Shaping corticospinal pathways in virtual reality: effects of task complexity and sensory feedback during mirror therapy in neurologically intact individuals.

BACKGROUND: Restoration of limb function for individuals with unilateral weakness typically requires volitional muscle control, which is often not present for individuals with severe impairment. Mirror therapy-interventions using a mirror box to reflect the less-impaired limb onto the more-impaired limb-can facilitate corticospinal excitability, leading to enhanced recovery in severely impaired clinical populations. However, the mirror box applies limitations on mirror therapy, namely that all movements appear bilateral and are confined to a small area, impeding integration of complex activities and multisensory feedback (e.g., visuo-tactile stimulation). These limitations can be addressed with virtual reality, but the resulting effect on corticospinal excitability is unclear. OBJECTIVE: Examine how virtual reality-based unilateral mirroring, complex activities during mirroring, and visuo-tactile stimulation prior to mirroring affect corticospinal excitability. MATERIALS AND METHODS: Participants with no known neurological conditions (n = 17) donned a virtual reality system (NeuRRoVR) that displayed a first-person perspective of a virtual avatar that matched their motions. Transcranial magnetic stimulation-induced motor evoked potentials in the nondominant hand muscles were used to evaluate corticospinal excitability in four conditions: resting, mirroring, mirroring with prior visuo-tactile stimulation (mirroring + TACT), and control. During mirroring, the movements of each participant's dominant limb were reflected onto the nondominant limb of the virtual avatar, and the avatar's dominant limb was kept immobile (i.e., unilateral mirroring). The mirroring + TACT condition was the same as the mirroring condition, except that mirroring was preceded by visuo-tactile stimulation of the nondominant limb. During the control condition, unilateral mirroring was disabled. During all conditions, participants performed simple (flex/extend fingers) and complex (stack virtual blocks) activities. RESULTS: We found that unilateral mirroring increased corticospinal excitability compared to no mirroring (p < 0.001), complex activities increased excitability compared to simple activities during mirroring (p < 0.001), and visuo-tactile stimulation prior to mirroring decreased excitability (p = 0.032). We also found that these features did not interact with each other. DISCUSSIONS: The findings of this study shed light onto the neurological mechanisms of mirror therapy and demonstrate the unique ways in which virtual reality can augment mirror therapy. The findings have important implications for rehabilitation for design of virtual reality systems for clinical populations.

Conditioning of Motor Evoked Responses After Anterior Cruciate Ligament Reconstruction: Effects of Stimulus Intensity.

BACKGROUND: Operant conditioning of motor evoked torque (MEPTORQUE) can directly target the corticospinal pathway in patients with anterior cruciate ligament (ACL) reconstruction. However, it remains unclear whether operant conditioning can elicit short-term improvements in corticospinal excitability and whether these improvements are influenced by stimulus intensity. HYPOTHESIS: Quadriceps MEPTORQUE responses can be upconditioned in a single session and will elicit short-term adaptations in corticospinal excitability, with higher stimulus intensities eliciting greater effects. STUDY DESIGN: Randomized controlled laboratory study. LEVEL OF EVIDENCE: Level 2. METHODS: Thirty-six participants were assessed during a single session of an operant conditioning protocol. Participants were randomized into 1 of 3 groups for stimulus intensity used during operant conditioning based on the participant's active motor threshold (AMT: 100%, 120%, and 140%). Quadriceps MEPTORQUE amplitude was evaluated during a block of control transcranial magnetic stimulation trials (CTRL) to establish baseline corticospinal excitability, and 3 blocks of conditioning trials (COND) during which participants trained to upcondition their MEPTORQUE. MEPTORQUE recruitment curves were collected to evaluate the effect of operant conditioning on acute corticospinal adaptations. RESULTS: Participants with ACL reconstruction could upcondition their MEPTORQUE in a single session (P < 0.01; CTRL, 17.27 ± 1.28; COND, 21.35 ± 1.28 [mean ± standard error [SE] in N·m]), but this ability was not influenced by the stimulus intensity used during training (P = 0.84). Furthermore, significant improvements in corticospinal excitability were observed (P = 0.05; PRE, 687.91 ± 50.15; POST, 761.08 ± 50.15 [mean ± SE in N·m %AMT]), but stimulus intensity did not influence corticospinal adaptations (P = 0.67). CONCLUSION: Operant conditioning can elicit short-term neural adaptations in ACL-reconstructed patients. Future operant conditioning paradigms may effectively use any of the 3 stimulus intensities studied herein. CLINICAL RELEVANCE: Operant conditioning may be a feasible approach to improve corticospinal excitability after ACL reconstruction.

Quadriceps torque complexity before and after anterior cruciate ligament reconstruction.

OBJECTIVES: The purpose of this project was to longitudinally examine quadriceps torque complexity in a group of individuals who tore their ACL and underwent ACL reconstruction. DESIGN: Cohort analysis. METHODS: Thirty-four individuals completed maximal effort bilateral isometric strength testing after ACL injury but pre-surgery, five months' post-surgery (mid-point of rehabilitation), and when cleared to return to activity. Sample entropy, a nonlinear analysis of quadriceps torque control (complexity), was calculated from maximal isometric contractions. Two 3 × 2 repeated measures analysis of variance were used to examine changes over time and between limbs for quadriceps torque complexity and peak torque. RESULTS: Quadriceps peak torque was lower in the involved limb when compared to the uninvolved limb at every time point (p < 0.001). Peak torque of the involved limb was decreased at mid-point of rehabilitation compared to before surgery (p = 0.023) and at mid-point compared to return to activity (p = 0.041). Quadriceps sample entropy was higher in the involved limb compared to the uninvolved limb at the mid-point of rehabilitation (p < 0.001) and return to activity (p < 0.001), indicating greater complexity. The involved limb also demonstrated increased torque sample entropy from pre-surgery to mid-point of rehabilitation (p = 0.023), but not from pre-surgery to return to activity (p = 0.169) or from mid-point to return to activity (p = 0.541). CONCLUSIONS: Not only does quadriceps strength decline with ACL reconstruction, but quality of the quadriceps muscle contraction is also compromised. Increased torque complexity experienced in the ACL limb after reconstruction may contribute to impaired physical function in individuals following ACL reconstruction.

Electrically Evoked Torque at Rest is Strongly Related to Quadriceps Muscle Size in Individuals with Anterior Cruciate Ligament Reconstruction.

Electrically evoked torque at rest (i.e., the torque produced from supramaximal stimul applied to a resting muscle) has been shown to be related to muscle size in healthy adults, but this relationship has not been evaluated in pathological populations where atrophy is present. This study aimed to evaluate the relationship between the electrically evoked torque at rest and vastus lateralis cross-sectional area (CSA) in individuals with anterior cruciate ligament (ACL) reconstruction. Eighteen individuals with ACL reconstruction participated. Quadriceps electrically evoked torque at rest was elicited bilaterally via sex-specific, standardized supramaximal triplet stimulations. Vastus lateralis CSA was measured at 50% of thigh length using ultrasound. Pearson's r and partial correlations were used to evaluate associations between outcomes. Evoked torque at rest was positively associated with vastus lateralis CSA in the ACL reconstructed limb (r=0.865, partial r=0.816, P<0.01), non-reconstructed limb (r=0.628, partial r=0.575, P<0.05), and side-to-side ratios (r=0.670, partial r=0.659, P<0.01). These results indicate that electrically evoked torque at rest may indirectly assess side-to-side differences in quadriceps muscle size after ACL reconstruction.

Quadriceps motor evoked torque is a reliable measure of corticospinal excitability in individuals with anterior cruciate ligament reconstruction.

This study comprehensively evaluated the test-retest reliability of raw and normalized quadriceps motor evoked responses elicited by transcranial magnetic stimulation (TMS) in individuals with anterior cruciate ligament (ACL) reconstruction. Fifteen participants were tested on three different days that were separated at least by 24 h. Motor evoked responses were collected during a small background contraction on the reconstructed leg across a range of TMS intensities using torque (MEPTORQUE) and electromyographic (MEPEMG) responses. MEPTORQUE and MEPEMG were evaluated using different normalization procedures (raw, normalized to maximum voluntary isometric contraction [MVIC], peak MEP, and background contraction). MEPTORQUE was also normalized to the magnetically-evoked peripheral resting twitch torque. The area under the recruitment curve was computed for both raw and normalized MEPs. Intraclass correlation coefficients (ICCs) were determined to assess test-retest reliability. Results indicated that MEPTORQUE generally showed greater reliability than MEPEMG for all normalization procedures. Vastus medialis MEPEMG generally showed greater reliability than rectus femoris MEPEMG. Finally, both MEPTORQUE and MEPEMG exhibited good reliability, even when not normalized. These findings indicate that MEPTORQUE and MEPEMG offer reliable measures of corticospinal function and suggest that MEPTORQUE is a suitable alternative to MEPEMG for measuring quadriceps corticospinal excitability in individuals with ACL reconstruction.

The Influence of Sex, Body Mass Index, and Age on Cartilage Metabolism Biomarkers in Patients After Anterior Cruciate Ligament Injury and Reconstruction.

CONTEXT: Serum biomarkers may allow for the early identification of posttraumatic osteoarthritis after anterior cruciate ligament (ACL) injury and reconstruction. Homeostasis of matrix-metalloproteinase-3 (MMP-3) and type II collagen turnover biomarkers (C2C:CPII ratio) is believed to be compromised in individuals with ACL injury, yet the influence of sex, body mass index (BMI), and age on these biomarkers before and after ACL reconstruction remains unknown. OBJECTIVE: To determine the relationship of sex, BMI, and age with serum levels of MMP-3 and C2C:CPII before and after ACL reconstruction. DESIGN: Descriptive laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-two (females = 18, males = 14) individuals with ACL injuries. MAIN OUTCOME MEASURE(S): Demographic variables and blood samples were collected before surgery and at return to activity. Serum was extracted from the blood and assays were used to quantify MMP-3 and C2C:CPII. Generalized linear mixed-effects regression models were used to assess the relationships between sex, BMI, age, time, and participant on the outcome variables. RESULTS: A significant time × sex interaction was identified for MMP-3 levels (P = .021), whereby MMP-3 levels were higher in males at return to activity (males, 2.71 ± 0.59 ng/mL; females, 1.92 ± 0.60 ng/mL; P = .017). Males also had higher MMP-3 levels at return to activity when compared with presurgery levels (P = .009). A main effect for age demonstrated that older age was associated with higher MMP-3 levels. No significant main or interaction effects were noted for C2C:CPII levels. CONCLUSIONS: Upregulation of MMP-3 serum levels may occur after ACL reconstruction, particularly in males, which may have deleterious consequences for the cartilage matrix. Sex, BMI, and time did not influence C2C:CPII ratios, but further research with larger sample sizes is needed to confirm these findings.

Estimates of voluntary activation in individuals with anterior cruciate ligament reconstruction: Effects of type of stimulator, number of stimuli, and quantification technique.

BACKGROUND: Accurate quantification of voluntary activation is important for understanding the extent of quadriceps dysfunction in individuals with anterior cruciate ligament reconstruction (ACLR). Voluntary activation has been quantified using both percent activation derived from the interpolated twitch technique and central activation ratio (CAR) derived from the burst superimposition technique, as well as by using different types of electrical stimulators and pulse train conditions. However, it is unclear how these parameters affect voluntary activation estimates in individuals with ACLR. This study was performed to fill this important knowledge gap in the anterior cruciate ligament literature. METHODS: Quadriceps strength and voluntary activation were examined in 18 ACLR participants (12 quadriceps/patellar tendon graft, 6 hamstring tendon graft; time since ACLR: 1.06 ± 0.82 years, mean ±  SD) at 90° of knee flexion using 2 stimulators (Digitimer and Grass) and pulse train conditions (3-pulse and 10-pulse). Voluntary activation was quantified by calculating both CAR and percent activation. RESULTS: Results indicated that voluntary activation was significantly overestimated by CAR when compared with percent activation (p < 0.001). Voluntary activation estimates were not affected by pulse train conditions when using percent activation; however, 3-pulse stimuli resulted in greater overestimation than 10-pulse stimuli when using CAR (p = 0.003). Voluntary activation did not differ between stimulators (p > 0.05); however, the Digitimer evoked greater torque at rest than the Grass (p < 0.001). CONCLUSION: These results indicate that percent activation derived from the interpolated twitch technique provides superior estimates of voluntary activation than CAR derived from burst superimposition and is less affected by pulse train conditions or stimulators in individuals with ACLR.

How does anterior cruciate ligament reconstruction affect the functioning of the brain and spinal cord? A systematic review with meta-analysis.

OBJECTIVE: To examine the effect of anterior cruciate ligament (ACL) reconstruction on spinal-reflex and corticospinal excitability of the quadriceps muscle. METHODS: A comprehensive electronic database search was performed to identify studies that objectively measured Hoffmann reflex to muscle response ratio, motor threshold, and motor evoked potentials after ACL reconstruction. Pooled standardized mean differences (SMDs) were computed using a random effects meta-analysis model. RESULTS: A total of 13 studies were eligible for analysis. The Hoffmann reflex to muscle response ratio was significantly higher on both the reconstructed and non-reconstructed legs when compared with the healthy control leg (SMD = 0.28, 95% confidence interval (95%CI): 0.08-0.49, p = 0.006 and SMD = 0.22, 95%CI: 0.04-0.40, p = 0.016, respectively) but did not differ between legs (SMD = 0.10, 95%CI: -0.01 to 0.21, p = 0.078). The motor threshold was significantly higher on both the reconstructed (SMD = 0.76, 95%CI: 0.40-1.12, p < 0.001) and non-reconstructed legs (SMD = 0.47, 95%CI: 0.00-0.95, p = 0.049) when compared with the legs of healthy controls. The reconstructed leg also had a higher motor threshold when compared with the non-reconstructed leg (SMD = 0.20, 95%CI: 0.06-0.34, p = 0.005). These changes were paralleled by bilateral reductions in quadriceps strength (ACL reconstructed: SMD = -0.78, 95%CI: -1.07 to -0.49, p < 0.001; non-reconstructed: SMD = -0.32, 95%CI: -0.63 to -0.01, p = 0.042) and quadriceps voluntary activation (ACL reconstructed: SMD = -0.73, 95%CI: -0.97 to -0.50, p < 0.001; non-reconstructed: SMD = -0.55, 95%CI: -0.82 to -0.27, p < 0.001) when compared with healthy controls. CONCLUSION: There is increased excitability of the spinal-reflex pathways and reduced excitability of the corticospinal pathways following ACL reconstruction. These changes are paralleled by reductions in quadriceps strength and voluntary activation, suggesting that rehabilitation interventions should focus on normalizing the excitability of neural pathways to effectively address quadriceps dysfunction after ACL reconstruction.

Type of measurement used influences central and peripheral contributions to quadriceps weakness after anterior cruciate ligament (ACL) reconstruction.

OBJECTIVE: The relative contribution of muscle size and voluntary activation (VA) on quadriceps strength after anterior cruciate ligament (ACL) reconstruction remains inconclusive. Here, we aimed to determine the contributions of muscle size and VA on quadriceps strength in ACL-reconstructed patients and determine if contributions were similar if unilateral outcomes (i.e. ACL-reconstructed limb) or the LSI was used. DESIGN: A cross-sectional study. SETTING: A university research laboratory. PARTICIPANTS: Sixteen individuals 6-12 months after ACL reconstruction (Age: 22.3 ± 6.0yr, Height: 1.7 ± 0.1 m, Mass: 68.7 ± 11.5 kg) were recruited. MAIN OUTCOME MEASURES: Quadriceps isometric strength and VA, via the interpolated triplet technique, were assessed bilaterally. Ultrasound images were acquired of the vastus lateralis to calculate cross-sectional area (CSA) in both legs. LSI's were computed for all variables by expressing values of the reconstructed leg as a percent of the non-reconstructed leg. Separate stepwise linear regressions were performed to examine the contribution of VA and CSA on quadriceps strength. Model 1 used LSI for all outcomes and model 2 used outcomes from the reconstructed leg. RESULTS: We observed between limb deficits of 27.78% in quadriceps strength, 13.61% in vastus lateralis CSA, and 13.18% in VA (P < 0.05). Strength LSI was significantly predicted by VA LSI (R2 = 0.45, P < 0.01), but not by CSA LSI (R2 = 0.01, P =0.87). Reconstructed leg strength was significantly predicted by VL CSA (R2 = 0.50, P < 0.01) but not quadriceps VA (R2 = 0.08, P =0.11). CONCLUSIONS: The contributions of VA and CSA on quadriceps PT differed greatly if LSI or reconstructed leg outcomes were used. Evaluation of VA and CSA in unison may be provide a more holistic understanding of the sources of muscle weakness after ACL reconstruction.