From dawn till dusk: Time-adaptive bayesian optimization for neurostimulation.

Stimulation optimization has garnered considerable interest in recent years in order to efficiently parametrize neuromodulation-based therapies. To date, efforts focused on automatically identifying settings from parameter spaces that do not change over time. A limitation of these approaches, however, is that they lack consideration for time dependent factors that may influence therapy outcomes. Disease progression and biological rhythmicity are two sources of variation that may influence optimal stimulation settings over time. To account for this, we present a novel time-varying Bayesian optimization (TV-BayesOpt) for tracking the optimum parameter set for neuromodulation therapy. We evaluate the performance of TV-BayesOpt for tracking gradual and periodic slow variations over time. The algorithm was investigated within the context of a computational model of phase-locked deep brain stimulation for treating oscillopathies representative of common movement disorders such as Parkinson's disease and Essential Tremor. When the optimal stimulation settings changed due to gradual and periodic sources, TV-BayesOpt outperformed standard time-invariant techniques and was able to identify the appropriate stimulation setting. Through incorporation of both a gradual "forgetting" and periodic covariance functions, the algorithm maintained robust performance when a priori knowledge differed from observed variations. This algorithm presents a broad framework that can be leveraged for the treatment of a range of neurological and psychiatric conditions and can be used to track variations in optimal stimulation settings such as amplitude, pulse-width, frequency and phase for invasive and non-invasive neuromodulation strategies.

Remarkable muscles, remarkable locomotion in desert-dwelling wildebeest.

Large mammals that live in arid and/or desert environments can cope with seasonal and local variations in rainfall, food and climate1 by moving long distances, often without reliable water or food en route. The capacity of an animal for this long-distance travel is substantially dependent on the rate of energy utilization and thus heat production during locomotion-the cost of transport2-4. The terrestrial cost of transport is much higher than for flying (7.5 times) and swimming (20 times)4. Terrestrial migrants are usually large1-3 with anatomical specializations for economical locomotion5-9, because the cost of transport reduces with increasing size and limb length5-7. Here we used GPS-tracking collars10 with movement and environmental sensors to show that blue wildebeest (Connochaetes taurinus, 220 kg) that live in a hot arid environment in Northern Botswana walked up to 80 km over five days without drinking. They predominantly travelled during the day and locomotion appeared to be unaffected by temperature and humidity, although some behavioural thermoregulation was apparent. We measured power and efficiency of work production (mechanical work and heat production) during cyclic contractions of intact muscle biopsies from the forelimb flexor carpi ulnaris of wildebeest and domestic cows (Bos taurus, 760 kg), a comparable but relatively sedentary ruminant. The energetic costs of isometric contraction (activation and force generation) in wildebeest and cows were similar to published values for smaller mammals. Wildebeest muscle was substantially more efficient (62.6%) than the same muscle from much larger cows (41.8%) and comparable measurements that were obtained from smaller mammals (mouse (34%)11 and rabbit (27%)). We used the direct energetic measurements on intact muscle fibres to model the contribution of high working efficiency of wildebeest muscle to minimizing thermoregulatory challenges during their long migrations under hot arid conditions.

Biomechanics of predator-prey arms race in lion, zebra, cheetah and impala.

The fastest and most manoeuvrable terrestrial animals are found in savannah habitats, where predators chase and capture running prey. Hunt outcome and success rate are critical to survival, so both predator and prey should evolve to be faster and/or more manoeuvrable. Here we compare locomotor characteristics in two pursuit predator-prey pairs, lion-zebra and cheetah-impala, in their natural savannah habitat in Botswana. We show that although cheetahs and impalas were universally more athletic than lions and zebras in terms of speed, acceleration and turning, within each predator-prey pair, the predators had 20% higher muscle fibre power than prey, 37% greater acceleration and 72% greater deceleration capacity than their prey. We simulated hunt dynamics with these data and showed that hunts at lower speeds enable prey to use their maximum manoeuvring capacity and favour prey survival, and that the predator needs to be more athletic than its prey to sustain a viable success rate.

The predominant stride-frequency for routine swimming in catsharks (Scyliorhinus canicula) generates high power at high efficiency in the red musculature.

Videos of free swimming of catsharks (Scyliorhinus canicula) were analysed to give values of swimming speed (units: FL (fish lengths) s-1), stride-length (forward movement in the direction of travel per cycle of body undulation (units: FL) and stride-frequency (units: s-1). Most of the swims (139 of 163, 85%) were at speeds less than 0.545 FL s-1 and were categorized as slow. The rest (24/163, 15%) were categorized as fast. Stride-lengths and stride-frequencies could be evaluated for 115 of the slow swims and 16 of the fast swims. We discuss the fast swim results, but there were so few fast swims that no firm conclusions could be made. As swim speed increased during slow swims, there was a strong increase stride-length [slope 0.965, P < 0.0001)] and a small increase in stride-frequency. Most stride-frequencies (70/115, 61%) were in the range 0.68-0.88 s-1. Previous experiments on red muscle isolated of catshark showed that in this range of frequencies of sinusoidal movement, high power was produced at high efficiency (Curtin and Woledge b). Lower frequencies gave less power and at higher frequencies the efficiency of energy conversion was lower. Thus, we conclude that during routine swimming catsharks choose a swimming speed that optimizes red muscle performance in terms of power and efficiency.

Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit.

Synchronization of neural oscillations is thought to facilitate communication in the brain. Neurodegenerative pathologies such as Parkinson's disease (PD) can result in synaptic reorganization of the motor circuit, leading to altered neuronal dynamics and impaired neural communication. Treatments for PD aim to restore network function via pharmacological means such as dopamine replacement, or by suppressing pathological oscillations with deep brain stimulation. We tested the hypothesis that brain stimulation can operate beyond a simple "reversible lesion" effect to augment network communication. Specifically, we examined the modulation of beta band (14-30 Hz) activity, a known biomarker of motor deficits and potential control signal for stimulation in Parkinson's. To do this we setup a neural mass model of population activity within the cortico-basal ganglia-thalamic (CBGT) circuit with parameters that were constrained to yield spectral features comparable to those in experimental Parkinsonism. We modulated the connectivity of two major pathways known to be disrupted in PD and constructed statistical summaries of the spectra and functional connectivity of the resulting spontaneous activity. These were then used to assess the network-wide outcomes of closed-loop stimulation delivered to motor cortex and phase locked to subthalamic beta activity. Our results demonstrate that the spatial pattern of beta synchrony is dependent upon the strength of inputs to the STN. Precisely timed stimulation has the capacity to recover network states, with stimulation phase inducing activity with distinct spectral and spatial properties. These results provide a theoretical basis for the design of the next-generation brain stimulators that aim to restore neural communication in disease.

Dynamics of cortical and corticomuscular connectivity during planning and execution of visually guided steps in humans.

The cortical mechanisms underlying the act of taking a step-including planning, execution, and modification-are not well understood. We hypothesized that oscillatory communication in a parieto-frontal and corticomuscular network is involved in the neural control of visually guided steps. We addressed this hypothesis using source reconstruction and lagged coherence analysis of electroencephalographic and electromyographic recordings during visually guided stepping and 2 control tasks that aimed to investigate processes involved in (i) preparing and taking a step and (ii) adjusting a step based on visual information. Steps were divided into planning, initiation, and execution phases. Taking a step was characterized by an upregulation of beta/gamma coherence within the parieto-frontal network during planning followed by a downregulation of alpha and beta/gamma coherence during initiation and execution. Step modification was characterized by bidirectional modulations of alpha and beta/gamma coherence in the parieto-frontal network during the phases leading up to step execution. Corticomuscular coherence did not exhibit task-related effects. We suggest that these task-related modulations indicate that the brain makes use of communication through coherence in the context of large-scale, whole-body movements, reflecting a process of flexibly fine-tuning inter-regional communication to achieve precision control during human stepping.

Motor Cortex Inputs at the Optimum Phase of Beta Cortical Oscillations Undergo More Rapid and Less Variable Corticospinal Propagation.

Brain oscillations involve rhythmic fluctuations of neuronal excitability and may play a crucial role in neural communication. The human corticomuscular system is characterized by beta activity and is readily probed by transcranial magnetic stimulation (TMS). TMS inputs arriving at the excitable phase of beta oscillations in the motor cortex are known to lead to muscle responses of greater amplitude. Here we explore two other possible manifestations of rhythmic excitability in the beta band; windows of reduced response variability and shortened latency. We delivered single-pulse TMS to the motor cortex of healthy human volunteers (10 females and 7 males) during electroencephalography recordings made at rest. TMS delivered at a particular phase of the beta oscillation benefited from not only stronger, but also less variable and more rapid transmission, as evidenced by the greater amplitude, lower coefficient of variation, and shorter latency of motor evoked potentials. Thus, inputs aligned to the optimal phase of the beta EEG in the motor cortex enjoy transmission amplitude gain, but may also benefit from less variability and shortened latencies at subsequent synapses. Neuronal phase may therefore impact corticospinal communication.SIGNIFICANCE STATEMENT Brain oscillations involve rhythmic fluctuations of neuronal excitability. Therefore, motor responses to transcranial magnetic stimulation are larger when a cortical input arrives at a particular phase of the beta activity in the motor cortex. Here, we demonstrate that inputs to corticospinal neurons which coincide with windows of higher excitability also benefit from more rapid and less variable corticospinal transmission. This shortening of latency and increased reproducibility may confer additional advantage to inputs at specific phases. Moreover, these benefits are conserved despite appreciable corticospinal conduction delays.

Inference of brain networks with approximate Bayesian computation - assessing face validity with an example application in Parkinsonism.

This paper describes and validates a novel framework using the Approximate Bayesian Computation (ABC) algorithm for parameter estimation and model selection in models of mesoscale brain network activity. We provide a proof of principle, first pass validation of this framework using a set of neural mass models of the cortico-basal ganglia thalamic circuit inverted upon spectral features from experimental, in vivo recordings. This optimization scheme relaxes an assumption of fixed-form posteriors (i.e. the Laplace approximation) taken in previous approaches to inverse modelling of spectral features. This enables the exploration of model dynamics beyond that approximated from local linearity assumptions and so fit to explicit, numerical solutions of the underlying non-linear system of equations. In this first paper, we establish a face validation of the optimization procedures in terms of: (i) the ability to approximate posterior densities over parameters that are plausible given the known causes of the data; (ii) the ability of the model comparison procedures to yield posterior model probabilities that can identify the model structure known to generate the data; and (iii) the robustness of these procedures to local minima in the face of different starting conditions. Finally, as an illustrative application we show (iv) that model comparison can yield plausible conclusions given the known neurobiology of the cortico-basal ganglia-thalamic circuit in Parkinsonism. These results lay the groundwork for future studies utilizing highly nonlinear or brittle models that can explain time dependant dynamics, such as oscillatory bursts, in terms of the underlying neural circuits.

Object recognition is enabled by an experience-dependent appraisal of visual features in the brain's value system.

This paper addresses perceptual synthesis by comparing responses evoked by visual stimuli before and after they are recognized, depending on prior exposure. Using magnetoencephalography, we analyzed distributed patterns of neuronal activity - evoked by Mooney figures - before and after they were recognized as meaningful objects. Recognition induced changes were first seen at 100-120 â€‹ms, for both faces and tools. These early effects - in right inferior and middle occipital regions - were characterized by an increase in power in the absence of any changes in spatial patterns of activity. Within a later 210-230 â€‹ms window, a quite different type of recognition effect appeared. Regions of the brain's value system (insula, entorhinal cortex and cingulate of the right hemisphere for faces and right orbitofrontal cortex for tools) evinced a reorganization of their neuronal activity without an overall power increase in the region. Finally, we found that during the perception of disambiguated face stimuli, a face-specific response in the right fusiform gyrus emerged at 240-290 â€‹ms, with a much greater latency than the well-known N170m component, and, crucially, followed the recognition effect in the value system regions. These results can clarify one of the most intriguing issues of perceptual synthesis, namely, how a limited set of high-level predictions, which is required to reduce the uncertainty when resolving the ill-posed inverse problem of perception, can be available before category-specific processing in visual cortex. We suggest that a subset of local spatial features serves as partial cues for a fast re-activation of object-specific appraisal by the value system. The ensuing top-down feedback from value system to visual cortex, in particular, the fusiform gyrus enables high levels of processing to form category-specific predictions. This descending influence of the value system was more prominent for faces than for tools, the fact that reflects different dependence of these categories on value-related information.

Measuring directed functional connectivity using non-parametric directionality analysis: Validation and comparison with non-parametric Granger Causality.

BACKGROUND: 'Non-parametric directionality' (NPD) is a novel method for estimation of directed functional connectivity (dFC) in neural data. The method has previously been verified in its ability to recover causal interactions in simulated spiking networks in Halliday et al. (2015). METHODS: This work presents a validation of NPD in continuous neural recordings (e.g. local field potentials). Specifically, we use autoregressive models to simulate time delayed correlations between neural signals. We then test for the accurate recovery of networks in the face of several confounds typically encountered in empirical data. We examine the effects of NPD under varying: a) signal-to-noise ratios, b) asymmetries in signal strength, c) instantaneous mixing, d) common drive, e) data length, and f) parallel/convergent signal routing. We also apply NPD to data from a patient who underwent simultaneous magnetoencephalography and deep brain recording. RESULTS: We demonstrate that NPD can accurately recover directed functional connectivity from simulations with known patterns of connectivity. The performance of the NPD measure is compared with non-parametric estimators of Granger causality (NPG), a well-established methodology for model-free estimation of dFC. A series of simulations investigating synthetically imposed confounds demonstrate that NPD provides estimates of connectivity that are equivalent to NPG, albeit with an increased sensitivity to data length. However, we provide evidence that: i) NPD is less sensitive than NPG to degradation by noise; ii) NPD is more robust to the generation of false positive identification of connectivity resulting from SNR asymmetries; iii) NPD is more robust to corruption via moderate amounts of instantaneous signal mixing. CONCLUSIONS: The results in this paper highlight that to be practically applied to neural data, connectivity metrics should not only be accurate in their recovery of causal networks but also resistant to the confounding effects often encountered in experimental recordings of multimodal data. Taken together, these findings position NPD at the state-of-the-art with respect to the estimation of directed functional connectivity in neuroimaging.

Energy turnover in mammalian skeletal muscle in contractions mimicking locomotion: effects of stimulus pattern on work, impulse and energetic cost and efficiency.

Active muscle performs various mechanical functions during locomotion: work output during shortening, work absorption when resisting (but not preventing) lengthening, and impulse (force-time integral) whenever there is active force. The energetic costs of these functions are important components in the energy budget during locomotion. We investigated how the pattern of stimulation and movement affects the mechanics and energetics of muscle fibre bundles isolated from wild rabbits (Oryctolagus cuniculus). The fibres were from muscles consisting of mainly fast-twitch, type 2 fibres. Fibre length was held constant (isometric) or a sinusoidal pattern of movement was imposed at a frequency similar to the stride frequency of running wild rabbits. Duty cycle (stimulation duration×movement frequency) and phase (timing of stimulation relative to movement) were varied. Work and impulse were measured as well as energy produced as heat. The sum of net work (work output-work input) and heat was taken as a measure of energetic cost. Maximum work output was produced with a long duty cycle and stimulation starting slightly before shortening, and was produced quite efficiently. However, efficiency was even higher with other stimulation patterns that produced less work. The highest impulse (considerably higher than isometric impulse) was produced when stimulation started while the muscle fibres were being lengthened. High impulse was produced very economically because of the low cost of producing force during lengthening. Thus, locomotion demanding high work, high impulse or economical work output or impulse requires a distinct pattern of stimulation and movement.

Propagation of beta/gamma rhythms in the cortico-basal ganglia circuits of the parkinsonian rat.

Much of the motor impairment associated with Parkinson's disease is thought to arise from pathological activity in the networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in parkinsonism, we investigated changes to the directed connectivity in BG networks following dopamine depletion. We recorded local field potentials (LFPs) in the cortex and basal ganglia of rats rendered parkinsonian by injection of 6-hydroxydopamine (6-OHDA) and in dopamine-intact controls. We performed systematic analyses of the networks using a novel tool for estimation of directed interactions (nonparametric directionality, NPD). We used a "conditioned" version of the NPD analysis that reveals the dependence of the correlation between two signals on a third reference signal. We find evidence of the dopamine dependency of both low-beta (14-20 Hz) and high-beta/low-gamma (20-40 Hz) directed network interactions. Notably, 6-OHDA lesions were associated with enhancement of the cortical "hyperdirect" connection to the subthalamic nucleus (STN) and its feedback to the cortex and striatum. We find that pathological beta synchronization resulting from 6-OHDA lesioning is widely distributed across the network and cannot be located to any individual structure. Furthermore, we provide evidence that high-beta/gamma oscillations propagate through the striatum in a pathway that is independent of STN. Rhythms at high beta/gamma show susceptibility to conditioning that indicates a hierarchical organization compared with those at low beta. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in parkinsonism. NEW & NOTEWORTHY We present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aim of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson's disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a "short-circuiting" of the network that gives rise to the conditions from which pathological synchronization may arise.

Association of intracellular and synaptic organization in cochlear inner hair cells revealed by 3D electron microscopy.

The ways in which cell architecture is modelled to meet cell function is a poorly understood facet of cell biology. To address this question, we have studied the cytoarchitecture of a cell with highly specialised organisation, the cochlear inner hair cell (IHC), using multiple hierarchies of three-dimensional (3D) electron microscopy analyses. We show that synaptic terminal distribution on the IHC surface correlates with cell shape, and the distribution of a highly organised network of membranes and mitochondria encompassing the infranuclear region of the cell. This network is juxtaposed to a population of small vesicles, which represents a potential new source of neurotransmitter vesicles for replenishment of the synapses. Structural linkages between organelles that underlie this organisation were identified by high-resolution imaging. Taken together, these results describe a cell-encompassing network of membranes and mitochondria present in IHCs that support efficient coding and transmission of auditory signals. Such techniques also have the potential for clarifying functionally specialised cytoarchitecture of other cell types.

Revisiting Frank-Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (ktr ) in a length-dependent fashion.

KEY POINTS: Regulatory light chain (RLC) phosphorylation has been shown to alter the ability of muscle to produce force and power during shortening and to alter the rate of force redevelopment (ktr ) at submaximal [Ca(2+) ]. Increasing RLC phosphorylation ∼50% from the in vivo level in maximally [Ca(2+) ]-activated cardiac trabecula accelerates ktr . Decreasing RLC phosphorylation to ∼70% of the in vivo control level slows ktr and reduces force generation. ktr is dependent on sarcomere length in the physiological range 1.85-1.94 µm and RLC phosphorylation modulates this response. We demonstrate that Frank-Starling is evident at maximal [Ca(2+) ] activation and therefore does not necessarily require length-dependent change in [Ca(2+) ]-sensitivity of thin filament activation. The stretch response is modulated by changes in RLC phosphorylation, pinpointing RLC phosphorylation as a modulator of the Frank-Starling law in the heart. These data provide an explanation for slowed systolic function in the intact heart in response to RLC phosphorylation reduction. ABSTRACT: Force and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (ktr ) in maximally activating [Ca(2+) ]. Activation was achieved by rapidly increasing the temperature (temperature-jump of 0.5-20ºC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85-1.94 µm). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates ktr by ∼50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows ktr by ∼50%, relative to the ktr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of ktr following step shortening or ramp shortening. Using a two-state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca(2+) ] and are not explained by changes in the Ca(2+) -sensitivity of acto-myosin interactions. The length-dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the Frank-Starling law of the heart.

A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation.

Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic "compensation" and congestive "decompensation." Nothing is known about the ability of uninfarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drives progression of compensation. We hypothesized that enhanced cross-bridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared with noninfarcted controls. Isometric force during submaximal activations was raised >2.4-fold, while power was 2-fold greater. Electron and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae.

Skinned fibres produce the same power and force as intact fibre bundles from muscle of wild rabbits.

Skinned fibres have advantages for comparing the muscle properties of different animal species because they can be prepared from a needle biopsy taken under field conditions. However, it is not clear how well the contractile properties of skinned fibres reflect the properties of the muscle fibres in vivo. Here, we compare the mechanical performance of intact fibre bundles and skinned fibres from muscle of the same animals. This is the first such direct comparison. Maximum power and isometric force were measured at 25 °C using peroneus longus (PL) and extensor digiti-V (ED-V) muscles from wild rabbits (Oryctolagus cuniculus). More than 90% of the fibres in these muscles are fast-twitch, type 2 fibres. Maximum power was measured in force-clamp experiments. We show that maximum power per volume was the same in intact (121.3 ± 16.1 W l(-1), mean ± s.e.m.; N=16) and skinned (122.6 ± 4.6 W l(-1); N=141) fibres. Maximum relative power (power/F(IM) Lo, where F(IM) is maximum isometric force and Lo is standard fibre length) was also similar in intact (0.645 ± 0.037; N=16) and skinned (0.589 ± 0.019; N=141) fibres. Relative power is independent of volume and thus not subject to errors in measurement of volume. Finally, maximum isometric force per cross-sectional area was also found to be the same for intact and skinned fibres (181.9 kPa ± 19.1; N=16; 207.8 kPa ± 4.8; N=141, respectively). These results contrast with previous measurements of performance at lower temperatures where skinned fibres produce much less power than intact fibres from both mammals and non-mammalian species.

Myosin regulatory light chain (RLC) phosphorylation change as a modulator of cardiac muscle contraction in disease.

Understanding how cardiac myosin regulatory light chain (RLC) phosphorylation alters cardiac muscle mechanics is important because it is often altered in cardiac disease. The effect this protein phosphorylation has on muscle mechanics during a physiological range of shortening velocities, during which the heart generates power and performs work, has not been addressed. We have expressed and phosphorylated recombinant Rattus norvegicus left ventricular RLC. In vitro we have phosphorylated these recombinant species with cardiac myosin light chain kinase and zipper-interacting protein kinase. We compare rat permeabilized cardiac trabeculae, which have undergone exchange with differently phosphorylated RLC species. We were able to enrich trabecular RLC phosphorylation by 40% compared with controls and, in a separate series, lower RLC phosphorylation to 60% of control values. Compared with the trabeculae with a low level of RLC phosphorylation, RLC phosphorylation enrichment increased isometric force by more than 3-fold and peak power output by more than 7-fold and approximately doubled both maximum shortening speed and the shortening velocity that generated peak power. We augmented these measurements by observing increased RLC phosphorylation of human and rat HF samples from endocardial left ventricular homogenate. These results demonstrate the importance of increased RLC phosphorylation in the up-regulation of myocardial performance and suggest that reduced RLC phosphorylation is a key aspect of impaired contractile function in the diseased myocardium.

The evidence for commercial house dust mite immunotherapy products: A pragmatic systematic review with narrative synthesis.

House dust mite (HDM) allergen immunotherapy (AIT) has an established role in the treatment of perennial allergic rhinitis (AR) and allergic asthma (AA) triggered by HDM sensitization. We aimed to identify all double-blind, randomized, placebo-controlled trials of HDM AIT for the treatment of AR and AA in humans and to summarize the evidence for AIT products that are currently manufactured and available for clinical use. A total of 56 eligible double-blind, randomized, placebo-controlled trials of HDM AIT for the treatment of AA and/or AR in humans fit the inclusion criteria and investigated a total of 14 commercial AIT products; together, the 56 studies enrolled a total of 14,619 patients. Of the 56 studies, 39 studies investigated the current manufacturer-recommended maintenance dose (MRMD) of the product, and 17 investigated other doses. We identified 39 studies (12,539 patients randomized) for 8 sublingual immunotherapy (SLIT) products and 17 studies (2,080 patients randomized) for subcutaneous immunotherapy products. For AR, 3 products, the ALK 12 standardized-quality (SQ-HDM) SLIT tablet, the ALK 6 SQ-HDM tablet, and the SG 300 index of reactivity SLIT tablet, had both dose-finding studies (DFSs) and phase III definitive studies (DSs) to demonstrate efficacy of the MRMD of the product. For AA, 2 products, the ALK 12 SQ-HDM SLIT tablet and the ALK 6 SQ-HDM tablet, had both DFSs and DSs for the MRMD. No subcutaneous immunotherapy product had a paired DFS and DS supporting the MRMD. A total of 30 studies of products no longer commercially manufactured were excluded. This study will help to inform clinical care and product selection for the treatment of HDM-induced AR and AA.

Navigated Simultaneous Lateral Minimally Invasive Tubular and Posterior Mini-Open Access for Removal and Revision of Triangular Sacroiliac Joint Implants: A Technical Note.

BACKGROUND: Sacroiliac joint (SIJ) fusion, to treat back pain caused by SIJ dysfunction, can employ open or minimally invasive surgery (MIS) techniques and either cylindrical (screw-shaped) or triangular (wedge-shaped) implants. Fusion nonunion sometimes explains recurrent SIJ pain following fusion and occasionally requires hardware revision. MIS revision minimizes patient pain, infection, and disability, but due to the triangular implant size and form factor, implant removal can present challenges for MIS access during the explantation and achieving good bony purchase for reinstrumentation. Here, we report a prone single-position lateral MIS/posterior mini-open procedure for triangular-implant SIJ fusion revision. METHODS: The patient is a 72-year-old female who underwent right SIJ fusion for lower back and leg pain sustained after a fall 2 years prior but experienced recurrent pain over the subsequent 2 years, with imaging findings of right SIJ peri-hardware lucencies and diagnostic injections confirming persistent right-sided sacroiliitis. RESULTS: The patient underwent hardware removal using the lateral MIS incision with table-mounted tubular access and image-guided navigation to maintain exposure, plus simultaneous reinstrumentation using a navigated S2-alar-iliac screw and iliac bolt construct with connecting rod through the posterior mini-open incision made for the navigation reference frame spinous process clamp. CONCLUSIONS: The use of navigation and MIS access can significantly decrease the complexity of lateral hardware removal, and mini-open navigated screw-and-rod constructs offer reinstrumentation options accessible to surgeons unfamiliar with specialized posterior SIJ systems.

Towards non-invasive imaging through spinal-cord generated magnetic fields.

Non-invasive imaging of the human spinal cord is a vital tool for understanding the mechanisms underlying its functions in both healthy and pathological conditions. However, non-invasive imaging presents a significant methodological challenge because the spinal cord is difficult to access with conventional neurophysiological approaches, due to its proximity to other organs and muscles, as well as the physiological movements caused by respiration, heartbeats, and cerebrospinal fluid (CSF) flow. Here, we discuss the present state and future directions of spinal cord imaging, with a focus on the estimation of current flow through magnetic field measurements. We discuss existing cryogenic (superconducting) and non-cryogenic (optically-pumped magnetometer-based, OPM) systems, and highlight their strengths and limitations for studying human spinal cord function. While significant challenges remain, particularly in source imaging and interference rejection, magnetic field-based neuroimaging offers a novel avenue for advancing research in various areas. These include sensorimotor processing, cortico-spinal interplay, brain and spinal cord plasticity during learning and recovery from injury, and pain perception. Additionally, this technology holds promise for diagnosing and optimizing the treatment of spinal cord disorders.