15-100 units [U], 1.9-15.2 U/kg), one received abobotulinumtoxinA (70 U, 9.0 U/kg), and one received incobotulinumtoxinA (25 U, 3.5 U/kg). Lower extremities were treated in 15 patients, upper extremities in 38, the sternocleidomastoid in two, and the salivary glands in one. Forty-five patients had no reported complications. One experienced transient fever, vomiting, and diarrhea. The parent of another reported subjective weakness in one muscle. BoNT injections in children less than one year of age appear to be safe.

Optimized Aesthetic Outcomes When Treating Glabellar Lines with Botulinum Toxin Type A: GLO 3 + 2: A Precise Technique Based on Anatomy.

Good patient outcomes after treatment of the glabellar complex with botulinum toxin type A entail elimination of glabellar lines and maintenance of a natural eyebrow position. A precise injection technique that accurately targets the muscles that influence eyebrow position is required to reduce the risk of adverse aesthetic outcomes or unmasking an underlying eyelid ptosis. Here, we describe the glabellar lines optimization (GLO 3 + 2) injection anatomy technique, a precise five-point injection pattern that is based on current understanding of facial functional anatomy and which aims to minimize the risk of affecting nontargeted muscles. Injection sites above the brow or that do not target the precise location of the muscles in the glabellar complex are likely to inadvertently expose the frontalis to botulinum toxin type A and result in undesirable aesthetic outcomes. Because the frontalis is a strong determinant of aesthetic outcomes, it is important to consider the overall effects of the interactions between the eyebrow depressors and the opposing forces of the frontalis on brow outcomes in both the resting brow position and during dynamic brow movement.

Epidural combined optical and electrical stimulation induces high-specificity activation of target muscles in spinal cord injured rats.

Epidural electrical stimulation (EES) has been shown to improve motor dysfunction after spinal cord injury (SCI) by activating residual locomotor neural networks. However, the stimulation current often spreads excessively, leading to activation of non-target muscles and reducing the accuracy of stimulation regulation. Near-infrared nerve stimulation (nINS) was combined with EES to explore its regulatory effect on lower limb muscle activity in spinal-cord-transected rats. In this study, stimulation electrodes were implanted into the rats' L3-L6 spinal cord segment with T8 cord transected. Firstly, a series of EES parameters (0.2-0.6 mA and 20-60 Hz) were tested to determine those that specifically regulate the tibialis anterior (TA) and medial gastrocnemius (MG). Subsequently, to determine the effect of combined optical and electrical stimulation, near-infrared laser with a wavelength of 808 nm was used to irradiate the L3-L6 spinal cord segment while EES was performed. The amplitude of electromyography (EMG), the specific activation intensity of the target muscle, and the minimum stimulus current intensity to induce joint movement (motor threshold) under a series of optical stimulation parameters (power: 0.0-2.0 W; pulse width: 0-10 ms) were investigated and analyzed. EES stimulation with 40 Hz at the L3 and L6 spinal cord segments specifically activated TA and MG, respectively. High stimulation intensity (>2 × motor threshold) activated non-target muscles, while low stimulation frequency (<20 Hz) produced intermittent contraction. Compared to electrical stimulation alone (0.577 ± 0.081 mV), the combined stimulation strategy could induce stronger EMG amplitude of MG (1.426 ± 0.365 mV) after spinal cord injury (p < 0.01). The combined application of nINS effectively decreased the EES-induced motor threshold of MG (from 0.237 ± 0.001 mA to 0.166 ± 0.028 mA, p < 0.001). Additionally, the pulse width (PW) of nINS had a slight impact on the regulation of muscle activity. The EMG amplitude of MG only increased by ~70% (from 3.978 ± 0.240 mV to 6.753 ± 0.263 mV) when the PW increased by 10-fold (from 1 to 10 ms). The study demonstrates the feasibility of epidural combined electrical and optical stimulation for highly specific regulation of muscle activity after SCI, and provides a new strategy for improving motor dysfunction caused by SCI.

Methodology of botulinum therapy in the treatment of dystonic scoliosis in generalized dystonia (clinical case)

Dystonic scoliosis as one of the forms of generalized dystonia is a highly disabling form of dystonia, which can lead to damage to internal organs (lungs, heart) and the peripheral nervous system, including the spinal cord. Almost always, those muscles that are involved in the formation of a dystonic posture in generalized dystonia have not been studied in terms of the effectiveness of treatment with botulinum toxin type A and are not reflected in the instructions. As a result, there is no understanding of the general motor interaction with differentiation into targeted and non-targeted muscles, administration doses and control methods.The aim of the work was to evaluate the efficacy and tolerability of high doses of botulinum toxin type A in dystonic scoliosis, as well as to present the introduction of botulinum toxin type A using ultrasound and electromyographic control. We have described a clinical case of a 19-year-old patient suffering from generalized dystonia with S-shaped dystonic scoliosis of the III degree. Deep brain stimulation was recommended as a treatment for the patient. During the waiting period for the timing of the operation, we attempted symptomatic therapy using the drug incobotulotoxin A. Over the next year and a half, 700 units of botulinum toxin type A were administered under ultrasound and electromyographic control every 3–4 months. As a result, treatment of trunk dystonia in the patient during the observation period led to a clinically significant decrease in the degree of curvature (from 37° to 27°, from III to II degree of scoliosis) in the absence of undesirable effects of the drug, including generalized muscle weakness. According to the repeated conclusion of the council of neurosurgeons, surgical intervention is not indicated for the patient due to the positive effect of the introduction of botulinum toxin type A.

Understanding corticomotor mechanisms for activation of non-target muscles during unilateral isometric contractions of leg muscles after stroke

Purpose Muscle activation often occurs in muscles ipsilateral to a voluntarily activated muscle and to a greater extent after stroke. In this study, we measured muscle activation in non-target, ipsilateral leg muscles and used transcranial magnetic stimulation (TMS) to provide insight into whether corticomotor pathways contribute to involuntary activation. Materials and methods Individuals with stroke performed unilateral isometric ankle dorsiflexion, ankle plantarflexion, knee extension, and knee flexion. To quantify involuntary muscle activation in non-target muscles, muscle activation was measured during contractions from the ipsilateral tibialis anterior (TA), medial gastrocnemius (MG), rectus femoris (RF), and biceps femoris (BF) and normalized to resting muscle activity. To provide insight into mechanisms of involuntary non-target muscle activation, TMS was applied to the contralateral hemisphere, and motor evoked potentials (MEPs) were recorded. Results We found significant muscle activation in nearly every non-target muscle during isometric unilateral contractions. MEPs were frequently observed in non-target muscles, but greater non-target MEP amplitude was not associated with greater non-target muscle activation. Conclusions Our results suggest that non-target muscle activation occurs frequently in individuals with chronic stroke. The lack of association between non-target TMS responses and non-target muscle activation suggests that non-target muscle activation may have a subcortical or spinal origin. Non-target muscle activation has important clinical implications because it may impair torque production, out-of-synergy movement, and muscle activation timing.

Muscle Specific Promotors for Gene Therapy - A Comparative Study in Proliferating and Differentiated Cells.

Depending on the therapy approach and disease background, the heterogeneity of muscular tissues complicates the development of targeted gene therapy, where either expression in all muscle types or restriction to only one muscle type is warranted. Muscle specificity can be achieved using promotors mediating tissue specific and sustained physiological expression in the desired muscle types but limited activity in non-targeted tissue. Several muscle specific promotors have been described, but direct comparisons between them are lacking. Here we present a direct comparison of muscle specific Desmin-, MHCK7, microRNA206- and Calpain3 promotor. To directly compare these muscle specific promotors we utilized transfection of reporter plasmids using an in vitro model based on electrical pulse stimulation (EPS) to provoke sarcomere formation in 2D cell culture for quantification of promotor activities in far differentiated mouse and human myotubes. We found that Desmin- and MHCK7 promotors showed stronger reporter gene expression levels in proliferating and differentiated myogenic cell lines than miR206 and CAPN3 promotor. However, Desmin and MHCK7 promotor promoted gene expression also cardiac cells whereas miR206 and CAPN3 promotor expression was restricted to skeletal muscle. Our results provides direct comparison of muscle specific promotors with regard to expression strengths and specificity as this is important feature to avoid undesired transgene expression in non-target muscle cells for a desired therapy approach.

Exploring high-density corticomuscular networks after stroke to enable a hybrid Brain-Computer Interface for hand motor rehabilitation

BackgroundBrain-Computer Interfaces (BCI) promote upper limb recovery in stroke patients reinforcing motor related brain activity (from electroencephalogaphy, EEG). Hybrid BCIs which include peripheral signals (electromyography, EMG) as control features could be employed to monitor post-stroke motor abnormalities. To ground the use of corticomuscular coherence (CMC) as a hybrid feature for a rehabilitative BCI, we analyzed high-density CMC networks (derived from multiple EEG and EMG channels) and their relation with upper limb motor deficit by comparing data from stroke patients with healthy participants during simple hand tasks.MethodsEEG (61 sensors) and EMG (8 muscles per arm) were simultaneously recorded from 12 stroke (EXP) and 12 healthy participants (CTRL) during simple hand movements performed with right/left (CTRL) and unaffected/affected hand (EXP, UH/AH). CMC networks were estimated for each movement and their properties were analyzed by means of indices derived ad-hoc from graph theory and compared among groups.ResultsBetween-group analysis showed that CMC weight of the whole brain network was significantly reduced in patients during AH movements. The network density was increased especially for those connections entailing bilateral non-target muscles. Such reduced muscle-specificity observed in patients was confirmed by muscle degree index (connections per muscle) which indicated a connections’ distribution among non-target and contralateral muscles and revealed a higher involvement of proximal muscles in patients. CMC network properties correlated with upper-limb motor impairment as assessed by Fugl-Meyer Assessment and Manual Muscle Test in patients.ConclusionsHigh-density CMC networks can capture motor abnormalities in stroke patients during simple hand movements. Correlations with upper limb motor impairment support their use in a BCI-based rehabilitative approach.

Motor overflow in the lower limb after stroke: Insights into mechanisms.

Motor overflow (involuntary muscle activation) is common after stroke, particularly in the non-paretic upper limb. Two potential cortical mechanisms are as follows: (1) The contralesional hemisphere controls both limbs, and (2) inhibition from the ipsilesional to the contralesional hemisphere is diminished. Few studies have differentiated between these hypotheses or investigated motor overflow in the lower limb after stroke. To investigate these potential mechanisms, individuals with chronic stroke performed unilateral isometric and dynamic dorsiflexion. Motor overflow was quantified in the contralateral, resting (non-target) ankle. Transcranial magnetic stimulation (TMS) was applied, and responses were measured in both legs. Relations between motor overflow, excitability of ipsilateral motor pathways, and interhemispheric inhibition were assessed. Non-target muscle activity (motor overflow) was greater during isometric and dynamic conditions than rest in both legs (p≤0.001) and was higher in the non-paretic than the paretic leg (p= 0.03). Some participants (25%) had motor overflow >4SD above the group mean in the non-paretic leg. Greater motor overflow in the non-paretic leg was associated with lesser inhibition from the ipsilesional to the contralesional hemisphere (p= 0.04). In both legs, non-target TMS responses were greater during the isometric and dynamic than the rest condition (p≤0.01) but not when normalized to background muscle activity. Overall, motor overflow occurred in both legs after stroke, suggesting a common bilateral mechanism. Our correlational results suggest that alterations in interhemispheric inhibition may contribute to motor overflow. Furthermore, the lack of differences in non-target motor evoked potentials MEPs between rest, isometric, and dynamic conditions suggests that subcortical and/or spinal pathways may contribute to motor overflow.

25487 Timing and strength of hand grasp that are affected by abnormal coupling between arm muscles following stroke: A pilot study

ABSTRACT IMPACT: Impaired neuromuscular control could lead to the failure in activation and deactivation of the target muscles in a timely manner, with the concurrence of activities of non-targeted muscles. OBJECTIVES/GOALS: Stroke leads to impaired capacity to manipulate objects with the hand in terms of timing and strength of grasp. The influence of abnormal coupling across more proximal arm muscles post stroke on the failure in normal functioning of finger flexor muscle activity is of interest to investigate. METHODS/STUDY POPULATION: We have recruited 12 participants with stroke hemiparesis in the sub-acute or chronic stage. Motor impairment of the arm was assessed using electromyography (EMG) and the Fugl-Meyer Upper Extremity (FMUE) assessment. Participants were requested to flex and relax the metacarpophalangeal (MCP) joints against motorized resistance in response to audible tones to determine timing and strength during flexion. They were asked to flex maximally, as quickly as possible, in response to the first of a pair of tones, and relax as quickly as possible after the second tone. Delays in initiation and termination were evaluated using EMG responses versus a predefined threshold. RESULTS/ANTICIPATED RESULTS: We anticipate greater delays in grasp initiation as well as in grasp termination in participants with a greater extent of abnormal coupling across more proximal muscles of the upper extremity in comparison to participants with a less extent, using the results of the FMUE assessment. Also it is expected that participants with a greater extent of the flexion synergy produce a less extent of force generation. The EMG results will show that activities of more proximal arm muscles precede the initiation of MCP flexion and their activity termination precedes that of MCP flexion, significantly more in participants with a greater extent of the flexion synergy. DISCUSSION/SIGNIFICANCE OF FINDINGS: The flexion synergy over the arm following stroke affects the timing and strength of hand grasp. Impaired neuromuscular control could lead to the failure in activation and deactivation of the target muscles in a timely manner, with the concurrence of activities of non-targeted muscles.

Change in motor cortex activation for muscle release by motor learning.

For central nervous system disorders' rehabilitation, it is important to accurately understand motor control and implement an appropriate motor learning process to induce neuroplastic changes. The neurophysiological studies have revealed that neural control mechanisms are crucial during both the onset of muscular activities and muscle release after contraction. When performing various movements during daily activities, muscle relaxation control enables precise force output and timing control. Moreover, surround inhibition is a functional mechanism in the motor system. Surround inhibition of the motor system may be involved in the selective execution of desired movements. This review demonstrates cortical excitability resulting from motor learning, movement control mechanisms including muscle relaxation and the suppression of nontarget muscle groups, and the voluntary drive's importance that is required for movement.

Dose–volume correlates of the prevalence of patient-reported trismus in long-term survivorship after oropharyngeal IMRT: A cross-sectional dosimetric analysis

PurposeTo ascertain the dose–toxicity relationship for the prevalence of self-reported trismus in long-term survivors after intensity-modulated radiotherapy (IMRT) for oropharyngeal carcinoma (OPC). Materials and methodsSelf-reported mouth opening was ascertained prospectively via a cross-sectional survey of OPC survivors using the intraoral finger-test. RT dose–volume histograms (DVHs) were generated for the following masticatory regions of interest: medial pterygoid, lateral pterygoid, and masseter muscles which were designated as ipsilateral or contralateral to the primary tumor. Trismus was defined as self-reported mouth opening of <3 finger-widths. Recursive partitioning analysis (RPA) was performed to identify the dose–volume thresholds associated with late trismus. ResultsAt a median follow-up time of 72 months (95% CI 68–74), 168 of the 587 (29%) survey respondents reported late trismus. Multivariate analysis demonstrated a significant association between late trismus and the following clinical variables: tonsillar primary site, advanced T stage, or higher total RT dose. RPA showed DVH-derived ipsilateral lateral pterygoid (ILP) mean dose of 61 Gy and volume receiving 27 Gy of at least 98.6% were independently associated with late trismus. The association between the ILP dosimetric parameters and the prevalence of late trismus was maintained after adjustment for clinical variables. ConclusionThe integral dose of IMRT results in unavoidable low/intermediate dose to non-target masticatory muscles that is associated with increased prevalence of late trismus in OPC survivors. Whenever clinically and technically applicable, applying the proposed dosimetric constraints to the ILP (V27 <98.6 and Dmean <61 Gy) may reduce the prevalence of late trismus after IMRT for OPC patients.

Repurposing of FDA-Approved Drugs for Treating Iatrogenic Botulism: A Paired 3D-QSAR/Docking Approach†.

Botulinum neurotoxin (BoNT) is widely used for the treatment of spasticity, focal dystonia, chronic migraine, facial hemispasm, and facial aesthetic treatments. Generally, treatment with botulinum toxin is a safe procedure when conducted by clinicians with expertise, and local side effects are rare and transient. However, occasionally adverse effects can occur due to the spread of the drug to nontargeted muscles and organs, producing dry mouth, fatigue, and flu-like symptoms, up to signs of systemic botulism, which appears to be more frequent in children treated for spasticity than in adults. In silico 3D-QSAR and molecular docking studies were performed to build a structure-based model on selected potent known botulinum neurotoxin type A inhibitors; this was used to screen the US Food and Drug Administration (FDA) database. Thirty molecules were identified as possible light-chain BoNT/A inhibitors. In this study, we applied a well-established ligand- and structure-based methodology for the identification of hit compounds among a database of FDA-approved drugs. The identification of budesonide, protirelin, and ciclesonide followed by other compounds can be considered a starting point for investigations of selected compounds that could bypass much of the time and costs involved in the drug approval process.

Agonist-Antagonist Coactivation Enhances Corticomotor Excitability of Ankle Muscles.

Spinal pathways underlying reciprocal flexion-extension contractions have been well characterized, but the extent to which cortically evoked motor-evoked potentials (MEPs) are influenced by antagonist muscle activation remains unclear. A majority of studies using transcranial magnetic stimulation- (TMS-) evoked MEPs to evaluate the excitability of the corticospinal pathway focus on upper extremity muscles. Due to functional and neural control differences between lower and upper limb muscles, there is a need to evaluate methodological factors influencing TMS-evoked MEPs specifically in lower limb musculature. If and to what extent the activation of the nontargeted muscles, such as antagonists, affects TMS-evoked MEPs is poorly understood, and such gaps in our knowledge may limit the rigor and reproducibility of TMS studies. Here, we evaluated the effect of the activation state of the antagonist muscle on TMS-evoked MEPs obtained from the target (agonist) ankle muscle for both tibialis anterior (TA) and soleus muscles. Fourteen able-bodied participants (11 females, age: 26.1 ± 4.1 years) completed one experimental session; data from 12 individuals were included in the analysis. TMS was delivered during 4 conditions: rest, TA activated, soleus activated, and TA and soleus coactivation. Three pairwise comparisons were made for MEP amplitude and coefficient of variability (CV): rest versus coactivation, rest versus antagonist activation, and agonist activation versus coactivation. We demonstrated that agonist-antagonist coactivation enhanced MEP amplitude and reduced MEP CVs for both TA and soleus muscles. Our results provide methodological considerations for future TMS studies and pave the way for future exploration of coactivation-dependent modulation of corticomotor excitability in pathological cohorts such as stroke or spinal cord injury.

Aftereffects of Intermittent Theta-Burst Stimulation in Adjacent, Non-Target Muscles

To assess motor cortex neurophysiology, including the mechanisms of neuroplasticity, transcranial magnetic stimulation (TMS) is typically applied to the motor “hotspot”— the optimal site for inducing a twitch in a given target muscle. It is known that the effects of suprathreshold repetitive TMS (rTMS) spread along functional connections beyond the specific cortical stimulation target, and yet, it is unknown whether the aftereffects of subthreshold intermittent theta-burst stimulation (iTBS), an ultra-high frequency patterned rTMS protocol, extend beyond the targeted muscle.We investigated whether and to what extent iTBS induces changes in the cortical output to other intrinsic hand muscles with adjacent cortical representation to the target. Sixteen healthy adults underwent neuronavigated TMS-iTBS targeting the first dorsal interosseus (FDI) hotspot. Proportion of motor evoked potentials (MEPs) at the resting motor threshold (RMT), baseline MEP amplitude, and iTBS-induced changes in MEP amplitude were compared between FDI, abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. MEP amplitudes recorded from the three muscles at RMT and suprathreshold intensities indicated the chosen hotspots were relatively selective for FDI. Nevertheless, iTBS induced significant facilitation of MEPs recorded from both FDI and APB, but not ADM. Surprisingly, the MEP modulation was greater in APB, even when controlling for the baseline MEP amplitude. These results indicate that iTBS modulation of cortico-spinal excitability extends beyond the representation of the targeted muscle. Results have implications both for how iTBS may be used in clinical treatment and for the safety guidelines for the application of iTBS.

Formation of Microbubbles for Targeted Ultrasound Contrast Imaging: Practical Translation Considerations.

For preparation of ligand-decorated microbubbles for targeted ultrasound contrast imaging, it is important to maximize the amount of ligand associated with the bubble shell. We describe optimization of the use of a biocompatible cosurfactant in the microbubble formulation media to maximize the incorporation of targeting ligand-lipid conjugate into the microbubble shell, and thus reduce the fraction of ligand not associated with microbubbles, following amalgamation preparation. The influence of the concentration of a helper cosurfactant propylene glycol (PG) on the efficacy of microbubble preparation by amalgamation and on the degree of association of fluorescent PEG-lipid with the microbubble shell was tested. Three sets of targeted bubbles were then prepared: with VCAM-1-targeting peptide VHPKQHRGGSK(FITC)GC-PEG-DSPE, cyclic RGDfK-PEG-DSPE, selective for αVβ3, and control cRADfK-PEG-DSPE, without such affinity. Microbubbles were prepared by 45 s amalgamation, with DSPC and PEG stearate as the main components of the shell, with 15% PG in aqueous saline. In vitro microbubble targeting was assessed with a parallel plate flow chamber with a recombinant receptor coated surface. In vivo targeting was assessed in MC-38 tumor-bearing mice (subcutaneous tumor in hind leg), 10 min after intravenous bolus of microbubble contrast agent (20 million particles per injection). Ultrasound imaging of the tumor and control nontarget muscle tissue in a contralateral leg was performed with a clinical scanner. Amalgamation technique with PG cosurfactant produced microbubbles at concentrations exceeding 2 × 109 particles/mL, and ∼50-60% or more of the added fluorescein-PEG-DSPE or VCAM-1-targeted fluorescent peptide was associated with microbubbles, about 2 times higher than that in the absence of PG. After intravenous injection, peptide-targeted bubbles selectively accumulated in the tumor vasculature, with negligible accumulation in nontumor contralateral leg muscle, or with control nontargeted microbubbles (assessed by contrast ultrasound imaging). For comparison, administration of RGD-decorated microbubbles prepared by traditional sonication, and purified from free peptide-PEG-lipid by repeated centrifugation, resulted in the same accumulation pattern as for translatable amalgamated microbubbles. Following amalgamation in the presence of PG, efficient transfer of ligand-PEG-lipid to microbubble shell was achieved and quantified. Purification of microbubbles from free peptide-PEG-lipid was not necessary, as proven by in vitro and in vivo targeting studies, so PG cosurfactant amalgamation technique generated peptide-targeted microbubbles are amenable for bedside preparation and clinical translation. The pathway to clinical translation is simplified by the fact that most of the materials used in this study either are on the United States Food and Drug Administration GRAS list or can be procured as pharmaceutical grade substances.

A prospective longitudinal assessment of MRI signal intensity kinetics of non-target muscles in patients with advanced stage oropharyngeal cancer in relationship to radiotherapy dose and post-treatment radiation-associated dysphagia: Preliminary findings from a randomized trial

PurposeTo assess quantitative signal intensity (SI) kinetics obtained from serial MRI of swallowing muscles as a potential imaging biomarker of radiation-induced dysphagia in oropharyngeal cancer (OPC) patients receiving radiotherapy (RT). MethodsPatients were enrolled under an IRB approved Phase II/III randomized trial. Patients underwent serial MRIs at pre-, mid-, and post-RT. Normalized T1, T1+ contrast (T1 + C), and T2 SI for swallowing muscle volumes-of-interest (VOIs) were collected and delta SI changes (Δ) were calculated. Mid- and post-RT SI relative to baseline were assessed and correlations between radiation dose and percent change in SI were calculated. Independent samples’ t-tests were used to compare the percent change of SI between patients divided into two groups based on dysphagia status post-RT. ResultsForty-six patients with stage III/IV HPV+ OPC were included in this study. Relative to baseline, mean T2 and T1 + C SIs for middle pharyngeal constrictor were both significantly higher at mid- and post-RT (p < 0.004 for all). Superior pharyngeal constrictor also showed a significant increase in T1 + C SI at mid-RT (p = 0.0004). Additional muscle VOIs showed significant changes post-RT, but not earlier at mid-RT. Both mid- and post-RT doses were significantly correlated with the percent change of normalized T2 and T1 + C SI for examined muscle VOIs (p < 0.002). Mean percent changes of normalized T2 SI at mid-RT relative to baseline for all muscle VOIs were significantly higher in patients who developed grade ≥2 dysphagia relative to patients with no/mild dysphasia (mean Δ%: 8.2% vs 1.9%; respectively, p = 0.002). However, at post-RT, these changes were only significant in T1 SI (11.2% vs −1.3%; p < 0.0001). ConclusionSignal intensity kinetics of radiation injury can be broadly correlated with the functional muscular defect. Serial MRI during the course of RT may provide an opportunity to quantitatively track muscular pathology for subclinical detection of patients at high risk to develop dysphagia.

(OA32) Chronic Radiation-Associated Dysphagia in Oropharyngeal Cancer Survivors: Towards Age-Adjusted Dose Constraints for Deglutitive Muscles

Chronic radiation-associated dysphagia (RAD) is a dreaded complication following head and neck radiotherapy. Different factors likely contribute to the development of late RAD. We hypothesize that age may be a significant factor predisposing patients to develop long term swallow dysfunction. We sought to model chronic RAD in patients treated with IMRT for oropharyngeal cancer as a function of age at time of treatment and dose to non-target swallowing muscle regions of interest (ROIs). We examined a group of 300 patients with T1-T4N0-3M0 oropharyngeal cancer patients who received definitive IMRT and concurrent chemotherapy at the University of Texas MD Anderson Cancer Center between 2002 - 2013. Chronic RAD was defined as any of the following ≥ 12 months post-IMRT: videoflouroscopy/endoscopy detected aspiration or stricture, gastrostomy tube, and/or aspiration pneumonia. DICOM-RT plan data were autosegmented using a validated region-of-interest (ROI) library and included inferior, middle and superior constrictors (IPC, MPC, and SPC), anterior and posterior digastrics (ADM, PDM), mylo/geniohyoid complex (MGM), intrinsic tongue muscles (ITM), and gengioglossus (GGM). Age was binned by decade of life, <50, 50-59, 60-69, and >=70 years of age. The probability of chronic RAD as a function of mean dose (to the above ROIs), stratified by age, was estimated by using logistic probability models and subsequent unsupervised nonlinear curve. Of 300 patients, 34 patients developed chronic RAD (11%). Age as a continuous and discrete variable was a significant correlate of chronic RAD, both independently and in concert with continuous dose for all muscle groups examined. Substantively distinct muscle-specific dose-response profiles were observed as a function of age (e.g. a patient in their 50s who received 60 Gy to the SPC had an observed 5% chronic-RAD rate, while a 70-year-old cohort (at the same dose level) exhibited a 20% rate.) Serial muscle-specific dose-response analysis demonstrated the effect to be stable across all observed muscle ROIs, with a FDR-corrected p<0.05 for all dose/muscle/age models, suggesting that an inclusion of dose as a covariate improves modeling of chronic RAD. Age at time of treatment appears to moderate dose-response probability of chronic RAD after chemo-IMRT for OPSCC. Our data demonstrate aging muscles show lower dose thresholds toward the development of potentially meaningful clinically apparent late RAD. Further investigation into age-specific dose constraints and age-adjusted dysphagia prophylaxis models appears warranted; however, our data suggest that uniform monolithic dose constraints may fail to accurately prognosticate or preclude clinical toxicity in aged populations.

S14-2. F wave and spinal excitability; masseteric contraction or motor imagery enhances ulnar nerve F wave

We tested the validity of instructing patients to clench the teeth to facilitate F-waves recorded from a limb muscle in clinical practice. We explored to study effect of motor imagery and voluntary contraction of the masseter muscles on F waves recorded from the first dorsal interosseous muscle in healthy subjects. F waves were recorded at rest, during motor imagery and during voluntary contraction monitored by a force transducer to maintain the level at 10% of maximal effort. F-wave persistence increased from at rest to during motor imagery, and during voluntary contraction. The trial average of F-waves increased from at rest to during motor imagery and during voluntary contraction. The F-wave latency revealed no significant changes. We have previously shown that motor imagery or slight voluntary contraction of the target muscle enhances F-wave persistence. The current study indicates the same process involving a non-target muscle can also cause a transient increase in distant motoneuron excitability, similar to Jendrassik maneuver. Central drive directed to the masseteric motoneurons can enhance the excitability of ulnar nerve anterior horn cells as evidenced by an increase of trial average of F-wave amplitudes.

Crosstalk Removal in Stimulus-evoked Forearm Electromyography

Abstract This paper presents the detection and reduction of crosstalk in stimulus-evoked electromyography (EMG) recorded from four forearm flexors: Flexor Carpi Radialis (FCR), Palmaris Longus (PL), Flexor Digitorum Superficialis (FDS) and the Flexor Carpi Ulnaris (FCU). Electrical stimulation was applied distal to the elbow, stimulating the medial and radial nerves singly. As the innervating nerve was stimulated, the M-wave was recorded from the target muscle and crosstalk from non-target muscles: for ulnar nerve stimulation, the M-wave was recorded from the FCU, and the FCR, PL and FDS were monitored for crosstalk. The branched electrode (BE) tripolar configuration was utilised for crosstalk reduction. The BE and double differential configurations are mathematically equivalent, only scaled by a factor of two. The benefit of the BE configuration is its ability for being used with a standard EMG device. A normalised peak-to-peak amplitude-based index was used to quantify the reduction in crosstalk, achieving a maximum reduction of 42.51% on the FDS, 12.43% on the PL and 7.68% on the FCU. An increase in peak-to-peak amplitude was recorded for the FCR, this is believed to be due to the challenge associated with electrode-skin impedance matching.

Neurophysiological Measures of Efficacy and Safety for Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations.

Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.