Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.

Quantitative somatosensory assessments in patients with persistent pain following groin hernia repair: A systematic review with a meta-analytical approach.

OBJECTIVES: Quantitative sensory testing (QST) provides an assessment of cutaneous and deep tissue sensitivity and pain perception under normal and pathological settings. Approximately 2-4% of individuals undergoing groin hernia repair (GHR) develop severe persistent postsurgical pain (PPSP). The aims of this systematic review of PPSP-patients were (1) to retrieve and methodologically characterize the available QST literature and (2) to explore the role of QST in understanding mechanisms underlying PPSP following GHR. METHODS: A systematic literature search was conducted from JAN-1992 to SEP-2022 in PubMed, EMBASE, and Google Scholar. For inclusion, studies had to report at least one QST-modality in patients with PPSP. Risk of bias assessment of the studies was conducted utilizing the Newcastle Ottawa Scale and Cochrane's Risk of Bias assessment tool 2.0. The review provided both a qualitative and quantitative analysis of the results. A random effects model was used for meta-analysis. RESULTS: Twenty-five studies were included (5 randomized controlled trials, 20 non-randomized controlled trials). Overall, risk of bias was low. Compared with the contralateral side or controls, there were significant alterations in somatosensory function of the surgical site in PPSP-patients. Following thresholds were significantly increased: mechanical detection thresholds for punctate stimuli (mean difference (95% CI) 3.3 (1.6, 6.9) mN (P = 0.002)), warmth detection thresholds (3.2 (1.6, 4.7) °C (P = 0.0001)), cool detection thresholds (-3.2 (-4.9, -1.6) °C (P = 0.0001)), and heat pain thresholds (1.9 (1.1, 2.7) °C (P = 0.00001)). However, the pressure pain thresholds were significantly decreased (-76 (-123, -30) kPa (P = 0.001)). CONCLUSION: Our review demonstrates a plethora of methods used regarding outcome assessments, data processing, and data interpretation. From a pathophysiological perspective, the most consistent findings were postsurgical cutaneous deafferentation and development of a pain generator in deeper connective tissues. TRIAL REGISTRATION: CRD42022331750.

Real-Time-Capable Muscle Force Estimation for Monitoring Robotic Rehabilitation Therapy in the Intensive Care Unit.

In this paper, a method is proposed to enable real-time monitoring of muscle forces during robotic rehabilitation therapy in the ICU. This method is solely based on sensor information provided by the rehabilitation robot. In current clinical practice, monitoring primarily takes place in the later stages of rehabilitation, but it would also be highly beneficial during early stages. Musculoskeletal models have large, mostly unrealized potential to support and improve patient monitoring. The method presented in this paper is based on a state-of-the-art muscle-tendon path model, which is applied to the use case of the robotic rehabilitation device VEMOTION. The muscle force estimation is validated against surface electromyography measurements of lower limb muscles from 12 healthy volunteers The results show an overall correlation of R = 0.70 0.25 for the single-joint muscle m. iliopsoas, which has a ±major contribution to hip flexion. Given this correlation, the proposed model could be used for real-time monitoring of active patient participation.

Estimating Joint Kinematics and Muscles Forces During Robotic Rehabilitation to Detect and Counteract Reduced Ankle Mobility.

The paper presents a solution to detect active ankle joint movement while a patient undergoes therapy with a robotic lower limb rehabilitation device that neither restricts nor actively supports ankle dorsi- or plantarflexion. The presented method requires the addition of only two accelerometer sensors to the system as well as a musculoskeletal model of the lower limb. Using forward kinematics and inverse dynamics, it enables knee and ankle joint kinematic tracking in the sagittal plane and muscle force estimation. This is an extension of a previous work in which only hip joint tracking was possible and, thus, muscle force estimation was limited. The correlation results of the current validation study with 12 healthy subjects show high correlation (R=0.88±0.09) between the kinematics estimated with the proposed method and those calculated from a gold standard motion capture setup for all three joints (hip, knee, and ankle). The correlation results of the estimated m. tibialis anterior muscle force against electromyography measurements (R = 0.62±0.27) are promising and a first application to a patient data set shows potential for future clinical application.

Individualized Training of Back Muscles Using Iterative Learning Control of a Compliant Balance Board.

Here we present the GyroTrainer, a bespoke mechatronic balance board system designed to trigger activation of the back muscles while the user engages in a balance-challenging game. The GyroTrainer uses admittance control coupled with an iterative learning approach so as to tailor the admittance control parameters, i.e. difficulty level, according to the user's skill. Our experimental evaluation demonstrated that an individualized admittance control stiffness could be identified for each user, which corresponds with a desired level of difficulty and increased back muscle activity. A first game implementation demonstrates the feasibility of utilizing the GyroTrainer system and the individually identified admittance control stiffness for gamification of back muscle training.

Monitoring Active Patient Participation During Robotic Rehabilitation: Comparison Between a Robot-Based Metric and an EMG-Based Metric.

While rehabilitation robots present a much-needed solution to improving early mobilization therapy in demanding clinical settings, they also present new challenges and opportunities in patient monitoring. Aside from the fundamental challenge of quantifying a patient's voluntary contribution during robot-led therapy motion, many sensors cannot be used in clinical settings due to time and space limitations. In this paper, we present and compare two metrics for monitoring a patient's active participation in the motion. The two metrics, each derived from first principles, have the same biomechanical interpretability, i.e., active work by the patient during the robotic mobilization therapy, but are calculated in two different spaces (Cartesian vs. muscle space). Furthermore, the sensors used to quantify these two metrics are fully independent from each other and the associated measurements are unrelated. Specifically, the robot-based work metric utilizes robot-integrated force sensors, while the EMG-based work metric requires electrophysiological sensors. We then apply the two metrics to therapy performed using a clinically certified, commercially available robotic system and compare them against the specific instructions given to the healthy subjects as well as against each other. Both metric outputs qualitatively match the expected behavior of the healthy subjects. Additionally, strong correlations (median [Formula: see text]) are shown between the two metrics, not only for healthy subjects (n = 12) but also for patients (n = 2), providing solid evidence for their validity and translatability. Importantly, the robot-based work metric does not rely on any sensors outside of those integrated into the robot, thus making it ideal for application in clinical settings.

Somatosensory Outcomes Following Re-Surgery in Persistent Severe Pain After Groin Hernia Repair: A Prospective Observational Study.

Purpose: After groin hernia repair (globally more than 20 million/year) 2-4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy. Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory "component" indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8-11.5) months before and 4.0 (3.5-4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed. Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of -2.0, -2.5, and -2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function ("deafferentation"). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001). Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep "pain generator". The QST-analyses are useful adjuncts in mechanism-based somatosensory research.

Pulsed electric fields stimulate microglial transmitter release of VEGF, IL-8 and GLP-1 and activate endothelial cells through paracrine signaling.

As action potentials propagate along an axon, pulsed extracellular electric fields (E-fields) are induced. We investigated the role of E-fields in activating microglia cells and affecting capillary function and found that E-fields control human microglia secretions in concert with purinergic factors. We generated E-fields by applying transcranial pulsed electromagnetic fields (T-PEMF) identical to those appearing outside neurons as action potentials propagate. T-PEMF alone enhanced mRNA synthesis for VEGF, IL-8, IL-6 and the proglucagon gene as well as the PC1/3 enzyme that cleaves the proglucagon protein to glucagon and GLP-1 proteins. We found that T-PEMF enhanced secretion from microglia of VEGF, IL-8 and GLP-1 proteins having angiogenic and proliferative profiles. Interestingly, T-PEMF and purinergic transmitters together enhanced secretions confirming synergy between their actions. ATP also induced nitric oxide (NO) syntheses in distinct locations in the nucleus and the mRNA synthesis for the responsible iNOS was reduced by T-PEMF. When the microglia-secretory fluid was added to brain endothelial cells we saw vivid Ca2+ signaling and enhanced transcription of mRNA for IL-8 and VEGF. Our previous work shows that applying T-PEMF to the human brain provides up to 60% remission for patients with refractory depressions within 8 weeks and improvements for Parkinson patients. Thus, physiological E-fields activate microglia, work synergistically with neurotransmitters, and cause paracrine secretions which cause activation of capillaries. Application of these E-Fields is effective for treating refractory depressions and appear promising for treating neurodegenerative brain diseases.

Testing robot-based assist-as-needed therapy for improving active participation of a patient during early neurorehabilitation: a case study.

In this study, a patient in the Intensive Care-Unit received robot-based mobilization therapy with an assist-as-needed (AAN) function over the course of three weeks. Therapists were able to adapt the hip range of motion $\beta$, the bed verticalization angle $\alpha$ and the leg load force FLoad for each therapy, based on the current condition of the patient. To evaluate the patient active participation, surface electromyography (sEMG) of the M. rectus femoris (RF) and M. biceps femoris (BF) were measured and analyzed. It was observed that the patient active participation, measured through sEMG, increased along with increased hip range of motion $\beta$, bed verticalization angle $\alpha$ and leg load force FLoad set by the therapists. The patient muscle activation pattern followed the pattern of healthy controls, in part. To the authors' best knowledge, this study is the first of its kind to be performed with an ICU patient.

The Harald Breivik lecture 2022. Pathophysiology in persistent severe pain after groin hernia repair.

The transition from a healthy to a persistent severe pain state following otherwise successful elective surgery is a feared complication. Groin hernia repair, previously considered minor surgery, is a standard surgical procedure annually performed on 2,000 individuals per one million residents. A trajectory into persistent severe pain is, unfortunately, seen in 2-4%, severely impeding physical and psychosocial daily functions.

Trajectories in severe persistent pain after groin hernia repair: a retrospective analysis.

OBJECTIVES: Severe persistent post-surgical pain (PPSP) remains a significant healthcare problem. In the third most common surgical procedure in the U.K., groin hernia repair, including 85,000 surgeries, estimated 1,500-3,000 patients will annually develop severe PPSP. While the trajectory of PPSP is generally considered a continuation of the acute post-surgery pain, recent data suggest the condition may develop with a delayed onset. This study evaluated pain-trajectories in a consecutive cohort referred from groin hernia repair-surgeons to a tertiary PPSP-center. Potential explanatory variables based on individual psychometric, sensory, and surgical profiles were analyzed. METHODS: Patients completed graphs on pain trajectories and questionnaires on neuropathic pain, pain-related functional assessments, and psychometrics. Surgical records and quantitative sensory testing profiles were obtained. Pain trajectories were normalized, and pre- and post-surgical segments were analyzed by a normalized area-under-the-curve (AUC) technique. Principal component analysis (PCA) was applied to the explanatory variables. Significant PCA-components were further examined using multiple logistic regression models. RESULTS: In 95 patients, the AUC identified groups of post-surgical pain trajectories (p<0.0001): group I (n=48), acute high-intensity pain progressing to PPSP; group II (n=28), delayed onset of PPSP; group III (n=7), repeat-surgery gradually inducing PPSP. Data from groups IV (n=3) and V (n=9) were not included in the statistical analysis due to small sample size and data heterogeneity, respectively. The PCA/logistic analyses indicated that neuropathic pain scores, composite pain scores, and pain-related functional assessments were explanatory variables for groups I and II. CONCLUSIONS: Pain trajectories in PPSP after groin hernia repair are heterogeneous but can be classified into meaningful groups. Examination of pain trajectories, mirroring the transition from acute to severe persistent post-surgical pain, has the potential of uncovering clinically relevant pathophysiological mechanisms.

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose µ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

A national center for persistent severe pain after groin hernia repair: Five-year prospective data.

Severe persistent pain after groin hernia repair impairs quality-of-life. Prospective, consecutive cohort study including patients with pain-related impairment of physical and social life. Relevant surgical records were obtained, and examinations were by standardized clinical and neurophysiological tests. Patients demonstrating pain sensitivity to pressure algometry in the operated groin underwent re-surgery, while patients with neuropathic pain received pharmacotherapy. Questionnaires at baseline (Q0) and at the 5-year time point (Q5Y) were used in outcome analyses of pain intensity (numeric rating scale [NRS] 0-10) and pain-related effect on the activity-of-daily-living (Activities Assessment Scale [AAS]). Data are mean (95% CI).Analyses were made in 172/204 (84%) eligible patients. In 54/172 (31%) patients re-surgery (meshectomy/selective neurectomy) was performed, while the remaining 118/172 (69%) patients received pharmacotherapy. In the re-surgery group, activity-related, and average NRS-scores at Q0 were 6.6 (5.6-7.9) and 5.9 (5.6-5.9), respectively. Correspondingly, NRS-scores at Q5Y was 4.1 (3.3-5.1) and 3.1 (2.3-4.0; Q0 vs. Q5Y: P < .0005), respectively. Although both groups experienced a significant improvement in AAS-scores comparing Q0 vs. Q5Y (re-surgery group: 28% (4-43%; P < .0001); pharmacotherapy group: 5% (0-11%; P = .005)) the improvement was significantly larger in the re-surgery group (P = .02).This 5-year cohort study in patients with severe persistent pain after groin hernia repair signals that selection to re-surgery or pharmacotherapy, based on examination of pain sensitivity, is associated with significant improvement in outcome. Analyzing composite endpoints, combining pain and physical function, are novel in exploring interventional effects.ClinicalTrials.gov Identifier NCT03713047.

Accuracy and precision of loadsol® insole force-sensors for the quantification of ground reaction force-based biomechanical running parameters.

Force plates represent the "gold standard" in measuring running kinetics to predict performance or to identify the sources of running-related injuries. As these measurements are generally limited to laboratory analyses, wireless high-quality sensors for measuring in the field are needed. This work analysed the accuracy and precision of a new wireless insole forcesensor for quantifying running-related kinetic parameters. Vertical ground reaction force (GRF) was simultaneously measured with pit-mounted force plates (1 kHz) and loadsol® sensors (100 Hz) under unshod forefoot and rearfoot running-step conditions. GRF data collections were repeated four times, each separated by 30 min treadmill running, to test influence of extended use. A repeated-measures ANOVA was used to identify differences between measurement devices. Additionally, mean bias and Bland-Altman limits of agreement (LoA) were calculated. We found a significant difference (p < .05) in ground contact time, peak force, and force rate, while there was no difference in parameters impulse, time to peak, and negative force rate. There was no influence of time point of measurement. The mean bias of ground contact time, impulse, peak force, and time to peak ranged between 0.6% and 3.4%, demonstrating high accuracy of loadsol® devices for these parameters. For these same parameters, the LoA analysis showed that 95% of all measurement differences between insole and force plate measurements were less than 12%, demonstrating high precision of the sensors. However, highly dynamic behaviour of GRF, such as force rate, is not yet sufficiently resolved by the insole devices, which is likely explained by the low sampling rate.

Design Considerations of a Fiber Optic Pressure Sensor Protective Housing for Intramuscular Pressure Measurements.

Intramuscular pressure (IMP), defined as skeletal muscle interstitial fluid pressure, reflects changes in individual muscle tension and may provide crucial insight into musculoskeletal biomechanics and pathologies. IMP may be measured using fiber-optic fluid pressure sensors, provided the sensor is adequately anchored to and shielded from surrounding muscle tissue. Ineffective anchoring enables sensor motion and inadequate shielding facilitates direct sensor-tissue interaction, which result in measurement artifacts and force-IMP dissociation. The purpose of this study was to compare the effectiveness of polyimide and nitinol protective housing designs to anchor pressure sensors to muscle tissue, prevent IMP measurement artifacts, and optimize the force-IMP correlation. Anchoring capacity was quantified as force required to dislodge sensors from muscle tissue. Force-IMP correlations and non-physiological measurement artifacts were quantified during isometric muscle activations of the rabbit tibialis anterior. Housing structural integrity was assessed after both anchoring and activation testing. Although there was no statistically significant difference in anchoring capacity, nitinol housings demonstrated greater structural integrity and superior force-IMP correlations. Further design improvements are needed to prevent tissue accumulation in the housing recess associated with artificially high IMP measurements. These findings emphasize fundamental protective housing design elements crucial for achieving reliable IMP measurements.

Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol: A randomized, double-blind, placebo-controlled, crossover trial with an enriched design.

Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose-response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days-days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1-4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8-512 mN) at primary and secondary hyperalgesia areas (days 1-4).The naloxone-induced unmasking of latent sensitization is an interesting model for exploring the transition from acute to chronic pain. The results from the present study may provide valuable information regarding future research in persistent postsurgical pain states.

Characterization of three dimensional volumetric strain distribution during passive tension of the human tibialis anterior using Cine Phase Contrast MRI.

Intramuscular pressure correlates strongly with muscle tension and is a promising tool for quantifying individual muscle force. However, clinical application is impeded by measurement variability that is not fully understood. Previous studies point to regional differences in IMP, specifically increasing pressure with muscle depth. Based on conservation of mass, intramuscular pressure and volumetric strain distributions may be inversely related. Therefore, we hypothesized volumetric strain would decrease with muscle depth. To test this we quantified 3D volumetric strain in the tibialis anterior of 12 healthy subjects using Cine Phase Contrast Magnetic Resonance Imaging. Cine Phase Contrast data were collected while a custom apparatus rotated the subjects' ankle continuously between neutral and plantarflexion. A T2-weighted image stack was used to define the resting tibials anterior position. Custom and commercial post-processing software were used to quantify the volumetric strain distribution. To characterize regional strain changes, the muscle was divided into superior-inferior sections and either medial-lateral or anterior-posterior slices. Mean volumetric strain was compared across the sections and slices. As hypothesized, volumetric strain demonstrated regional differences with a decreasing trend from the anterior (superficial) to the posterior (deep) muscle regions. Statistical tests showed significant main effects and interactions of superior-inferior and anterior-posterior position as well as superior-inferior and medial-lateral position on regional strain. These data support our hypothesis and imply a potential relationship between regional volumetric strain and intramuscular pressure. This finding may advance our understanding of intramuscular pressure variability sources and lead to more reliable measurement solutions in the future.

A principal component analysis approach to correcting the knee flexion axis during gait.

Accurate and precise knee flexion axis identification is critical for prescribing and assessing tibial and femoral derotation osteotomies, but is highly prone to marker misplacement-induced error. The purpose of this study was to develop an efficient algorithm for post-hoc correction of the knee flexion axis and test its efficacy relative to other established algorithms. Gait data were collected on twelve healthy subjects using standard marker placement as well as intentionally misplaced lateral knee markers. The efficacy of the algorithm was assessed by quantifying the reduction in knee angle errors. Crosstalk error was quantified from the coefficient of determination (r(2)) between knee flexion and adduction angles. Mean rotation offset error (αo) was quantified from the knee and hip rotation kinematics across the gait cycle. The principal component analysis (PCA)-based algorithm significantly reduced r(2) (p<0.001) and caused αo,knee to converge toward 11.9±8.0° of external rotation, demonstrating improved certainty of the knee kinematics. The within-subject standard deviation of αo,hip between marker placements was reduced from 13.5±1.5° to 0.7±0.2° (p<0.001), demonstrating improved precision of the knee kinematics. The PCA-based algorithm performed at levels comparable to a knee abduction-adduction minimization algorithm (Baker et al., 1999) and better than a null space algorithm (Schwartz and Rozumalski, 2005) for this healthy subject population.