Fiber Recruitment Research Articles

An Overview of Blood Flow Restriction Physiology and Clinical Considerations.

The utilization of blood flow restriction has garnished considerable attention due to its widespread application and benefits that include strength enhancement, muscle hypertrophy, and increased level of function for specific populations. Blood flow restriction induces a hypoxic environment within a muscle group, initiating a metabolic cascade that stimulates muscle protein synthesis, altered gene regulation of muscle satellite cells, and increased muscle fiber recruitment, ultimately resulting in improved strength and endurance. When using blood flow restriction, consideration of the individual patient, occlusion pressure, cuff width, and cuff size are paramount. Blood flow restriction has been proven to be a consistently safe and effective tool for augmenting rehabilitative regimens for the upper and lower extremity.

Explicit consideration of fiber recruitment in vascular constitutive formulation using beta functions

Constitutive models are of fundamental importance for describing the mechanical behavior of vascular tissues. In this article, we present a constitutive model that explicitly accounts for collagen fiber recruitment. The formulation, developed based two experimental observations, consists in a systematic use of beta functions. The distribution of random waviness is modeled by beta distribution, and the fiber stresses are represented by incomplete beta functions which are shown to be flexible in capturing different types of responses data. A four-point dispersion model, derived in the context of planar von Mises distribution, is developed to take into account of the orientation distribution of fibers. The dispersion weights appear as Bernstein polynomials of a single dispersion parameter. The descriptive and predictive capabilities are assessed using three groups of experimental data encompassing the responses of porcine thoracic aorta, human intracranial aneurysm, and human ascending thoracic aortic aneurysm tissues. The descriptive performance is evaluated by the quality of constitutive fitting. The predictive ability is tested based on the accuracy in predicting unfitted responses as well as in finite element simulations. The assessment indicates that the model has excellent descriptive and predictive capabilities.

A mathematical model for viscoelastic properties of biological soft tissue.

A quaternary viscoelastic structure model with two characteristic times is presented to describe the viscoelastic properties of parallel-fibered collagen tissue. The comparison results of model prediction and experimental data of rabbit medial collateral ligaments show that the model could accurately describe viscoelastic behavior such as stress-relaxation, strain-strengthening and creep of bio-soft-tissue within a small scope of errors. To study the biomechanical mechanism of viscoelasticity that biological soft tissue shows, the influence of model parameters on viscoelastic behavior of bio-soft-tissue is analyzed and researched, which indicated that the major influential elements of stress-relaxation in bio-soft-tissue are elastic modulus, relaxation time and strain rate of proteoglycan-rich matrix. The influence of elastic modulus of collagen fibers on stress-relaxation is not significant. However, the nonlinearity of stress-strain curve and viscoelastic behavior of bio-soft-tissue mostly depends on recruitment and reorientation of collagen fibers under external loading.

A Numerical Model of the Acute Cardiac Effects Provoked by Cervical Vagus Nerve Stimulation.

Today, the diverse acute cardiac effects of vagus nerve stimulation (VNS) are still not fully understood. Therefore, we propose a numerical model that can predict the acute cardiac responses to VNS and explain the underlying mechanisms on different levels. We integrated a model of vagal nerve fiber recruitment and acetylcholine (ACh) kinetics at vagal nerve terminals into a cardiovascular system model. A sensitivity analysis was performed to identify the most important parameters of vagal cardiac pathways. These parameters were tuned, and the model was validated based on published data of experiments in anesthetized sheep. The four most important parameters are related to vagus nerve anatomy (electrode-fiber distances, fiber diameters) and ACh kinetics in the vagal neuroeffector junction (rate of ACh release and -hydrolysis) which together explain >53% of the observed variability in acute cardiac responses to VNS. The mean electrode-fiber distance and nerve fiber diameters obtained from tuning are 1.3 ± 0.09 mm, and 4.9 ± 0.25 μm; the ACh release and -hydrolysis rate constants are 0.023 s-1 and 0.77 s-1, respectively. With this parameterization, the model could accurately predict published data on the acute cardiac effects of VNS. The model can explain the cardiac responses to VNS on multiple levels. The results highlight the importance of four parameters tied to ACh dynamics and vagus nerve anatomy for predicting the cardiac effects of VNS. The model represents a substantial improvement in terms of comprehensibility of the underlying mechanisms of the acute cardiac responses to VNS.

Peristimulus Time Responses Predict Adaptation and Spontaneous Firing of Auditory-Nerve Fibers: From Rodents Data to Humans.

Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to predict the adaptation kinetics and spontaneous rate of the ANFs tuned at the PSTR probe frequency. The predictive model derived from gerbils was then validated in female mice and finally applied to humans by recording PSTRs from the auditory nerve in normal-hearing patients who underwent cerebellopontine angle surgeries. A rapid adaptation time constant of ∼3 ms and a mean spontaneous rate of ∼22 spikes/s in the 4 kHz frequency range were found. This study offers a promising diagnostic tool to map the human auditory nerve, thus opening new avenues to better understanding auditory neuropathies, tinnitus, and hyperacusis.SIGNIFICANCE STATEMENT Neural adaptation in auditory nerve fibers corresponds to the reduction in the neuronal activity to prolonged or repeated sound stimulation. For obvious ethical reasons, single-fiber recordings from the auditory nerve are not feasible in humans, creating a critical gap in extending data obtained using animal models to humans. Using electrocochleography in rodents, we inferred adaptation kinetics and spontaneous discharge rates of the auditory nerve fibers in humans. Routinely used in basic and clinical laboratories, this tool will provide a better understanding of auditory disorders such as neuropathies, tinnitus, and hyperacusis, and will help to improve hearing-aid fittings.

Design, analysis, and validation of an orderly recruitment valve for bio-inspired fluidic artificial muscles

Biological musculature employs variable recruitment of muscle fibers from smaller to larger units as the load increases. This orderly recruitment strategy has certain physiological advantages like minimizing fatigue and providing finer motor control. Recently fluidic artificial muscles (FAM) are gaining popularity as actuators due to their increased efficiency by employing bio-inspired recruitment strategies such as active variable recruitment (AVR). AVR systems use a multi-valve system (MVS) configuration to selectively recruit individual FAMs depending on the load. However, when using an MVS configuration, an increase in the number of motor units in a bundle corresponds to an increase in the number of valves in the system. This introduces greater complexity and weight. The objective of this paper is to propose, analyze, and demonstrate an orderly recruitment valve (ORV) concept that enables orderly recruitment of multiple FAMs in the system using a single valve. A mathematical model of an ORV-controlled FAM bundle is presented and validated by experiments performed on a proof-of-concept ORV experiment. The modeling is extended to explore a case study of a 1-DOF robot arm system consisting of an electrohydraulic pressurization system, ORV, and a FAM-actuated rotating arm plant and its dynamics are simulated to further demonstrate the capabilities of an ORV-controlled closed-loop system. An orderly recruitment strategy was implemented through a model-based feed forward controller. To benchmark the performance of the ORV, a conventional MVS with equivalent dynamics and controller was also implemented. Trajectory tracking simulations on both the systems revealed lower tracking error for the ORV controlled system compared to the MVS controlled system due to the unique cross-flow effects present in the ORV. However, the MVS, due to its independent and multiple valve setup, proved to be more adaptable for performance. For example, modifications to the recruitment thresholds of the MVS demonstrated improvement in tracking error, albeit with a sacrifice in efficiency. In the ORV, tracking performance remained insensitive to any variation in recruitment threshold. The results show that compared to the MVS, the ORV offers a simpler and more compact valving architecture at the expense of moderate losses in control flexibility and performance.

Remodeling of extracellular matrix in the urinary bladder of paraplegic rats results in increased compliance and delayed fiber recruitment 16 weeks after spinal cord injury

The ability of the urinary bladder to maintain low intravesical pressures while storing urine is key in ensuring proper organ function and highlights the key role that tissue mechanics plays in the lower urinary tract. Loss of supraspinal neuronal connections to the bladder after spinal cord injury can lead to remodeling of the structure of the bladder wall, which may alter its mechanical characteristics. In this study, we investigate if the morphology and mechanical properties of the bladder extracellular matrix are altered in rats 16 weeks after spinal cord injury as compared to animals who underwent sham surgery. We measured and quantified the changes in bladder geometry and mechanical behavior using histological analysis, tensile testing, and constitutive modeling. Our results suggest bladder compliance is increased in paraplegic animals 16 weeks post-injury. Furthermore, constitutive modeling showed that increased distensibility was driven by an increase in collagen fiber waviness, which altered the distribution of fiber recruitment during loading. Statement of significanceThe ability of the urinary bladder to store urine under low pressure is key in ensuring proper organ function. This highlights the important role that mechanics plays in the lower urinary tract. Loss of control of neurologic connection to the bladder from spinal cord injury can lead to changes of the structure of the bladder wall, resulting in altered mechanical characteristics. We found that the bladder wall's microstructure in rats 16 weeks after spinal cord injury is more compliant than in healthy animals. This is significant since it is the longest time post-injury analyzed, to date. Understanding the extreme remodeling capabilities of the bladder in pathological conditions is key to inform new possible therapies.

Augmented Transcutaneous Stimulation Using an Injectable Electrode: A Computational Study.

Minimally invasive neuromodulation technologies seek to marry the neural selectivity of implantable devices with the low-cost and non-invasive nature of transcutaneous electrical stimulation (TES). The Injectrode® is a needle-delivered electrode that is injected onto neural structures under image guidance. Power is then transcutaneously delivered to the Injectrode using surface electrodes. The Injectrode serves as a low-impedance conduit to guide current to the deep on-target nerve, reducing activation thresholds by an order of magnitude compared to using only surface stimulation electrodes. To minimize off-target recruitment of cutaneous fibers, the energy transfer efficiency from the surface electrodes to the Injectrode must be optimized. TES energy is transferred to the Injectrode through both capacitive and resistive mechanisms. Electrostatic finite element models generally used in TES research consider only the resistive means of energy transfer by defining tissue conductivities. Here, we present an electroquasistatic model, taking into consideration both the conductivity and permittivity of tissue, to understand transcutaneous power delivery to the Injectrode. The model was validated with measurements taken from (n = 4) swine cadavers. We used the validated model to investigate system and anatomic parameters that influence the coupling efficiency of the Injectrode energy delivery system. Our work suggests the relevance of electroquasistatic models to account for capacitive charge transfer mechanisms when studying TES, particularly when high-frequency voltage components are present, such as those used for voltage-controlled pulses and sinusoidal nerve blocks.

The root of the matter: nitrate-rich beetroot juice reduces skeletal muscle O2 uptake during exercise.

The root of the matter: nitrate-rich beetroot juice reduces skeletal muscle O2 uptake during exercise.

Enthesis strength, toughness and stiffness: an image-based model comparing tendon insertions with varying bony attachment geometries.

Tendons of the body differ dramatically in their function, mechanics and range of motion, but all connect to bone via an enthesis. Effective force transfer at the enthesis enables joint stability and mobility, with strength and stiffness arising from a fibrous architecture. However, how enthesis toughness arises across tendons with diverse loading orientations remains unclear. To study this, we performed simultaneous imaging of the bone and tendon in entheses that represent the range of tendon-to-bone insertions and extended a mathematical model to account for variations in insertion and bone geometry. We tested the hypothesis that toughness, across a range of tendon entheses, could be explained by differences observed in interactions between fibre architecture and bone architecture. In the model, toughness arose from fibre reorientation, recruitment and rupture, mediated by interactions between fibres at the enthesis and the bony ridge abutting it. When applied to tendons sometimes characterized as either energy-storing or positional, the model predicted that entheses of the former prioritize toughness over strength, while those of the latter prioritize consistent stiffness across loading directions. Results provide insight into techniques for surgical repair of tendon-to-bone attachments, and more broadly into mechanisms for the attachment of highly dissimilar materials.

Effects of acute static stretching on exercise efficiency during high-intensity cycling exercise.

Static stretching has been shown to reduce exercise efficiency and performance of aerobic exercises as well as decreasing the ability to generate maximum muscle force in momentary movements such as jumping. As a mechanism for the reduced efficiency, the possibility that changes in muscle fiber recruitment occur to compensate for the decrease in maximum voluntary contraction (MVC) has been suggested. We examined whether the stretching-induced decrease in exercise efficiency is accompanied by a decrease in MVC and changes in electromyographic (EMG) activities of exercising muscles. Eight healthy subjects performed 6 min of cycling exercise at 70% of maximal oxygen uptake in the conditions with and without pre-exercise static stretching (stretching condition [SC] and control condition [CC]). MVC was measured before stretching maneuvers (or the resting period in CC) and after the end of exercise. In the 6-min exercise test, respiratory parameters and EMG activities of knee extensors were measured. Oxygen uptake at 3 min and 6 min during the cycling exercise were higher in the SC than in the CC (P<0.05). There was no difference in MVC at the end of 6 min exercise between the two conditions. Similarly, there were no differences in EMG activities during the 6-min exercise between the two conditions. The results suggest that pre-exercise static stretching reduces exercise efficiency independent of its negative effect on MVC exertional capacity.

Comparison of Threshold and Tolerance Nociceptive Withdrawal Reflexes in Horses.

Simple SummaryNociception is the physiological basis of the complex experience of pain. An established model for its quantification in equine studies is based on the nociceptive withdrawal reflex evoked by electrical stimulation of a sensory nerve. The reflex is recorded via electromyography and it is common to determine the threshold at which a nociceptive-specific reflex activity can be observed. In the present study, the classical methodology was expanded for a deeper understanding of the physiology of nociceptive reflexes in horses. First, for each individual horse, a threshold was determined as the minimal stimulation intensity able to evoke a nociceptive withdrawal reflex. Second, the stimulation intensity was stepwise increased up to tolerance, which was defined as the stimulus that is able to elicit the maximal tolerable behavioral reaction. The characteristics of the reflex activity on the electromyographic records were compared for threshold and tolerance stimulation intensities. At tolerance, the reflex became faster and wider than at threshold, indicating that either a spinal summation mechanism or the recruitment of faster sensory fibers occurs in response to high-intensity noxious stimuli. A novel endpoint (i.e., tolerance) can now be considered when applying the nociceptive withdrawal reflex model in equine studies.The nociceptive withdrawal reflex (NWR) is used to investigate nociception in horses. The NWR threshold is a classical model endpoint. The aims of this study were to determine NWR tolerance and to compare threshold and tolerance reflexes in horses. In 12 horses, the NWR was evoked through electrical stimulation of the digital nerve and recorded via electromyography from the deltoid. Behavioral reactions were scored from 0 to 5 (tolerance). First, the individual NWR threshold was defined, then stimulation intensity was increased to tolerance. The median NWR threshold was 7.0 mA, whereas NWR tolerance was 10.7 mA. Upon visual inspection of the records, two main reflex components R1 (median latency 44 ms) and R2 (median latency 81 ms) were identified at threshold. Increasing stimulation intensity to tolerance led to a significant increase in the amplitude and duration of R1 and R2, whereas their latency decreased. At tolerance, a single burst of early, high-amplitude reflex activity, with a median latency of 39 ms, was detected in 15 out of 23 stimulations (65%). The results of this study suggest that (1) it is feasible to determine NWR tolerance in horses and (2) high-intensity stimuli initiate ultrafast bursts of reflex activity, which is well known in practice and has now been quantified using the NWR model.

Distribution of M-Wave and H-Reflex in Hand Muscles Evoked via Transcutaneous Nerve Stimulation: A Preliminary Report.

Neuromuscular electrical stimulation (NMES) targeting the muscle belly is commonly used to restore muscle strength in individuals with neurological disorders. However, early onset of muscle fatigue is a major limiting factor. Transcutaneous nerve stimulation (TNS) can delay muscle fatigue compared with traditional NMES techniques. However, the recruitment of Ia afferent fibers has not be specifically targeted to maximize muscle activation through the reflex pathway, which can lead to more orderly recruitment of motor units, further delaying fatigue. This preliminary study assessed the distribution of M-wave and H-reflex of intrinsic and extrinsic finger muscles. TNS was delivered using an electrode array placed along the medial side of the upper arm. Selective electrode pairs targeted the median and ulnar nerves innervating the finger flexors. High-density electromyography (HD EMG) was utilized to quantify the spatial distribution of the elicited activation of finger intrinsic and extrinsic muscles along the hand and forearm. The spatial patterns were characterized through isolation of the M-wave and H-reflex across various stimulation levels and EMG channels. Our preliminary results showed that, by altering the stimulation amplitude, distinct M-wave and H-reflex responses were evoked across EMG channels. In addition, distinct stimulation locations appeared to result in varied levels of reflex recruitment. Our findings indicate that it is possible to adjust stimulation parameters to maximize reflex activation, which can potentially facilitate physiological recruitment order of motoneurons.

Larger improvements in fatigue resistance and mitochondrial function with high- than with low-intensity contractions during interval training of mouse skeletal muscle.

Interval training (IT) results in improved fatigue resistance in skeletal muscle mainly due to an increased aerobic capacity, which involves increased muscle mitochondrial content and/or improved mitochondrial function. We hypothesized that IT with high-intensity contractions is more effective in increasing mitochondrial function, and hence fatigue resistance, than low-intensity contractions. To study this hypothesis without interference from differences in muscle fiber recruitment obliged to occur during voluntary contractions, IT was performed with in situ supramaximal electrical stimulation where all muscle fibers are recruited. We compared the effect of IT with repeated low-intensity (20 Hz stimulation, IT20) and high-intensity (100 Hz stimulation, IT100) contractions on fatigue resistance and mitochondrial content and function in mouse plantar flexor muscles. Muscles were stimulated every other day for 4 weeks. The averaged peak torque during IT bouts was 4.2-fold higher with IT100 than with IT20. Both stimulation protocols markedly improved in situ fatigue resistance, although the improvement was larger with IT100. The citrate synthase activity, a biomarker of mitochondrial content, was similarly increased with IT20 and IT100. Conversely, increased expression of mitochondrial respiratory chain (MRC) complexes I, III, and IV was only observed with IT100 and this was accompanied by increases in MRC supercomplex formation and pyruvate-malate-driven state 3 respiration in isolated mitochondria. In conclusion, the IT-induced increase in fatigue resistance is larger with high-intensity than with low-intensity contractions and this is linked to improved mitochondrial function due to increased expression of MRC complexes and assembly of MRC supercomplexes.

Stimulation of the dorsal root ganglion using an Injectrode®

Objective. The goal of this work was to compare afferent fiber recruitment by dorsal root ganglion (DRG) stimulation using an injectable polymer electrode (Injectrode®) and a more traditional cylindrical metal electrode. Approach. We exposed the L6 and L7 DRG in four cats via a partial laminectomy or burr hole. We stimulated the DRG using an Injectrode or a stainless steel (SS) electrode using biphasic pulses at three different pulse widths (80, 150, 300 μs) and pulse amplitudes spanning the range used for clinical DRG stimulation. We recorded antidromic evoked compound action potentials (ECAPs) in the sciatic, tibial, and common peroneal nerves using nerve cuffs. We calculated the conduction velocity of the ECAPs and determined the charge-thresholds and recruitment rates for ECAPs from Aα, Aβ, and Aδ fibers. We also performed electrochemical impedance spectroscopy measurements for both electrode types. Main results. The ECAP thresholds for the Injectrode did not differ from the SS electrode across all primary afferents (Aα, Aβ, Aδ) and pulse widths; charge-thresholds increased with wider pulse widths. Thresholds for generating ECAPs from Aβ fibers were 100.0 ± 32.3 nC using the SS electrode, and 90.9 ± 42.9 nC using the Injectrode. The ECAP thresholds from the Injectrode were consistent over several hours of stimulation. The rate of recruitment was similar between the Injectrodes and SS electrode and decreased with wider pulse widths. Significance. The Injectrode can effectively excite primary afferents when used for DRG stimulation within the range of parameters used for clinical DRG stimulation. The Injectrode can be implanted through minimally invasive techniques while achieving similar neural activation to conventional electrodes, making it an excellent candidate for future DRG stimulation and neuroprosthetic applications.

Uniaxial properties of ascending aortic aneurysms in light of effective stretch

A constitutive model that explicitly considers the gradual recruitment of collagen fibers is applied to investigate the uniaxial properties of human ascending aortic aneurysms. The model uses an effective stretch, which is a continuum scale kinematic variable measuring the true stretch of the tissue, to formulate the fiber stress. The constitutive equation contains two shape parameters characterizing the stochastic distribution of fiber waviness, and two elastic parameters accounting for, respectively, the elastic properties of ground substance and the straightened collagen fibers. The model is applied to 156 sets of uniaxial stress-stretch data obtained from 52 aneurysm samples. Major findings include (1) the uniaxial response can be well described by a quadratic strain energy function of the effective strain; (2) the ultimate stretches, when measured in terms of the effective stretch, are closely clustered around 1.1, in contrast to a much wider range in the original stretch; and (3) the ultimate stress correlates positively with the fiber stiffness. The age dependence and directional differences of constitutive parameters are also investigated. Results indicate that only the waviness depends strongly on age; no clear alterations occur in elastic parameters. Further, the fibers are wavier and stiffer in the circumferential direction than in the longitudinal direction. No other parameters exhibit significant direction difference. Statement of significanceWe introduced a constitutive model which explicitly accounts for collagen fiber recruitment to investigate the uniaxial properties of human ascending aortic aneurysm tissues. Uniaxial response data from 156 specimens were considered in the study. It was found that the seemingly dissimilar response curves are, in fact, similar if we measure the deformation using an effective stretch which factors out the uncrimping deformation. The rupture stretches in terms of the effective stretch are closely packed around 1.1. And the stress-stretch curves collapse to a canonical curve after a transformation.

Simulating the time evolving geometry, mechanical properties, and fibrous structure of bioprosthetic heart valve leaflets under cyclic loading

Currently, the most common replacement heart valve design is the ‘bioprosthetic’ heart valve (BHV), which has important advantages in that it does not require permanent anti-coagulation therapy, operates noiselessly, and has blood flow characteristics similar to the native valve. BHVs are typically fabricated from glutaraldehyde-crosslinked pericardial xenograft tissue biomaterials (XTBs) attached to a rigid, semi-flexible, or fully collapsible stent in the case of the increasingly popular transcutaneous aortic valve replacement (TAVR). While current TAVR assessments are positive, clinical results to date are generally limited to <2 years. Since TAVR leaflets are constructed using thinner XTBs, their mechanical demands are substantially greater than surgical BHV due to the increased stresses during in vivo operation, potentially resulting in decreased durability. Given the functional complexity of heart valve operation, in-silico predictive simulations clearly have potential to greatly improve the TAVR development process. As such simulations must start with accurate material models, we have developed a novel time-evolving constitutive model for pericardial xenograft tissue biomaterials (XTB) utilized in BHV (doi: 10.1016/j.jmbbm.2017.07.013). This model was able to simulate the observed tissue plasticity effects that occur in approximately in the first two years of in vivo function (50 million cycles). In the present work, we implemented this model into a complete simulation pipeline to predict the BHV time evolving geometry to 50 million cycles. The pipeline was implemented within an isogeometric finite element formulation that directly integrated our established BHV NURBS-based geometry (doi: 10.1007/s00466-015-1166-x). Simulations of successive loading cycles indicated continual changes in leaflet shape, as indicated by spatially varying increases in leaflet curvature. While the simulation model assumed an initial uniform fiber orientation distribution, anisotropic regional changes in leaflet tissue plastic strain induced a complex changes in regional fiber orientation. We have previously noted in our time-evolving constitutive model that the increases in collagen fiber recruitment with cyclic loading placed an upper bound on plastic strain levels. This effect was manifested by restricting further changes in leaflet geometry past 50 million cycles. Such phenomena was accurately captured in the valve-level simulations due to the use of a tissue-level structural-based modeling approach. Changes in basic leaflet dimensions agreed well with extant experimental studies. As a whole, the results of the present study indicate the complexity of BHV responses to cyclic loading, including changes in leaflet shape and internal fibrous structure. It should be noted that the later effect also influences changes in local mechanical behavior (i.e. changes in leaflet anisotropic tissue stress-strain relationship) due to internal fibrous structure resulting from plastic strains. Such mechanism-based simulations can help pave the way towards the application of sophisticated simulation technologies in the development of replacement heart valve technology.

Incorporating fiber recruitment in hyperelastic modeling of vascular tissues by means of kinematic average.

We present a framework for considering the gradual recruitment of collagen fibers in hyperelastic constitutive modeling. An effective stretch, which is a response variable representing the true stretch at the tissue-scale, is introduced. Properties of the effective stretch are discussed in detail. The effective stretch and strain invariants derived from it are used in selected hyperelastic constitutive models to describe the tissue response. This construction is investigated in conjunction with Holzapfel-Gasser-Ogden family strain energy functions. The ensuing models are validated against a large body of uniaxial and bi-axial stress-strain response data from human aortic aneurysm tissues. Both the descriptive and the predictive capabilities are examined. The former is evaluated by the quality of constitutive fitting, and the latter is assessed using finite element simulation. The models significantly improve the quality of fitting, and reproduce the experiment displacement, stress, and strain distributions with high fidelity in the finite element simulation.

Very Low Frequencies Maintain Pain Relief From Dorsal Root Ganglion Stimulation: An Evaluation of Dorsal Root Ganglion Neurostimulation Frequency Tapering

BackgroundDorsal root ganglion neurostimulation (DRG-S) is effective in treating various refractory chronic pain syndromes. In preclinical studies, DRG-S at very low frequencies (<5 Hz) reduces excitatory output in the superficial dorsal horn. Clinically, we have also observed the effectiveness of DRG-S at low frequencies. We conducted a case series to describe the effect of very low-frequency DRG-S stimulation on clinical outcomes. Materials and MethodsDRG-S for refractory low back pain was initiated at parameters consistent with published values. Thereafter, the stimulation frequency of DRG-S was reduced in a stepwise fashion to the lowest frequency that maintained pain relief. Pain intensity, disability, and general health status data were collected at baseline, prior to initiation of tapering, and at four weeks after each patient’s lowest effective stimulation frequency was reached. ResultsAfter device activation (N = 20), DRG-S frequency was tapered from 16 to 4 Hz over a 4- to 17-week period, reducing charge-per-second by nearly two-thirds. Even so, pain relief was maintained at more than 75%, with consistent findings in the other measures. ConclusionDRG-S may have utility in treating chronic pain at lower stimulation frequencies than previously recognized. We have previously theorized that the mechanism of action may involve preferential recruitment of low-threshold mechanoreceptor fibers via the endogenous opioid system. Of clinical relevance, lower frequency stimulation maintains DRG-S efficacy regarding improvements in pain, disability, and quality of life. It can extend battery life and may potentially lead to the development of smaller implantable pulse generators.

Light stimulation during postnatal development is not determinant for glutamatergic neurotransmission from the retinohypothalamic tract to the suprachiasmatic nucleus in rats.

The hypothalamic suprachiasmatic nucleus (SCN) is the leading circadian pacemaker in mammals, which synchronizes with environmental light through the retinohypothalamic tract (RHT). Although the SCN regulates circadian rhythms before birth, postnatal synaptic changes are needed for the RHT-SCN pathway to achieve total functional development. However, it is unknown whether visual experience affects developmental maturation. Here, we studied the effects of constant darkness (DD) rearing on the physiology (at pre- and postsynaptic levels) of glutamatergic neurotransmission between RHT and SCN during postnatal development in rats. Upon recording spontaneous and evoked excitatory postsynaptic currents (EPSCs) by electrical stimulation of RHT fibers, we found that DD animals at early postnatal ages (P3-19) exhibited different frequencies of spontaneous EPSCs and lower synaptic performance (short-term depression, release sites, and recruitment of RHT fibers) when compared with their normal light/dark (LD) counterparts. At the oldest age evaluated (P30-35), there was a synaptic response strengthening (probability of release, vesicular re-filling rate, and reduced synaptic depression) in DD rats, which functionally equaled (or surmounted) that of LD animals. Control experiments evaluating EPSCs in ventral SCN neurons of LD rats during day and night revealed no significant differences in spontaneous or evoked EPSCs by high-frequency trains in the RHT at any postnatal age. Our results suggest that DD conditions induce a compensatory mechanism in the glutamatergic signaling of the circadian system to increase the chances of synchronization to light at adult ages, and that the synaptic properties of RHT terminals during postnatal development are not critically influenced by environmental light.