Shear wave elastography to assess the effect of botulinum toxin in muscle hypertonia following stroke

Introduction Sonoelastography is a method capable of evaluating the mechanical properties of soft tissues by ultrasound (US). A further development of this technique is shear wave elastography (SWE), which provides a quantitative evaluation of the elastic properties - in terms of tissutal stiffness - by measuring the propagation velocities of the directional shear waves, produced by an ultrasound pulse. Spasticity often appears in stroke patients in the affected limbs. It corresponds to velocity-dependent muscle hypertonia in relation to the hyperexcitability of the stretch reflex. Over time, the paretic muscles develop intrinsic alterations with consequent muscle shortening and increased fibrosis related to reduced use and immobilization. Intramuscular injections of botulinum toxin A (BoNT-A) is an effective treatment which reduces muscle activity by inhibiting the release of acetylcholine at the neuromuscular junction level and is therefore able to reduce neuromediated muscle hypertonicity. The study aims to evaluate the effectiveness of SWE to appreciate changes in stiffness in spastic muscles after treatment with BoNT-A and possibly detect differences between affected muscles and unaffected contralateral ones related to fibrous-fatty remodeling. Materials & Methods 14 adult patients (5F; age: 58,4\ub114,1 years, m\ub1SD; range:46-78) affected by spasticity were recruited after ischemic or hemorrhagic stroke diagnosed for at least 3 months and with a time interval from the last injection of at least 4 months, if already treated with BoNT-A. They patients underwent a physical examination in which muscle hypertonia was assessed using the modified Ashworth scale (MAS). The assessments were carried out on a sample muscle among the spastic ones favoring the greater volume and better accessibility to the ultrasound probe. SWE was also performed on the homologue non-paretic contralateral muscle. Spasticity was measured as the average electromyographic activity recorded during stretching (reflex by stretching) of the selected muscle at a reproducible speed, according to a previously validated methodology. The SWE evaluation was carried out with US scans across and along the direction of muscular fibers - as assessed by conventional US - covering the entire belly of the selected muscle to obtain a comprehensive estimate of the muscle stiffness both with the maximum shortened and elongated muscle position. Muscle fibrosis was also estimated on conventional B-mode US using the modified Heckmatt scale. All evaluations were performed shortly before botulinum toxin infiltration (T0) and one month later (T1). Clinical, electromyographic and ultrasound evaluation were performed by three different blinded examiners. Depending on data distribution, non-parametric statistical tests for paired data were performed for comparison; Spearman\u2019s r was calculated to assess data correlations. Results A total of 224 SWE values resulted considering both time points. Overall, SWE measurements on paretic muscles assessed with a longitudinal positioning of the probe showed statistically significant reduction at T1 versus T0 both in non stretched conditions (p=0.001) and in stretched conditions (p=0.0029). After BoNT-A injection, a significant reduction in MAS (p=0.009), spastic dystonia (p=0.0043), spasticity (p=0.0019) and longitudinal SWE measurements, both in non stretched conditions (p=0.001) and in stretched conditions (p=0.0029), was observed. No significant changes in SWE parameters were observed on non-paretic versus contralateral muscle . All SWE measurements were higher in the paretic limb than in the contralateral one (p<0.01); higher SWE measurements resulted along the direction of muscular fibers versus across them (p<0.01). Cohen\u2019s d estimate a larger effect on EMG values than longitudinal SWE ones (either in non stretched and in stretched condition), with narrower 95%CI for SWE measurements. No changes resulted by the modified Heckmatt scale US assessments; there was a positive correlation (r: 0.46-0.84) between MHS scores and SWE values. Conclusion This is the first study evaluating the effect of BoNT-A on muscle hypertonia following stroke, assessed by mean of SWE and compared with the stretch reflex. The treatment resulted in a reduction of MAS, stretch reflex and muscular stiffness, in relation to the reduction of the neuro-mediated hypertonia. We have therefore shown that SWE is able to appreciate a reduction in neuro-mediated stiffness. Abolishing the neuro-mediated contribution by keeping the limb in a shortened position and moreover after BoNT-A injection, the SWE values resulted higher in the paretic muscle than in the healthy muscle in the same position. Hence, SWE-driven comparison between the spastic muscle and the contralateral unaffected homologous one is able to disclose the amount of stiffness due only to intrinsic muscular involutive remodeling. Alongside sEMG, SWE could therefore constitute an added-value to clinicians who manage spasticity for the assessment of responses to treatments and monitoring therapeutic interventions

New approaches to the study of neurorehabilitation protocols in dogs and cats with acute or chronic spinal cord injury with or without deep pain sensation and possible spinal shock signs

Tese de Doutoramento em Ciências Veterinárias na especialidade Clínica, área científica de ClínicaABSTRACT - Intensive neurorehabilitation protocols (INRP) with rehabilitation modalities and weight supported treadmill training (BWSTT), are suggested as treatment to obtain ambulation in dogs and cats with complete (DPP-), discomplete and incomplete (DPP+) compressive or non-compressive spinal cord injury (SCI), similarly to what is performed in human medicine.The first study is a cohort, prospective, controlled and blinded study that was performed in 22 dogs with T11-L3 Hansen type I, revealing ambulation in 100% of the BWSTT group, within a mean of 4.6 weeks. One other study, a retrospective controlled clinical study, was developed in 367 acute post-surgical dogs, with T10-L3 Hansen type I. A new functional neurorehabilitation scale (FNRS-DPP-) was performed to evaluate the DPP- or discomplete dogs, that were able to achieve spinal reflex locomotion (SRL). A strong significance between groups was verified in the DPP+ (p<0.001), with 99.4% of ambulation. The same difference was seen in the DPP- (p=0.007) with 58,5% of ambulation and a tendency (p=0.058) was observed in regard to DPP recovery, with 37.2% achieving SRL, within a maximum of 3 months. INRP was demonstrated to be safe and ambulation recovery achieved earlier. The same population was included in another study, on 16 dogs with incomplete recovery 3 months after surgery. DPP- were under INRP associated with 4-aminopyridine administration, achieving 78% of SRL at day 45 and automatic micturition within a mean of 62 days. Also, 100% of ambulation in the DPP+ within a mean of 47 days and positive follow-up evolution. Ambulatory status was achieved in 88%, establishing this INRP as a therapeutic option to reduce euthanasia. Non-compressive myelopathies with contusive patterns were also referred in a prospective study of 9 cats that revealed 56% (n=5) of ambulation and 44% (n=4) of SRL, showing that INRP should be considered to improve quality of life and the well-being of our patients. Some dogs may develop spinal shock following SCI, including in acute noncompressive nucleus pulposus extrusion. Thus, a cohort prospective study applied a spinal shock scale as a monitoring tool, suggesting spinal shock as a negative factor for a quick recovery. INRP was shown to be safe, tolerable and feasible, allowing 32% of ambulation within 7 days and 94% within 60 days. Follow-ups until 4 years revealed a positive evolution. These studies should be continued, considering each limitationRESUMO - Nova abordagem aos protocolos de neuroreabilitação em cães e gatos com lesão medular aguda ou crónica, com/sem sensibilidade à dor profunda e choque espinhal. - Os protocolos de neuroreabilitação intensiva (INRP), com as modalidades de reabilitação e o treino locomotor em tapete rolante com suporte de peso (BWSTT), são sugeridos como terapêutica para obter a ambulação em cães e gatos de lesão medular compressiva / não compressiva, completa (DPP-), “discompleta” e incompleta (DPP+), tal como na medicina humana. Assim, apresenta-se o primeiro artigo, estudo de coorte, prospetivo, controlado e cego, em 22 cães com lesão T11-L3 Hansen tipo I, que demonstrou 100% de ambulação no grupo BWSTT, em média de 4.6 semanas. O segundo artigo refere-se ao estudo controlado e retrospetivo de 367 cães pós-cirúrgicos com lesão aguda T10-L3 de Hansen tipo I. A escala de neuroreabilitação funcional (FNRS-DPP-) foi elaborada e aplicada nestes cães, DPP- ou incompletos, capazes de atingir a locomoção espinhal por reflexos (SRL). Verificaram-se diferenças significativas entre grupos, nos DPP+ (p<0,001) com 99,4% de ambulação, e nos DPP- (p=0,007) com 58,5%. Em relação à recuperação da sensibilidade profunda (p=0,058), ocorreu 37.3% de SRL, no máximo em 3 meses. O INRP demonstrou-se seguro e a recuperação foi atingida de forma mais precoce. O mesmo foi estudado em 16 cães com recuperação incompleta 3 meses após cirurgia, sendo associada a administração de 4- aminopiridina nos DPP- com 78% de SRL até 45 dias e micção automática em ~62 dias. Obteve-se 100% de ambulação nos cães DPP+, em ~47 dias, com evolução positiva nas consultas de seguimento. A ambulação total foi de 88%, estabelecendo este INRP como opção terapêutica, reduzindo o número de eutanásias em âmbito clínico. As mielopatias não compressivas foram, também, estudadas. Assim sendo, estudo propectivo em 9 gatos revelou 56% de ambulação e 44% de SRL, demostrando que o INRP poderá ser considerado, no sentido de melhorar a qualidade de vida e bem-estar destes doentes. Após a lesão medular, alguns cães podem desenvolver o choque espinhal, principalmente na extrusão aguda não compressiva do núcleo pulposo. Assim, foi desenvolvido estudo propectivo coorte que elaborou e aplicou escala de choque espinhal para monitorização, sugerindo o choque espinhal como fator negativo para a rápida recuperação. Este INRP revelou-se seguro, tolerável e viável, com 32% de ambulação em 7 dias e 94% em 60 dias. Consultas de seguimento até 4 anos revelaram evolução positiva. Estes estudos devem ser continuados considerando as suas limitações.N/

Musculoskeletal stiffness and Achilles tendon mechanical property changes following exercise-induced muscle damage

This thesis investigated the affect of exercise induced muscle damage (EIMD) on musculoskeletal stiffness (MSS), Achilles tendon (AT) stiffness and AT strain. Furthermore, this thesis determined the reliability of a protocol used to measure MSS with the aim to apply this protocol in the investigation of the EIMD associated changes in MSS, AT stiffness and AT strain. Three studies were conducted as part of this thesis

Impact of static stretch and muscular contractions on force production within the human triceps surae muscle-tendon complex

Pre-performance routines commonly include stretching and intense muscular contractions in an attempt to optimise muscular performance and reduce injury risk. However, the isolated and combined effects of stretching and muscle contractions on neuromuscular performance are not well described. The aims of this research were to examine the effects of acute static stretch and intense muscular contractions on force production of the human plantarflexors and to examine possible mechanical and neuromuscular mechanisms underpinning any changes. Techniques including isokinetic dynamometry, electromyography (EMG), sonography and motion analysis were used in three studies on recreationally active human volunteers (n=20). In the first study, three 60-s passive stretches was found to significantly reduce concentric plantarflexor joint moment (5.0%; P\u3c0.05), which was correlated (r = 0.81; P\u3c0.01) with a reduction in EMG amplitude (9.2%; P\u3c0.05). No reduction in Achilles tendon stiffness or gastrocnemius medialis (GM) muscle operating length was found, and all measures recovered by 30 min. This indicates that post-stretch force losses are transient and are largely associated with reduced neuromuscular activity (EMG amplitude) rather than changes in the muscles’ operating lengths. Nonetheless, strong muscular contractions, commonly performed during preperformance routines and incorporated into research designs, may influence the effects of stretch. In the second study it was found that six 8-s maximal isometric contractions reduced Achilles tendon stiffness (10.9%; P\u3c0.01) and passive joint moment (4.9%; P\u3c0.01) and also significantly reduced concentric moment (11.5%; P\u3c0.01), which was again correlated (r = 0.90; P\u3c0.01) with a reduction in EMG amplitude (21.0%; P\u3c0.01). Importantly, a subsequent bout of static stretch, which was identical to that used in study 1, did not result in a further change in any measure (P \u3e 0.05). Whilst concentric moment and EMG recovered 30 min later, the decreases in Achilles tendon stiffness and passive moment remained. Thus, the normal stretch-induced reductions in force production were removed when isometric contractions were performed prior to stretch, but this was because concentric strength and neuromuscular activity were already affected; the reduction in concentric moment without a decrease in isometric moment indicates a contraction mode-specific response. The final study revealed that the use of concentric contractions (6×8-s) also resulted in similar reductions in Achilles tendon stiffness (11.7%; P\u3c0.01) and concentric joint moment (6.6%; P\u3c0.01) as the isometric contractions, and these were correlated (r = 0.94; P\u3c0.01) with a reduction in EMG amplitude (10.2%; P\u3c0.01). However, a further reduction in concentric moment was detected following an identical bout of static stretch (5.8%; P\u3c0.01) with no further change in EMG. Importantly, EMG recovered 30 min later while concentric moment remained depressed (9.2%; P\u3c0.01), indicating a musclebased mechanism for these force losses. No reduction in GM muscle operating length was found, removing this as a mechanism underpinning the losses in force. The findings from the present series of studies have important implications for research study design as the warm-up imposed on subjects prior to stretch seems to strongly influence the impact of stretch. Furthermore, the results also have important practical implications in the formulation of preperformance routines where maximal force production in the plantarflexors is an important goal

Mechanisms of Impaired Motor Unit Firing Behavior in the Vastus Lateralis Muscle after Stroke

The purpose of this dissertation research project was to examine the role of impaired motor unit firing behavior on force generation after a stroke. We studied the relationship between intrinsic motoneuron properties and inhibitory sensory pathways to deficient motoneuron activity in the vastus lateralis muscle after a stroke. Individuals with stroke often have deficits with force generation and volitional relaxation. Current models of impaired force output after a stroke focus primarily on the pathology within the corticospinal pathway because of decreased descending drive. Though this is an important aspect of deficient motoneuron output, it is incomplete because motoneurons receive other inputs that can shape motor output. Because the motoneuron is the last site of signal integration for muscle contractions, using methods that study motor unit activity can provide a window to the activity in the spinal circuitry. This research study utilized a novel algorithm that decomposed electromyography (EMG) signals into the contributions of the individual motor units. This provided the individual firing instances for a large number of concurrently active motor units during isometric contractions of the knee extensors. In the first aim, the association between the hyperemic response and motor unit firing rate modulation to intermittent, fatiguing contractions was investigated. It was found that the magnitude of blood flow was lower for individuals with stroke compared to healthy controls, but both groups increased blood flow similarly in response to fatiguing contractions. This did not relate to changes in muscle fiber contractibility for the participants with stroke; rather, participants better able to increase blood flow showed greater modulation in motor unit firing rates. To further investigate how ischemic conditions impact motor unit output, the second aim used a blood pressure cuff to completely occlude blood flow through the femoral artery with the intent of activating inhibitory afferent pathways. We found that ischemic conditions had a greater inhibitory impact on motor unit output for individuals with stroke compared to healthy controls, possibly because of hyper-excitable group III/IV afferent pathways. The final aim investigated how stroke related changes in the intrinsic excitability of the motoneurons impacted prolonged motor unit firing during voluntary relaxation. A serotonin reuptake inhibitor was administered to quantify motoneuron sensitivity to neuromodulatory inputs. This study found that the serotonin reuptake inhibitor increased muscle relaxation and may have reduced persistent inward current contributions to prolonged motor unit firing. In conclusion, while damage to the corticospinal tract is a major component to poor functionality, the intrinsic properties of the motoneuron and sensory pathways to the motoneuron pool are essential for understanding deficient motor control after a stroke

Deep muscle function in the cervical spine: Application to musculoskeletal modelling

Neck pain in occupational tasks is a problem that involves a high cost to society therefore, understanding the mechanics of musculoskeletal loading is important in formulating preventative rehabilitation strategies. Musculoskeletal modelling of the neck provides a means by which to calculate loads on the components and muscles of the neck thus allowing quantitative data to be gained non-invasivcly for a wide range of occupational tasks. Anatomically detailed, electromyography (EMG) driven neck models require deep muscle EMG activation profiles which arc difficult to attain without invasive EMG procedures. The aim of this study was to determine whether EMG activity of semispinalis capitis (a posterior deep neck muscle) could be predicted from the EMG activity of trapezius (a posterior superficial neck muscle) and whether EMG activity from splenius capitis (a posterolateral deep neck muscle) could be predicted from the EMG activity of levator scapulae (a representative posterolateral superficial muscle). Surface EMG was recorded unilaterally from two sites around the neck at the C4/5 level and intramuscular EMG was recorded using fine-wire EMG electrodes on six healthy male subjects. Subjects performed a series of maximal and sub-maximal isometric contractions against the torque arm of an isokinetic dynamometer in the direction of extension and right lateral bending with the head in neutral and non-neutral (20° flexion, 35° extension and 30° lateral bending) postures. EMG data were normalised using maximum voluntary isometric contractions (MVlC\u27s) based on a reliability study that was also conducted. The root mean of the squared differences (RMS difference) was used to compare the surface and intramuscular EMG waveforms. RMS difference was chosen as the best indication of predicability, as a quantitative assessment of amplitude difference was obtained using this method. The mean of the RMS difference values between surface and deep musculature in this study was 19.H %MVIC for the posterior aspect of the neck and 23.9 %MVIC for the posterolateral aspect of the neck. Due to the magnitude of difference between the surface and intramuscular EMG electrodes, it was concluded that EMG activity of the surface muscles docs not represent activity of deep musculature in the posterior and posterolateral aspects of the neck

Central and peripheral determinants of fatigue in acute hypoxia

This thesis was submitted for the degree of Docter of Philosophy and awarded by Brunel University on 24th March 2011.Fatigue is defined as an exercise-induced decrease in maximal voluntary force produced by a muscle. Fatigue may arise from central and/or peripheral mechanisms. Supraspinal fatigue (a component of central fatigue) is defined as a suboptimal output from the motor cortex and measured using transcranial magnetic stimulation (TMS). Reductions in O2 supply (hypoxia) exacerbate fatigue and as the severity of hypoxia increases, central mechanisms of fatigue are thought to contribute more to exercise intolerance. In study 1, the feasibility of TMS to measure cortical voluntary activation and supraspinal fatigue of human knee-extensors was determined. TMS produced reliable measurements of cortical voluntary activation within- and between-days, and enabled the assessment of supraspinal fatigue. In study 2, the mechanisms of fatigue during single-limb exercise in normoxia (arterial O2 saturation [SaO2] ~98%), and mild to severe hypoxia (SaO2 93-80%) were determined. Hypoxia did not alter neuromuscular function or cortical voluntary activation of the knee-extensors at rest, despite large reductions in cerebral oxygenation. Maximal force declined by ~30% after single-limb exercise in all conditions, despite reduced exercise time in severe-hypoxia compared to normoxia (15.9 ± 5.4 vs. 24.7 ± 5.5 min; p < 0.05). Peripheral mechanisms of fatigue contributed more to the reduction in force generating capacity of the knee-extensors following single-limb exercise in normoxia and mild- to moderate-hypoxia, whereas supraspinal fatigue played a greater role in severe-hypoxia. In study 3, the effect of constant-load cycling exercise to the limit of tolerance in hypoxia (SaO2 ~80%) and normoxia was investigated. Time to the limit of tolerance was significantly shorter in hypoxia compared to normoxia (3.6 ± 1.3 vs. 8.1 ± 2.9 min; p < 0.001). The reductions in maximal voluntary force and knee-extensor twitch force at task-failure were not different in hypoxia compared to normoxia. However, the level of supraspinal fatigue was exacerbated in hypoxia, and occurred in parallel with reductions in cerebral oxygenation and O2 delivery. Supraspinal fatigue contributes to the decrease in whole-body exercise tolerance in hypoxia, presumably as a consequence of inadequate O2 delivery to the brain

The Influence of Cerebral Blood Flow and Carbon Dioxide on Neuromuscular Responses During Environmental Stress

Although reductions in cerebral blood flow (CBF) may be implicated in the development of central fatigue during environmental stress, the contribution from hypocapnia-induced reductions in CBF versus reductions in CBF per se has yet to be isolated. The current research program examined the influence of CBF, with and without consequent hypocapnia, on neuromuscular responses during hypoxia and passive heat stress. To this end, neuromuscular responses, as indicated by motor evoked potentials (MEP), maximal M-wave (Mmax) and cortical voluntary activation (cVA) of the flexor carpi radialis muscle during isometric wrist flexion, was assessed in three separate projects: 1) hypocapnia, independent of concomitant reductions in CBF; 2) altered CBF during severe hypoxia and; 3) thermal hyperpnea-mediated reductions in CBF, independent of hypocapnia. All projects employed a custom-built dynamic end-tidal forcing system to control end-tidal PCO2 (PETCO2), independent of the prevailing environmental conditions, and cyclooxygenase inhibition using indomethacin (Indomethacin, 1.2 mg·Kg-1) to selectively reduce CBF (estimated using transcranial Doppler ultrasound) without changes in PETCO2. A primary finding of the present research program is that the excitability of the corticospinal tract is inherently sensitive to changes in PaCO2, as demonstrated by a 12% increase in MEP amplitude in response to moderate hypocapnia. Conversely, CBF mediated reductions in cerebral O2 delivery appear to decrease corticospinal excitability, as indicated by a 51-64% and 4% decrease in MEP amplitude in response to hypoxia and passive heat stress, respectively. The collective evidence from this research program suggests that impaired voluntary activation is associated with reductions in CBF; however, it must be noted that changes in cVA were not linearly correlated with changes in CBF. Therefore, other factors independent of CBF, such as increased perception of effort, distress or discomfort, may have contributed to the reductions in cVA. Despite the functional association between reductions in CBF and hypocapnia, both variables have distinct and independent influence on the neuromuscular system. Therefore, future studies should control or acknowledge the separate mechanistic influence of these two factors

Evaluation of the Long-term Reliability of Motor Uni Discharge Rates obtained by Decomposition of the Surface Electromyographic Signal

This study evaluated the long-term reliability of motor unit discharge rates (MUDRs) during isometric contractions at 60% maximum voluntary contraction (MVC), obtained by decomposition of the surface electromyographic (sEMG) signal from the flexor carpi radialis (FCR) and tibialis anterior (TA). There were four test sessions: one week between sessions 1 and 2; six weeks between sessions 2, 3, and 4. Participants performed 3 maximal isometric contractions of the wrist flexors and 3-isometric ramp contractions to 60% MVC. A load cell and 5-pin electrode (dEMG System, Delsys, Inc., Boston, MA) were used to monitor force and sEMG, respectively. The MUDRs were obtained using the Precision Decomposition Algorithm III in the dEMG Analysis software, and calculated as the inverse of the smoothed firing intervals. The mean discharge rate was calculated during a one-second window centered at the plateau portion of the 60% MVC ramp contraction. Maximal isometric strength during wrist flexion and dorsiflexion was also monitored. Across the four test sessions, maximal isometric strength of the wrist flexors and dorsiflexors increased 10 and 11.85%, respectively (p’s0.94). The MUDRs for the FCR (5.2%) and TA (7.8%) also exhibited slight fluctuations across the four test sessions (p’s<0.01). The consistency of MUDR values within each subject was still considered good, as the intraclass correlation coefficient for both measures was R=0.79. It was concluded that the overall long-term reliability of MUDRs in both the FCR and TA was good

TEMPORAL NEUROMUSCULAR ALTERATIONS OF THE QUADRICEPS AFTER UNILATERAL ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION

Objective: The primary aim of this research was to examine the temporal pattern of neuromuscular quadriceps deficits in both the involved and uninvolved limbs of patients assigned to the control group after anterior cruciate ligament reconstruction (ACLr), by assessing quadriceps strength, voluntary activation, and corticomotor excitability prior to surgery (baseline), three months after ACLr, and six months after ACLr. A secondary aim of this research was to determine whether quadriceps strength, voluntary activation, and/or corticomotor excitability assessed in patients prior to ACLr and/or at three months after surgery, is predictive of lower extremity postural control and/or self-reported function at six months after ACLr. Lastly, a tertiary aim of this research was to determine if a 12-week home-based neuromuscular electrical stimulation (Home-NMES) program elicits greater bilateral improvements in quadriceps strength, voluntary activation, and corticomotor excitability of patients at three and six months after ACLr compared to a 12-week standard home-exercise program (control group). Participants: Fifty patients scheduled to undergo unilateral ACLr were randomly allocated to the home-NMES group (19 Female, 6 Male; age: 18.9 ± 5.4 years; height: 170.8 ± 9.7 cm; weight: 74.6 ± 18.5 kg; 28.0±20.0 days-post-injury) or control group (14 Female, 11 Male; age: 19.4 ± 4.5 years; height: 171.1 ± 11.5 cm; weight: 70.7 ± 11.9 kg). Methods: A randomized clinical trial design was used in this study. Prior to ACLr, isometric quadriceps strength and voluntary quadriceps activation were assessed in both limbs of patients, and corticomotor excitability was assessed in the involved limb. Three days after ACLr, both groups were instructed to begin their allocated interventions. The Home-NMES group administered NMES to their involved limb’s quadriceps three sessions a day for 15 minutes, and five days a week for 12 weeks using a portable NMES device. The control group was treated according to the current standard-of-care, but they were also instructed to perform volitional isometric quadriceps contractions for the same duration and frequency as the Home-Based NMES protocol. The outcomes measures were reassessed in both groups at three and six months post-ACLr. Main Outcome Measures: Quadriceps strength and voluntary activation were assessed using maximal voluntary isometric contractions and the superimposed burst technique, respectively. Normalized peak knee extension torque and central activation ratio were used to quantify isometric quadriceps strength and activation, respectively. Corticomotor excitability was evaluated with transcranial magnetic stimulation, and quantified with active motor threshold). The Y-balance test anterior reach (YBT-A) and Knee Injury and Osteoarthritis Outcome Score (KOOS) were used to assess the patients lower extremity knee function at six months post-ACLr. Statistical Analyses: Specific Aim 1: A 2x3 (limb x time) mixed model, ANOVA with repeated measures was performed in the control group to assess differences between the involved limb and the uninvolved limb for isometric quadriceps strength, and voluntary quadriceps activation over time. A one-way mixed model, ANOVA with repeated measures was performed in the control group to assess differences in corticomotor excitability over time. Post-hoc comparisons were performed when appropriate. Specific Aim 2: Separate, mixed model, linear regression analyses were performed in the control group (involved limb) to determine the effect that the neuromuscular quadriceps outcome measures assessed at baseline and 3 months post-ACLr, had on lower extremity knee functional outcome measures assessed at 6 months post-ACLr. Specific Aim 3: A 2x2x3 (group x limb x time) mixed model, ANOVA with repeated measures was performed to assess group differences between the involved limb and the uninvolved limb in isometric quadriceps strength, and voluntary quadriceps activation over time. A 2x3 (group x time) mixed model, ANOVA with repeated measures was performed to assess group differences in corticomotor excitability over time. Post-hoc comparisons were performed when appropriate. Results: Aim 1: Patients demonstrated lower quadriceps strength on their involved limb compared to their uninvolved limb at baseline, three months post-ACLr, and six months post-ACLr. Quadriceps strength progressively decreased in the involved limb of patients from baseline to 3 months post-ACLr, baseline to 6 months post-ACLr, and increased from 3 months to 6 months post-ACLr. Quadriceps strength was also decreased in the uninvolved limb of patients from baseline to 6 months post-ACLr. ). Irrespective of when it was assessed, voluntary quadriceps activation was higher in the involved limb of patients compared to their uninvolved limb. There were no changes in corticomotor excitability of the involved limb over time. Specific Aim 2: The quadriceps strength of patients at three months post-ACLr had a significant positive effect on their 6-month YBT-A performance KOOS score. ). Neither voluntary quadriceps activation or corticomotor excitability or AMT (at baseline or 3-month post-ACLr) had a significant effect on any of the 6-month lower extremity functional outcome measures. Specific Aim 3: Irrespective of limb or when it was assessed, quadriceps strength was higher in the control group compared to the Home-NMES group. Both groups demonstrated lower quadriceps strength on their involved limbs compared to their uninvolved limbs at baseline, three months post-ACLr, and six months post-ACLr. Quadriceps progressively decreased in the involved limbs of both groups from baseline to three months post-ACLr and baseline to six months post-ACLr, and increased from three months to six months post- ACLr. At baseline, voluntary quadriceps activation was higher in the involved limbs of both groups compared to their uninvolved limbs. There were no group differences or changes over time observed in the involved limb of both groups with corticomotor excitability. Conclusion: Although quadriceps weakness is more apparent in the involved limb of patients after ACLr, the quadriceps strength of their uninvolved limb was also affected. Clinicians are encouraged to not rely on a quadriceps strength limb symmetry index when making return-sport-decisions for their patients after recovering from ACLr. The quadriceps in the uninvolved limb of patients demonstrated more inhibition, which may explain the quadriceps strength deficits observed in the uninvolved limb of patients following ACLr. To reduce the risk of subsequent injury upon return-to-sport and protect against the development of knee OA, we recommend that clinicians incorporate bilateral interventions aimed at restoring quadriceps strength and disinhibiting the quadriceps. Intensive quadriceps strengthening should be performed in the early stages of ACLr rehabilitation, so that lower extremity function can be improved in patients later on. Lastly, the effectiveness of home-based NMES as a modality for restoring quadriceps strength and activation in patients after ACLr is inconclusive. Home-based NMES provides patients with the ability to receive higher doses of NMES to the quadriceps; but its effectiveness may be limited by low contraction intensities and poor treatment compliance in patients